Treatment Options
Current standard treatment options include infection control measures, routine supportive care, and medications including antiviral, monoclonal antibody, immunomodulator, and corticosteroid drugs
- Many other drugs (of several classes) have been or still are being used under clinical trial and compassionate use protocols based on in vitro activity (against this or related viruses) and clinical experience
- Information on therapeutic trials and expanded access is available at ClinicalTrials.gov and at WHO International Clinical Trials Registry Platform r69r70
- Drugs are generally selected according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process. Thus, antivirals and monoclonal antibodies directed at viral components are most effective when used early in the course of infection (to prevent cell entry and viral replication); antiinflammatory drugs (eg, dexamethasone) and immunomodulators are of most benefit during the hyperinflammatory response in later phases of severe disease r15
- Given extensive potential medication interactions, clinicians are advised to use a drug interactions checker (eg, University of Liverpool offers one) r71
- Recommendations below summarize major treatment guidelines from NIH, WHO, Surviving Sepsis Campaign, and Infectious Diseases Society of America r4r6r15r72r73
Infection control measures include isolation, source control, and transmission precautions r74
- Patients with COVID-19 in a health care setting should wear a face mask (or, if supplies are critically low, at least a cloth face cover) to reduce droplet spread, should be placed in a single-person closed room pending further evaluation and disposition decisions, and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow
- Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection r74
- If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
Initiate supportive care for hospitalized patients, including oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) r6
- Appropriate testing (eg, blood cultures in those with severe or critical illness) and treatment for other pathogens (eg, influenza, malaria) should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r6
- Evidence does not support routine use of antibiotics for all patients with COVID-19, especially in those with low suspicion of bacterial infection. If empiric coverage is begun, use antibiotic de-escalation protocols (eg, daily reassessment of need for antibiotics) when patient's clinical status has been stabilized and there is no evidence of bacterial coinfection r6r15
- Coagulopathy is common; both venous and arterial thromboembolism have been reported in patients with COVID-19. Guidelines from NIH, WHO, American Society of Hematology, Surviving Sepsis Campaign, and American College of Chest Physicians offer recommendations on anticoagulation for critically ill patients r4r6r15r75r76r77r78
- Guidelines suggest or recommend use of prophylactic dose over intermediate dose or therapeutic dose for critically ill patients r15r75r76r77r78r79
- Where specified, heparins are preferred over oral anticoagulants and low-molecular-weight heparin is preferred over unfractionated heparin r4r15r75
- Guidelines also recommend monitoring and evaluation for thromboembolic disease, such as in patients with rapid deterioration of pulmonary, cardiac, or neurologic function or sudden, localized loss of peripheral perfusion; universal screening is not recommended r6r15
- NIH guidelines also recommend continuation of anticoagulation in hospital for those already on therapeutic doses for another indication r15
- NIH and American Society of Hematology recommend against continuing prophylaxis after discharge from hospital for those without venous thromboembolism r15r79
- Extended prophylaxis against venous thromboembolism after hospital discharge can be considered for patients with indications similar to those in patients without COVID-19 who qualify
- Therapeutic doses of anticoagulation should be used for patients with documented venous or arterial thrombosis, or for those with high clinical suspicion of thromboembolic disease when diagnostic imaging is not possible r15r78
- Patients on extracorporeal membrane oxygenation or continuous renal replacement therapy should have the same anticoagulation as patients on those therapies without COVID-19 r15
- Management of septic shock includes use of vasopressors if fluid administration does not restore adequate perfusion. Surviving Sepsis Campaign,r4NIH,r15 and WHOr6 treatment guidelines provide guidance specific to treatment of shock in patients with COVID-19 d3d3d3d3d3d3d3d3
- WHO definitions for septic shock: r6
- Adults: suspected or confirmed infection; vasopressors are needed to maintain mean arterial pressure at or above 65 mm Hg; and lactate level is 2 mmol/L or more, in the absence of hypovolemia
