Treatment Options
Current standard treatment options include infection control measures, routine supportive care, and medications including antiviral, monoclonal antibody, immunomodulator, and corticosteroid drugs
- Many 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 r68r69
- 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 r4
- Given extensive potential medication interactions, clinicians are advised to use a drug interactions checker (eg, University of Liverpool offers one) r70
- Recommendations below summarize major treatment guidelines from NIH, WHO, Surviving Sepsis Campaign, and Infectious Diseases Society of America r4r6r7r71r72
Infection control measures include isolation, source control, and transmission precautions r73
- Patients with COVID-19 in a health care setting should wear a face mask to reduce droplet and aerosol 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
- 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)
- Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection r73
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) r7
- 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 r7
- 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 r4r7
- 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 r4r6r7r74r75r76r77r78
- Guidelines suggest or recommend use of prophylactic dose over intermediate dose or therapeutic dose for critically ill patients, including a recommendation to switch from therapeutic dose to prophylactic dose in patients transferred to an ICU, unless a thrombosis has been documented r4r74r76r78
- Where specified, heparins are preferred over oral anticoagulants and low-molecular-weight heparin is preferred over unfractionated heparin r4r6r7r75
- 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 r4r7
- NIH guidelines also recommend continuation of anticoagulation in hospital for those already on therapeutic doses for another indication r4
- NIH and American Society of Hematology recommend against continuing prophylaxis after discharge from hospital for those without venous thromboembolism r4r79
- 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 r4r80
- Patients on extracorporeal membrane oxygenation or continuous renal replacement therapy should have the same anticoagulation as patients on those therapies without COVID-19 r4
- Management of septic shock includes use of vasopressors if fluid administration does not restore adequate perfusion. Surviving Sepsis Campaign,r6NIH,r4 and WHOr7 treatment guidelines provide guidance specific to treatment of shock in patients with COVID-19 d3d3d3d3d3d3d3d3
- WHO definitions for septic shock: r7
- Adults: suspected or confirmed infection; persistent hypotension despite volume resuscitation; vasopressors are needed to maintain mean arterial pressure at or above 65 mm Hg; and lactate level is 2 mmol/L or more
- 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 r4r6
- 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) r4r6
- 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 r7r81
- In adults for whom vasopressors are needed, begin with norepinephrine; epinephrine or vasopressin is preferred as second line over dopamine if norepinephrine is unavailable r4r6r7
- 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 r4r6r7
- In patients without adequate response to usual doses of norepinephrine, Surviving Sepsis guidelines recommend adding vasopressin rather than further titrating norepinephrine r6
- 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 r6
- For adults and children with refractory septic shock, NIH guidelines recommend addition of low-dose corticosteroids if corticosteroids are not already being administered for other indications r4
- In children, epinephrine or norepinephrine are considered the first line agents r4r7
- Specific hemodynamic targets for children are not known; NIH COVID-19 treatment guidelines and Surviving Sepsis pediatric guidelines (pre-COVID) suggest a target mean arterial pressure either between the 5th and 50th percentile, or above the 50th percentile, for age r4r82
- Evidence is insufficient to recommend for or against use of inodilatorsr4 (eg, dobutamine or milrinone) in children with cardiac dysfunction and hypoperfusion despite fluid resuscitation and vasopressors
Corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r4r6r71r72
- 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 tocilizumabr83 and sarilumabr84; Janus kinase inhibitors such as baricitinibr85 and tofacitinibr86)
- Surviving Sepsis guidelines do not address immunomodulators r6
- Baricitinib (a Janus kinase inhibitor)
- Baricitinib has FDA approval for treatment of adults, and emergency use authorization for treatment of children aged 2 years or older, for hospitalized patients with COVID-19 on oxygen supplementation (including mechanical ventilation or extracorporeal membrane oxygenation) r87r88r89
- 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 r88
- Additional data from COV-BARRIER trial (studying efficacy and safety of baricitinib for hospitalized adults with COVID-19) indicated that baricitinib did not impact disease progression, but was associated with a 38.2% relative reduction in mortality r90
- NIH guidelines recommend use of baricitinib (or tocilizumab) 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) r4
- 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 for this indication
- NIH further recommends use of baricitinib (with dexamethasone) for hospitalized patients who need high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation; because of a stronger evidence base, the recommendation for baricitinib is stronger than for tocilizumab, which is an alternative
