COVID-19 Critical Care

History

• Mean incubation period for Omicron variants is 3 days; incubation for more than 14 days occurs in a small percentage of patients ^r11
  • Patients may or may not report close contact with an infected person; the high transmissibility of Omicron variants contributes to the number of cases with unknown exposure history
• Critical illness typically develops 10 to 12 days from symptom onset ^r5
• Common presenting complaints include fever, cough (which may or may not be productive), fatigue, anorexia, shortness of breath, myalgia, sore throat, nasal congestion, headache, nausea, vomiting, diarrhea, loss of smell or taste ^{r4r12r13r14r15r16}
  • Likelihood of certain symptoms has changed depending on variants and prior immunity due to vaccination and prior infection ^r17
    • Fever and shortness of breath are less common, while sore throat, rhinorrhea, nasal congestion, and sneezing are more common
• Patients with moderate to severe disease often complain of dyspnea; however, some patients with severe hypoxemia do not perceive dyspnea ^r14r18
  • Hemoptysis has been reported in a small percentage of patients ^r14
  • Pleuritic chest pain has been reported ^r19
• Patients with severe or critical disease most commonly have pulmonary disease; however, cardiac, vascular, and neurologic manifestations may accompany pulmonary disease ^c1c2c3c4
  • The most common symptoms among severe or critically ill patients are fever, cough, dyspnea, chest tightness, and fatigue ^r20

Physical examination

• Physical findings may include systemic, neurologic, dermatologic, gastrointestinal, or others, but clinicians should be particularly attuned to pulmonary and hemodynamic indicators of critical illness
  • Patients with severe disease may appear quite ill, with tachypnea and labored respirations ^c5c6
  • Patients in apparent distress require immediate assessment of airway, breathing, and circulation
  • Clinicians should be aware of the COVID-19–related phenomenon of silent (or "happy") hypoxemia: absence of signs of respiratory distress may be misleading ^r18r21c7
  • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry) ^r4
    • Pulse oximetry has been demonstrated to be less effective in patients with darker skin tones of all ages, with risk of occult hypoxemia (arterial oxygen saturation less than 88% with concurrent pulse oximetry reading of 92% or more) being highest in Black patients ^r22r23r24r25
  • Tachyarrhythmias may be noted on auscultation or cardiac monitor ^r26c8
• Fever is typical, often exceeding 39 °C, but may be low-grade or absent in early disease, especially in vaccinated people. Patients in the extremes of age or with immunodeficiency may not develop fever ^r14r17c9
• Conjunctival secretions, injection, and chemosis have been reported ^r27
• Signs of arterial or deep venous thrombosis may be detected (eg, stroke, pulmonary embolism, acute limb ischemia, deep venous thrombosis) ^r28r29
• Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign ^r30c10c11c12
• Patients may be agitated, confused, or poorly responsive ^r30c13c14
• A variety of skin changes have been described, including purpura^r32 and petechiae^r33; vesicular^r34 and nonspecific erythematous exanthems^r35 typical of viral infections; and acral lesions^r36r37 resembling chilblains or Janeway lesions, particularly in young patients. Typical viral eruptions generally occur early in the disease, but remnants may be apparent in patients presenting with severe disease ^r31c15c16c17
• Hypotension, tachycardia, and cool/clammy extremities suggest shock ^c18c19c20
  • In children, manifestations of shock include: ^r4
    • Hypotension (systolic blood pressure less than 5th percentile or 2 standard deviations below the lower reference limit for age)
    • Altered mental status ^c21
    • Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children) ^c22
    • Prolonged capillary refill (more than 2 seconds) ^c23
    • Weak pulse, or warm vasodilation and bounding pulses
    • Tachypnea ^c24
    • Mottled or cool skin, petechiae, or purpura ^c25c26c27
    • Oliguria ^c28
    • Hyperthermia or hypothermia ^c29c30

Causes

• Infection due to SARS-CoV-2 ^c31
  • Person to person transmission occurs primarily through exposure to infectious respiratory droplets and aerosols of various sizes (eg, inhalation, contact of mucous membranes) during close contact, but other modes are also possible: long-distance airborne transmission, transmission via infected surfaces and fomites, transmission from infected animals, in utero transmission, and transmission through nonrespiratory fluids ^r19r38