- Children: hypotension (systolic blood pressure less than the 5th percentile or more than 2 standard deviations below normal for age), or 2 or more of the following: altered mental status; bradycardia or tachycardia (heart rate less than 90 or more than 160 beats per minute in infants, or less than 70 or more than 150 beats per minute in children); prolonged capillary refill more than 2 seconds or weak pulses; tachypnea; oliguria; hypothermia or hyperthermia; increased lactate level; or skin that is mottled, cold, or with petechial or purpuric rash
- Conservative fluid resuscitation is advised over liberal fluid strategy, owing to risk of volume overload
- Crystalloids are recommended for fluid resuscitation; Surviving Sepsis and NIH guidelines recommend balanced crystalloids over unbalanced crystalloids r4r15
- WHO, NIH, and Surviving Sepsis guidelines recommend against starches or gelatins
- Surviving Sepsis and NIH guidelines recommend against the use of albumin (weak or moderate recommendations) r4r15
- WHO does not offer guidance specific to albumin in recommending against hypotonic crystalloids, starches, or gelatins but mentions that the weak recommendation for the use of albumin in those receiving large volumes of crystalloids in the Surviving Sepsis general guideline (non–COVID-19–specific guideline) is based on low-quality evidence r6r80
- In adults for whom vasopressors are needed, begin with norepinephrine; epinephrine or vasopressin is preferred as second line over dopamine if norepinephrine is unavailable r4r6r15
- Hemodynamic goal: mean arterial pressure of 60 to 65 mm Hg (NIH and Surviving Sepsis guidelines); WHO suggests mean arterial pressure of 65 mm Hg or more r4r6r15
- In patients without adequate response to usual doses of norepinephrine, Surviving Sepsis guideline recommends adding vasopressin rather than further titrating norepinephrine r4
- For adults with COVID-19, refractory shock despite fluid and norepinephrine, and evidence of cardiac dysfunction, Surviving Sepsis and NIH guidelines recommend adding dobutamine rather than further titrating norepinephrine r4
- For adults with refractory septic shock, NIH guideline recommends addition of low-dose corticosteroids if corticosteroids are not already being administered for other indications r15
- In children, epinephrine is considered the first line agent, and norepinephrine may be added if necessary r6
Corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r4r15r72r73
- For patients with critical illness, guidelines recommend or strongly recommend use of corticosteroids; guidelines that specify a corticosteroid recommend dexamethasone (when available) over alternatives
- For patients with severe illness, guidelines suggest or recommend use of corticosteroids, and those which specify a corticosteroid suggest dexamethasone
- In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
Immunomodulators are being used for mitigation of cytokine release syndrome believed to be a factor in severe acute respiratory distress syndrome and shock in COVID-19 (eg, monoclonal antibodies against interleukin-6 receptors, such as tocilizumabr81 and sarilumabr82; Janus kinase inhibitors such as baricitinibr83 and tofacitinibr84)
- Surviving Sepsis guideline does not address immunomodulators r4
- Baricitinib (Janus kinase inhibitor)
- Baricitinib, currently approved for use in refractory rheumatoid arthritis owing to its antiinflammatory effect, has received emergency use authorization for treatment of adult and pediatric patients (aged 2 years or older) on oxygen supplementation (including mechanical ventilation or extracorporeal membrane oxygenation) r85r86
- FDA reviewed data from the ACTT-2 trial (Adaptive COVID-19 Treatment Trial 2), which compared remdesivir plus baricitinib (515 patients) against remdesivir plus placebo (518 patients) in patients with documented SARS-CoV-2 infection and either pulmonary infiltrates, oxygen saturation less than 94%, or requirement for some degree of oxygen supplementation. Patients who received baricitinib were more likely to have better clinical status (based on an 8-point score) at day 15 than those who did not. Median time to recovery was 7 days in the baricitinib group versus 8 days in the placebo group. The odds of dying or progressing to noninvasive/high-flow oxygen or invasive ventilation were significantly lower for patients in the baricitinib group r86
- Additional data from COV-BARRIER trial (studying efficacy and safety of baricitinib for hospitalized adults with COVID-19) indicated that baricitinib was associated with reduced mortality but not a reduction in the frequency of disease progression r87
- NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone, or with remdesivir and dexamethasone, in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r15