- Infectious Diseases Society of America guidelines suggest use of baricitinib in hospitalized patients with severe COVID-19 along with corticosteroids (unless contraindicated) or remdesivir in patients who cannot receive corticosteroids r72
- Patients receiving baricitinib should not receive tocilizumab or other interleukin-6 inhibitors
- Some 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 r71
- Choice of whether to use baricitinib versus IL-6 receptor blockers (tocilizumab or sarilumab) is based on availability and clinical factors
- Tocilizumab (a monoclonal interleukin-6 receptor blocker)
- NIH guidelines recommend use of tocilizumab as follows: r4
- Use tocilizumab (or baricitinib) with remdesivir and dexamethasone or with dexamethasone alone 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 for this indication
- In patients receiving high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, use tocilizumab (with dexamethasone) as an alternative to baricitinib (which currently has more evidence than tocilizumab)
- Best initiated within 24 hours of admission to ICU
- Guideline recommends against giving baricitinib to patients on tocilizumab
- In patients admitted to hospital with COVID-19, Infectious Diseases Society of America guidelines suggest 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 guideline recommends use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r71
- WHO guideline summarizes evidence for use of interleukin-6 inhibitors (tocilizumab or sarilumab) from over 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 r71
- 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 r91r92
- Sarilumab (a monoclonal interleukin-6 receptor blocker)
- NIH guidelines recommend use of sarilumab (along with dexamethasone or dexamethasone plus remdesivir) 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) r4
- NIH guidelines also recommend use of sarilumab when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation
- WHO guideline recommends use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids r71
- 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 r4r92
- Tofacitinib (a Janus kinase inhibitor)
- NIH guidelines recommend use of tofacitinib (along with dexamethasone or dexamethasone plus remdesivir) 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) r4
- NIH guidelines also recommend use of tofacitinib when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation
- Infectious Diseases Society of America guidelines suggest 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 r71
- 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 r4r93
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 for treatment of SARS-CoV-2–positive adults and children aged 28 days or older weighing 3 kg or more who are hospitalized (as well as nonhospitalized patients who are at high risk of progression to severe disease) r94r95
- 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 or extracorporeal membrane oxygenation r4
- If remdesivir has already been started and the patient worsens to require mechanical ventilation or extracorporeal membrane oxygenation, 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 is under review for this indication r4r6r71r72
- 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 guidelines make no recommendation on duration of therapy
- NIH guidelines recommend against use of remdesivir without immunomodulators for patients requiring high-flow oxygen or noninvasive ventilation
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 r96
- 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 r4
- 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
- Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists r4
Several other treatments are not currently recommended under any guidelines but continue to be studied; avoid use outside clinical trials
- These include lopinavir-ritonavir and other HIV medications, ivermectin, chloroquine, hydroxychloroquine, azithromycin, nitazoxanide, colchicine, fluvoxamine, famotidine, stem cells, interferons, intravenous immunoglobulin (except as indicated for multisystem inflammatory syndrome), immunomodulators not mentioned above, and various vitamin supplements r4r71r72d1
Drug therapy
- Antiviral agent
- Remdesivir r94r97c43
- For patients NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation:
- Remdesivir Solution for injection; Neonates†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for up to 10 days is being used in an ongoing investigational study (NCT04431453) in neonates 14 to 27 days of age, gestational age more than 37 weeks, and weight 2.5 kg or more. 2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days was successfully used in a case report of 2 ex-premature neonates.
- Remdesivir Solution for injection; Infants, Children, and Adolescents weighing 3 to 39 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:
- Guidelines do not recommend initiation of remdesivir in these patients; however, treatment course may be completed in those whose condition worsened to require mechanical ventilation or extracorporeal membrane oxygenation
- Remdesivir Solution for injection; Neonates†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for up to 10 days is being used in an ongoing investigational study (NCT04431453) in neonates 14 to 27 days of age, gestational age more than 37 weeks, and weight 2.5 kg or more. 2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days was successfully used in a case report of 2 ex-premature neonates.