- In patients receiving just supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding baricitinib to dexamethasone is of benefit; they recommend baricitinib plus remdesivir for such patients when corticosteroids cannot be used
- Guideline recommends against giving tocilizumab or other interleukin-6 inhibitors to patients receiving baricitinib
- There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa
- Infectious Diseases Society of America guideline suggests use of baricitinib in hospitalized patients with severe COVID-19 with elevated inflammatory markers (along with remdesivir and corticosteroids), and it suggests use of baricitinib with remdesivir for those with severe COVID-19 who cannot receive corticosteroids r72
- Patients receiving baricitinib should not receive tocilizumab or other interleukin-6 inhibitors
- Benefits of baricitinib in patients requiring mechanical ventilation are uncertain, but limited data suggest a mortality benefit even among those requiring mechanical ventilation
- WHO guideline strongly recommends use of baricitinib along with corticosteroids in patients with severe or critical illness
- Choice of whether to use baricitinib versus IL-6 receptor blockers (tocilizumab or sarilumab) is based on availability and clinical factors
- Tofacitinib (Janus kinase inhibitor)
- NIH guideline recommends use of tofacitinib when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir r15
- In the STOP-COVID trial (Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia), hospitalized patients treated with tofacitinib had a lower risk of death or respiratory failure through day 28 than those on placebo, but overall the evidence for tofacitinib is less extensive than that for baricitinib, to date r15r88
- Infectious Diseases Society of America guideline suggests use of tofacitinib in hospitalized patients with severe COVID-19 who do not require mechanical ventilation (noninvasive or invasive), along with remdesivir and corticosteroids (unless contraindicated) r72
- Patients should also receive at least prophylactic dose of anticoagulant
- Patients receiving tofacitinib should not receive tocilizumab or other interleukin-6 inhibitors
- WHO guideline suggests not using tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab, and sarilumab are all unavailable, as there is insufficient evidence for their use r73
- Tocilizumab (monoclonal interleukin-6 receptor blocker)
- WHO guideline summarizes evidence for use of interleukin-6 inhibitors (tocilizumab or sarilumab) from up to 27 studies for 6 outcomes; overall, interleukin-6 inhibitors reduce mortality, decrease need for mechanical ventilation, and may decrease duration of mechanical ventilation and hospitalization, with little evidence for adverse events leading to discontinuation of drug, including secondary bacterial infections r73
- There is insufficient evidence to recommend tocilizumab over sarilumab or vice versa
- A review of data from 5 randomized controlled trials comparing tocilizumab to usual care (with or without placebo) did not show a 28-day mortality benefit, but it did show a lower relative risk of clinical deterioration (ie, ICU admission, mechanical ventilation, death), although evidence was of low certainty r72
- REMAP-CAP and RECOVERY trials both indicate a mortality benefit for tocilizumab among patients who experienced rapid respiratory decompensation and were recently admitted to ICU, and the RECOVERY trial showed benefit in those who require high-flow oxygen or noninvasive ventilation r89r90
- NIH guidelines recommend use of tocilizumab in 2 situations, as follows: r15
- Use tocilizumab (or baricitinib) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers)
- There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa
- Use tocilizumab with dexamethasone within 24 hours of admission to ICU for patients requiring mechanical ventilation or extracorporeal membrane oxygenation
- In patients receiving supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding tocilizumab to dexamethasone is of benefit; they recommend tocilizumab plus remdesivir for such patients when corticosteroids cannot be used
- Guideline recommends against giving baricitinib to patients on tocilizumab
- In patients admitted to hospital with COVID-19, Infectious Diseases Society of America guideline suggests tocilizumab in addition to standard care (steroids) for patients with progressive severe or critical COVID-19 who have elevated levels of markers of systemic inflammation r72
- WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r73
- Sarilumab (monoclonal interleukin-6 receptor blocker)
- NIH guidelines recommend use of sarilumab only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir r15
- WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids r73
- REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but the evidence for the use of tocilizumab is more extensive r15r89
Several antiviral agents (eg, remdesivir, ritonavir-boosted nirmatrelvir, molnupiravir) with action against SARS-CoV-2 are now available, primarily for prevention of severe disease and not for use in critically ill patients. However, remdesivir is FDA-approved specifically for treatmentr2 of COVID-19 in hospitalized adults and children aged 12 years or older weighing 40 kg or more. Emergency use authorization has been granted for the use of remdesivir for hospitalized children weighing 3.5 kg or more r2r91
- For patients with critical illness, guidelines suggest against initiation of remdesivir, as the benefit of remdesivir has not been shown for patients requiring mechanical ventilation
- If remdesivir has already been started and the patient worsens to require mechanical ventilation, NIH suggests completion of the course
- For patients with severe illness requiring oxygen, guidelines from NIH, Infectious Diseases Society of America, and Surviving Sepsis suggest use of remdesivir; WHO guideline which suggests against use of remdesivir notes this recommendation does not represent current evidence and is under review r4r15r72r73
- Infectious Diseases Society of America suggests a 5-day course rather than a 10-day course; NIH suggests a 5-day course that may be extended to 10 days if there is no substantial clinical improvement by day 5; Surviving Sepsis guideline makes no recommendation on duration of therapy
Medications including monoclonal antibodies against SARS-CoV-2 spike protein and convalescent plasma may be used in prevention or treatment of COVID-19 but have no role for critically ill patients
Several medications with a mechanism of action which could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms r92
- NIH guidelines recommend that patients taking ACE inhibitors, angiotensin receptor blockers, statin drugs, NSAIDs, corticosteroids (oral, inhaled, or intranasal), and acid suppressive drugs for underlying medical conditions should not discontinue these medications r15
- In addition, none of the above classes of medications should be started for the purpose of treatment or prevention of COVID-19, except as noted above for corticosteroid treatment
- Infectious Diseases Society of America guidelines similarly do not recommend initiating or discontinuing any of the above medications for treatment or prevention of COVID-19 r72
Several other treatments are not currently recommended under any guidelines but continue to be studied
- These include lopinavir-ritonavir and other HIV protease inhibitors, ivermectin, chloroquine, hydroxychloroquine, azithromycin, nitazoxanide, colchicine, fluvoxamine, famotidine, stem cells, immunomodulators and antivirals not mentioned above, and various vitamin supplements r15r72r73d1
Drug therapy
- Antiviral agent
- Remdesivir r91r93c46
- For patients NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO):
- Remdesivir Solution for injection; Neonates weighing 3.5 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
- Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
- Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
- Remdesivir Solution for injection; Children and Adolescents weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
- Remdesivir Solution for injection; Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
- For patients REQUIRING invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO):
- Remdesivir Solution for injection; Neonates weighing 3.5 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.
- Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 9 days.
- Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.
- Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
- Remdesivir Solution for injection; Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
- Immunomodulators
- Baricitinib c47
- Baricitinib Oral tablet; Children 2 to less than 9 years: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
- Baricitinib Oral tablet; Children and Adolescents 9 years of age and older: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
- Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines recommend use with dexamethasone (with or without remdesivir) IF on supplemental oxygen, including noninvasive ventilation or high-flow oxygen, AND there is evidence of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone.
- Tocilizumab c48
- Tocilizumab Solution for injection; Adults: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend a single 8 mg/kg (actual body weight, up to 800 mg) IV dose given with dexamethasone (with or without remdesivir) for hospitalized patients on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, NIH recommends use with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours.