- Remdesivir Solution for injection; Infants, Children, and Adolescents weighing 3 to 39 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. 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; Children and Adolescents 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 r85c44
- Baricitinib Oral tablet; Children 2 to 8 years†: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Baricitinib Oral tablet; Children and Adolescents 9 to 17 years†: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Tocilizumab r83c45
- Tocilizumab Solution for injection; Adults: 8 mg/kg (Max: 800 mg/dose) IV infusion once with a systemic corticosteroid. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
- Sarilumab r84c46
- 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, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
- Tofacitinib r86
- 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, high-flow oxygen, mechanical ventilation, or ECMO. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
- Vasopressors
- Norepinephrine c47
- 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 c48
- 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 c49
- Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion, initially; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
- Inotrope
- Dobutamine c50
- Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
- Corticosteroid
- For treatment of severe COVID-19 in patients requiring supplemental oxygen
- Dexamethasone c51
- Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: 0.15 mg/kg/dose (Max: 6 mg/dose) IV once daily for up to 10 days for hospitalized pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO.
- Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: 0.15 mg/kg/dose (Max: 6 mg/dose) IV once daily for up to 10 days for hospitalized pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO.
- Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first) for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO.
- Methylprednisolone c52
- 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 c53
- 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 c54
- Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion.
- Anticoagulants (prophylactic intensity)
- Enoxaparin c55
- 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.
- 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: 100 International Units/kg/dose subcutaneously every 12 hours or 200 International Units/kg/dose subcutaneously once daily (Max: 18,000 International Units/day).
- Sedatives (for mechanically ventilated patients)
- Dexmedetomidine c56
- Dexmedetomidine Hydrochloride Solution for injection; Term Neonates†: 0.05 to 0.5 mcg/kg IV, followed by 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, followed by 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, followed by 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, followed by 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 c57
- 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 c58
- Intermittent IV dosage (preferred over continuous infusion, where clinically possible)
- 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 c59
WHO,r7NIH,r4 and Surviving Sepsis Campaignr6 provide specific guidance for oxygenation, ventilation, hemodynamics, fluid management, and prevention of complications in COVID-19
- Oxygenation and ventilation c60c61
- Begin supplemental oxygen therapy when SpO₂ (peripheral oxygen saturation) falls below 90% to 92% for nonpregnant patients, or below 95% for pregnant patients r4r6r7
- Specific target SpO₂ is not definitively known
- WHO guidelines suggest initial target during resuscitation of 94% or more in all patients, and once stable, a target of more than 90% SpO₂ in nonpregnant adults and children and at least 92% to 95% in pregnant patients r7
- NIH guidelines suggest a target SpO₂ of 92% to 96% for nonpregnant adults, 95% or more in pregnant patients, and 92% to 97% for children; consider target less than 92% in children with severe acute respiratory distress syndrome to minimize exposure to high FIO₂ (fraction of inspired oxygen) r4
- Surviving Sepsis recommends that SpO₂ be maintained no higher than 96% for adults r6
- Conventional oxygenation may use a variety of delivery methods (eg, nasal cannula at 5 L/minute, face mask with reservoir bag at 10 to 15 L/minute) r7c62
- High-flow nasal cannula is recommended for patients with persistent respiratory failure despite conventional oxygen therapy r4r98c63c64
- High-flow nasal cannula is recommended for adults 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 r4r6
- For infants and children not needing intubation, a trial of high-flow oxygen or noninvasive ventilation is recommended, with insufficient evidence to recommend one method over another r4
- WHO guideline recommends high-flow oxygen, CPAP (continuous positive airway pressure), or BPAP (bilevel positive airway pressure) over standard oxygen therapy for patients with severe or critical disease and acute hypoxemic respiratory failure not needing emergent intubation; no recommendation is given for one over another, owing to lack of evidence r7
- 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 r7
- Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended r4r7
- Guidelines do not advise on method of delivery (eg, helmet, face mask) for NIV, owing to limited evidence comparing one with another