- Sarilumab c49
- Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 mg IV dose given with dexamethasone (with or without remdesivir) to treat hospitalized adults on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
- Tofacitinib
- Tofacitinib Oral tablet; Adults: The NIH COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation and high-flow oxygen, with rapidly increasing oxygen needs and systemic inflammation. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
- Vasopressors
- Norepinephrine c50
- Norepinephrine Bitartrate Solution for injection; Neonates†: 0.1 to 0.5 mcg/kg/minute continuous IV infusion; titrate every 30 minutes to clinical response (Usual Max: 2 mcg/kg/minute).
- Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion; titrate to clinical response (Usual Max: 2 mcg/kg/minute).
- Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate by 0.02 mcg/kg/minute (or more in emergency cases) to clinical response. Usual dosage range: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.
- Epinephrine c51
- Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate to clinical response.
- Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes to clinical response.
- Vasopressin c52
- Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
- Inotrope
- Dobutamine c53
- Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Usual dosage range: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
- Corticosteroid
- For treatment of severe COVID-19 in patients requiring supplemental oxygen
- Dexamethasone c54
- Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: The NIH guidelines recommend 0.15 mg/kg/dose (maximum dose of 6 mg) IV once daily for up to 10 days for pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO. Not routinely recommended for pediatric patients requiring only low oxygen support. Use in pediatric patients who are profoundly immunocompromised should be considered on a case-by-case basis
- Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: The NIH guidelines recommend 0.15 mg/kg/dose (maximum dose of 6 mg) IV once daily for up to 10 days for pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO. Not routinely recommended for pediatric patients requiring only low oxygen support. Use in pediatric patients who are profoundly immunocompromised should be considered on a case-by-case basis
- Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first) is recommended by the NIH guidelines for use in hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The WHO strongly recommends systemic corticosteroids for 7 to 10 days in patients with severe or critical COVID-19. Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
- Methylprednisolone c55
- Methylprednisolone Sodium Succinate Solution for injection; Adults: 8 mg IV every 6 hours or 16 mg IV every 12 hours for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends methylprednisolone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 32 mg IV once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
- Prednisone c56
- Prednisone Oral solution; Adults: 40 mg PO daily for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends prednisone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 40 mg PO once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
- For treatment of COVID-19–related septic shock refractory to vasopressors and fluids
- Hydrocortisone c57
- Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion.
- Anticoagulants (prophylactic intensity)
- Enoxaparin c58
- Enoxaparin Sodium (Porcine) Solution for injection; Neonates and Infants younger than 2 months†: 0.75 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
- Enoxaparin Sodium (Porcine) Solution for injection; Infants, Children, and Adolescents 2 months to 17 years†: 0.5 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
- Enoxaparin Sodium (Porcine) Solution for injection; General medical Adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe respiratory disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and inflammatory bowel disease): 40 mg subcutaneously once daily for 14 days or less.
- Dalteparin
- Dalteparin Sodium (Porcine) Solution for injection; Infants†, Children, and Adolescents: 92 International Units/kg subcutaneously once daily; adjust dose to maintain an anti-factor Xa level of 0.1 to 0.3 International Units/mL.
- Dalteparin Sodium (Porcine) Solution for injection; General medical adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe lung disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and/or inflammatory bowel disease): 5,000 International Units subcutaneously once daily for up to 14 days.
- Anticoagulants (therapeutic intensity for those with suspected or proven thromboembolism)
- Enoxaparin
- Enoxaparin Sodium (Porcine) Solution for injection; Infants 1 to 2 months†: 1.5 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.8 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours post-dose or 0.5 to 0.8 units/mL 2 to 6 hours post-dose.
- Enoxaparin Sodium (Porcine) Solution for injection; Infants 3 to 11 months†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.5 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
- Enoxaparin Sodium (Porcine) Solution for injection; Children 1 to 5 years†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.2 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
- Enoxaparin Sodium (Porcine) Solution for injection; Children and Adolescents 6 to 17 years†: 1 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
- Enoxaparin Sodium (Porcine) Solution for injection; Adults: 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours. Start warfarin therapy when appropriate, as early as day 1 and usually within 72 hours of initiation of enoxaparin. Continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved.
- Dalteparin
- Dalteparin Sodium (Porcine) Solution for injection; Infants, Children, Adolescents: 129 International Units/kg/dose subcutaneously once daily; adjust dose to maintain anti-Xa concentration of 0.5 to 1 International Unit/mL drawn 4 hours after injection. Give 5 to 10 days until target INR is reached; or give for duration of treatment (6 months or longer for idiopathic DVT or until risk factor is resolved and 3 months or longer for secondary DVT). If VTE is CVL-related, remove CVL if possible. If not, give prophylactic doses after treatment until CVL is removed.
- Dalteparin Sodium (Porcine) Solution for injection; Adults: 200 International Units/kg/dose (Max: 18,000 International Units/dose) subcutaneously once daily or 100 International Units/kg/dose subcutaneously every 12 hours with warfarin on day 1. Stop dalteparin after at least 5 days of combined therapy once the INR is therapeutic.
- Sedatives (for mechanically ventilated patients)
- Dexmedetomidine c59
- Dexmedetomidine Hydrochloride Solution for injection; Term Neonates†: 0.05 to 0.5 mcg/kg IV, then 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 2.5 mcg/kg/hour.
- Dexmedetomidine Hydrochloride Solution for injection; Infants†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
- Dexmedetomidine Hydrochloride Solution for injection; Children† and Adolescents†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
- Dexmedetomidine Hydrochloride Solution for injection; Adults: 1 mcg/kg IV, then 0.2 to 0.7 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 1.5 mcg/kg/hour.
- Propofol c60
- Propofol Emulsion for injection; Adolescents 17 years: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
- Propofol Emulsion for injection; Adults: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
- Neuromuscular blockers (for mechanically ventilated patients)
- Rocuronium c61
- Intermittent IV dosage
- Rocuronium Bromide Solution for injection; Neonates: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg IV once, followed by 0.1 to 1 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Continuous infusion IV dosage
- Rocuronium Bromide Solution for injection; Neonates: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg IV bolus, followed by 8 to 12 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Usual dosage range: 4 to 16 mcg/kg/minute. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Nondrug and supportive care
Excellent supportive care remains the mainstay of treatment to date in COVID-19 c62
WHO,r6NIH,r15 and Surviving Sepsis Campaignr4 provide specific guidance for oxygenation, ventilation, hemodynamics, fluid management, and prevention of complications in COVID-19
- Oxygenation and ventilation c63c64
- Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% r4r6
- Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute r6c65
- Titrate to reach SpO₂ of 94% or more initially; Surviving Sepsis recommends that SpO₂ be maintained no higher than 96%
- Once stable, target SpO₂ of 90% or higher in nonpregnant adults; 92% or higher in pregnant patients
- In most children the target SpO₂ is 90% or greater; for those who require urgent resuscitation (eg, those with apnea or obstructed breathing, severe respiratory distress, central cyanosis, shock, seizures, or coma), a target SpO₂ of 94% or higher is recommended
- High-flow nasal cannula is recommended for adults with persistent respiratory failure despite conventional oxygen therapy r94c66c67
- High-flow nasal cannula is recommended over noninvasive positive pressure ventilation by NIH and Surviving Sepsis; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation with close monitoring may be used if high-flow nasal oxygen is not available r4r15