- 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 guidelines find insufficient evidence to make a recommendation r4c65
- 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)
- Pregnant patients may be placed in left lateral decubitus or fully prone position, as tolerated r4
- 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) c66
- Categorization of degree of acute respiratory distress syndrome in adults, by PaO₂/FIO₂ ratio (mm Hg): r7
- 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: r7
- 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 SpO₂ (peripheral oxygen saturation as measured by pulse oximetry)
- 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 r4r6
- 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 r7
- For children, cuffed endotracheal tubes are recommended over uncuffed r4
- 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 r4r6r71
- 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 (or less than or equal to 32 cm H₂O for those with impaired chest wall compliance) r4r7
- 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) r4r6r7c67d5d5d5d5d5d5d5d5
- In children, permissive hypercapnia (pH more than 7.15 to 7.30) is recommended if needed to maintain the above lung-protective ventilation strategies, unless the patient has a condition that would be worsened by acidosis (eg, pulmonary hypertension, ventricular dysfunction, intracranial hypertension) r4
- For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, prone positioning for 12 to 16 hours/day is recommended r4r6r7c68
- Lateral decubitus position may be used for pregnant patients, especially in the third trimester r7
- Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate agents and monitoring for adults and children r99r100
- Guidelines suggests intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion r4r6r7c69c70
- 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 r4r6
- 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 r4r6
- 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 usedr16 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 guidelines find insufficient evidence to recommend for or against use r4r6r7c71
- 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
- Evidence is insufficient to recommend for or against high frequency oscillatory ventilation in children with severe acute respiratory distress syndrome and refractory hypoxemia r4
- Fluid management
- Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome; guidelines call for conservative rather than aggressive fluid management r4r6r7
- Assess fluid responsiveness with dynamic parameters (eg, stroke volume variation, pulse pressure variation, passive leg raise), skin temperature, capillary refill time, or lactate levels, rather than static parameters (eg, mean arterial pressure, central venous pressure) r4r7
- An increase in cardiac output (by echocardiography or transpulmonary thermodilution) 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 r101
- Physical examination findings may be less accurate predictors of fluid responsiveness r101
- Based on non–COVID-19 patient data, early lactate clearance–guided resuscitation may be beneficial compared with central venous oxygen saturation–guided therapy r4
- To monitor resuscitation in children, a combination of serial clinical assessments, cardiac ultrasonography or echocardiography, and/or laboratory markers (including lactate levels) is recommended r4
- In patients with shock:
- Administration of crystalloids is recommended (preferably buffered/balanced, eg, lactated Ringer solution); WHO guideline provides the following guidance: r7
- Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hgr6 (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
Procedures
Extracorporeal membrane oxygenation c72
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 r6
Contraindications- Neurologic impairment
- Severe preexisting disease
Complications- Limb ischemia distal to vascular access catheters
Comorbidities
- Severe COVID-19 has been associated with many underlying conditions (eg, diabetes, hypertension); overall treatment of critically ill patients does not differ for those with specific conditions with few exceptions r48c73c74
- For patients who are immunocompromised due to medications, immunomodulatory drug regimens may need to be adjusted to reduce the risk of drug-drug interactions, overlapping toxicities, and secondary infections; any dosage changes should be done in consultation with appropriate specialists r4
- Pay close attention to drug-drug interactions, and do not discontinue or adjust current medications (eg, chemotherapy, antiretroviral therapy) without appropriate specialist consultation, in patients with comorbid conditions such as active malignancy and HIV r4
Special populations
- Pregnant patients
- NIH guidelines contain 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 r4r102r103
- 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 r4r102r103
- COVID-19 in pregnancy is associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy r4r102r103
- 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 r4
- Pediatric patients
- Evidence to guide treatment in pediatric populations is limited; guidance is generally based on safety and outcomes data in adults r4
- General management of critically ill children is also based on guidance for non-COVID critical illness, such as Surviving Sepsis Campaign septic shock guideliner82 and Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in childrenr100