- Noninvasive positive pressure ventilation, such as CPAP and BPAP, may be used in monitored settings with immediate availability of endotracheal intubation if needed; if indications for endotracheal intubation are already present, high-flow nasal cannula or noninvasive positive pressure ventilation should not be used to delay needed mechanical ventilation r6
- Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended r6
- For patients with persistent hypoxemia but without other indications for intubation, WHO suggests and NIH recommends a trial of awake prone positioning to improve oxygenation; Surviving Sepsis guideline finds insufficient evidence to make a recommendation r15c68
- NIH recommends against using prone positioning in an attempt to avert the need for mechanical ventilation in patients who otherwise require it (eg, respiratory distress, hemodynamic instability)
- Mechanical ventilation may become necessary for patients in whom oxygenation targets cannot be met with less invasive measures or who cannot maintain the work of breathing; indications for intubation are the same as for non–COVID-19 conditions (eg, PaO₂/FIO₂ ratio less than 300 mm Hg, coma) c69
- Categorization of degree of acute respiratory distress syndrome in adults, by PaO₂/FIO₂ ratio (mm Hg):
- Mild: PaO₂/FIO₂ ratio less than 300 but more than 200, with PEEP or CPAP at 5 cm H₂O or more
- Moderate: PaO₂/FIO₂ ratio of 200 or less but more than 100, with PEEP at 5 cm H₂O or more
- Severe: PaO₂/FIO₂ ratio of 100 or less, with PEEP at 5 cm H₂O or more
- Categorization of degree of acute respiratory distress syndrome in children:
- Indices:
- Oxygenation index is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by PaO₂ (mm Hg)
- Oxygen saturation index is a noninvasive surrogate for oxygenation index and is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by the oxygen saturation as measured by pulse oximetry (SpO₂)
- Mild (invasively ventilated): oxygenation index from 4 to less than 8 or oxygen saturation index from 5 to less than 7.5
- Moderate (invasively ventilated): oxygenation index from 8 to less than 16 or oxygen saturation index from 7.5 to less than 12.3
- Severe (invasively ventilated): oxygenation index of 16 or more or oxygen saturation index of 12.3 or more
- Intubation should be performed by experienced personnel, using video laryngoscopy where available; N95 respirators or comparable, along with eye protection, gown, and gloves, are recommended for use during intubation and other aerosol-generating procedures and when caring for mechanically ventilated patients, to prevent exposure during unexpected ventilator circuit disruptions r4r15
- WHO additionally recommends against disconnection from ventilators, which risks exposing health care workers, and suggests consideration of airway clearance techniques for excessive secretions only with strict infection control practices r6
- Guidelines have a strong recommendation for lower tidal volume of 4 to 8 mL/kg (predicted body weight) over higher tidal volumes and plateau pressures less than 30 cm H₂O for adults r4r15r73
- In children, target tidal volumes of 5 to 8 mL/kg (predicted body weight) for preserved lung compliance and 3 to 6 mL/kg for poor compliance; plateau pressures should be less than 28 cm H₂O r6
- Guidelines suggest a higher PEEP strategy over lower PEEP, with close monitoring for barotrauma and with consideration of risks (eg, overdistention, higher pulmonary vascular resistance) and benefits (eg, improved alveolar recruitment) r4r6r15c70d5d5d5d5d5d5d5d5
- For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, prone positioning for 12 to 16 hours/day is recommended r4r6r15c71
- Lateral decubitus position may be used for pregnant patients, especially in the third trimester r6
- Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate agentsr95 (eg, propofol, dexmedetomidine) and monitoring; shortages may occur and the American Society of Health-System Pharmacists offers guidance on substitutionsr96
- Guidelines suggests intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion r4r6r15c72c73
- Continuous neuromuscular blockade may be needed for patient-ventilator dyssynchrony, prone ventilation, persistently high plateau pressures, or other need for deep sedation; guidelines recommend no more than 48 hours r4r15
- Routine use of inhaled nitric oxide is not recommended by either Surviving Sepsis Campaign or NIH guidelines; both note that a trial may be reasonable as a rescue strategy in patients who remain hypoxemic despite all other measures r4r15
- Similarly, in patients on mechanical ventilation with persistent hypoxemia despite all other measures, recruitment maneuvers (eg, brief high PEEP or CPAP) are suggested except incremental (staircase) PEEP
- Tracheostomy may be required; it should be performed for indications similar to those in patients without COVID-19 (eg, prolonged mechanical ventilation, secretion management, failed extubation, inability to protect airway)
- Extracorporeal membrane oxygenation has been usedr18 since the early pandemic in severely ill patients; Surviving Sepsis and WHO suggest using venovenous type, or referral for extracorporeal membrane oxygenation, if all other measures have not alleviated refractory hypoxemia; NIH guideline finds insufficient evidence to recommend for or against use r4r6r15c74
- WHO definition of refractory hypoxemia is: PaO₂/FIO₂ ratio of less than 50 mm Hg for 3 hours, or less than 80 mm Hg for more than 6 hours
- Fluid management
- Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome
- An assessment of likely fluid responsiveness may be made by measuring the change in cardiac output (by echocardiography or transpulmonary thermodilution) on passive leg raise; an increase in cardiac output after 1 minute of passive leg raise has been shown to be a reliable predictor of response and helps to avoid overhydration in patients unlikely to respond r97
- In patients with shock:
- Administration of crystalloids is recommended (preferably buffered/balanced, eg, lactated Ringer solution); WHOr6 provides the following guidance:
- Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hgr4 (if invasive pressure monitoring is available)
- Children: 10 to 20 mL/kg bolus over the first 30 to 60 minutes
- If there is no response to fluid bolus or if signs of fluid overload exist, discontinue or reduce fluid administration
- For patients who respond to initial bolus and are without evidence of fluid overload, titrate continued fluid to achieve improvement in clinical signs (capillary refill, heart rate, tactile temperature of extremities, palpable pulses), urine output (0.5 mL/kg/hour in adults, 1 mL/kg/hour in children), and hemodynamic parameters (mean arterial pressure more than 65 mm Hg in adults)
- Administer vasopressors in adults if shock persists after fluid bolus, and in children after 2 fluid boluses or if there are signs of fluid overload
- Management of acute kidney injury
- NIH guideline recommends continuous renal replacement therapy if available for patients with acute kidney injury who require renal replacement therapy r15
- If continuous renal replacement therapy is not available or not possible owing to limited resources, NIH guideline recommends prolonged intermittent renal replacement therapy rather than intermittent hemodialysis
Procedures
Extracorporeal membrane oxygenation c75
General explanation- Heart-lung bypass is a technique in which blood is circulated from patient through bypass machine, where transmembrane exchange of oxygen and carbon dioxide occurs before blood is returned to patient; method can also be used to support arterial blood pressure
Indication- Refractory hypoxemia with or without hemodynamic compromise despite standard supportive measures
- May be helpful if resources and expertise are available r4
Contraindications- Neurologic impairment
- Severe preexisting disease
Complications- Limb ischemia distal to vascular access catheters
Comorbidities
- Severe COVID-19 has been associated with various underlying chronic conditions (eg, diabetes, hypertension) r47c76c77
Special populations
- Pregnant patients
- NIH guideline contains a summary of considerations for pregnant and breastfeeding patients; American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine also have guidance regarding pregnant patients with COVID-19 r15r98r99
- Compared with nonpregnant patients, pregnant patients with COVID-19 have an increased risk of severe disease, including ICU admission, mechanical ventilation, need for extracorporeal membrane oxygenation, and death r15r98r99
- COVID-19 in pregnancy is associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy r15r98r99
- In general, therapeutic management of pregnant patients should be the same as for nonpregnant patients; potentially effective treatments for COVID-19 should not be withheld because of theoretical concerns related to the safety of using those drugs in pregnancy r15
- Pediatric patients
- Evidence to guide treatment in pediatric populations is limited; guidance is generally based on safety and outcomes data in adults r15
- General management of critically ill children is also based on guidance for non-COVID critical illness, such as Surviving Sepsis Campaign septic shock guideliner100 and Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in childrenr101