Risk factors and/or associations

Primary diagnostic tools

• Most patients who are critically ill with COVID-19 will already be diagnosed with COVID-19 via a positive result on a nucleic acid amplification test (eg, polymerase chain reaction) or antigen test
• In cases where COVID-19 is suspected in a critically ill patient (eg, requiring mechanical ventilation) without a confirmed diagnosis, lower respiratory tract samples may be sent if upper respiratory tract samples are negative, taking care for potential aerosolization ^r48
  • Upper respiratory tract samples include nasopharyngeal, nasal midturbinate, anterior nasal, nasopharyngeal wash or aspirate, or oropharyngeal specimens
  • Lower respiratory tract samples include bronchoalveolar lavage fluid, tracheal aspirate, pleural fluid, lung biopsy specimen, and sputum
  • Care must be taken to minimize risks associated with aerosolization during specimen collection. Clinicians should not attempt to induce sputum, because the process may increase aerosolization and risk of transmission
  • Commercial, institutional, and public health laboratories may have different requirements and should be consulted for questions about collection site, swabs, transport media, or handling
• Serologic testing is not recommended for routine use in diagnosis, but it may be useful in the diagnosis of multisystem inflammatory syndrome because patients might present as critically ill with no prior diagnosis of COVID-19 ^r49d2
• Other testing should be performed concurrently, if indicated, to identify alternative pathogens (eg, influenza, respiratory syncytial, and other viruses; bacterial pathogens) ^{r4d3d3d3d3d3d3d3d3}
  • Coinfections occur, but bacterial coinfection at presentation is uncommon, from 0 to 6% ^r5r50r51
  • Influenza may be clinically indistinguishable from COVID-19, and coinfection occurs ^r5r52
    • When influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection
    • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
      • If only antigen testing for COVID-19 is readily available and results are negative, obtain confirmation with nucleic acid testing (eg, polymerase chain reaction); antigen test for influenza has lower sensitivity and is not recommended
• Chest imaging may be indicated to assess severity, but it is not recommended as a sole test for diagnosis, because radiographic features of COVID-19 overlap with those of many other conditions; plain radiography, CT, and ultrasonography have been used ^r16r53
  • During the initial outbreak in Wuhan, China, CT scan was considered a surrogate diagnostic modality, based on the following factors: greater sensitivity compared with chest radiographs; the observation that CT may find characteristic abnormalities even in the absence of a positive molecular test result; the high prevalence of COVID-19 in that geographic area at the time; and the public health goal of detecting and isolating all infected persons ^r54
  • In patients with moderate to severe disease, chest imaging is essential to document extent and severity of lung involvement and to serve as a baseline against which to compare should respiratory status worsen ^r16r54c32c33
    • In patients with severe disease, CT may offer an advantage over plain radiographs in distinguishing progression of infection from heart failure due to myocarditis or from pulmonary embolism (both commonly associated with COVID-19) ^r54
• Routine blood work should be ordered as appropriate for clinical management based on disease severity (eg, CBC, coagulation studies, chemistry panel including tests of hepatic and renal function and—if sepsis is suspected—lactate level and blood cultures) ^{r4d4d4d4d4d4d4d4d4}
• Public health reporting requirements vary by jurisdiction; clinicians should consult local authorities. In some regions, public health authorities may be able to facilitate testing and undertake contact tracing and monitoring

Laboratory

• Positive identification of SARS-CoV-2 RNA by nucleic acid amplification test is considered confirmation of diagnosis
  • Reverse transcription polymerase chain reaction is the most common nucleic acid amplification test, but isothermal amplification methods are also available (eg, loop-mediated isothermal amplification)
  • Laboratory-based polymerase chain reaction testing has high sensitivity and high specificity and is thus the reference standard. Point of care polymerase chain reaction testing has moderate sensitivity and high specificity ^r49
  • False-negative results have been reported and may be due to a variety of factors, including inadequate sensitivity, poor or unrepresentative specimen, or time course of disease. Repeated sampling should be done if suspicion for COVID-19 is high and initial result is negative ^r49
• Antigen tests are also available for use in diagnosis, and they have the advantage of rapid turnaround ^r49
  • In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent
    • False-positive results are uncommon but do occur; they are more likely in a low-prevalence setting
    • False-negative results are common, depending on the test. A negative result may warrant retesting with polymerase chain reaction, or repeated antigen testing, if there is a high suspicion for infection based on clinical or epidemiologic indicators
• For patients with severe or critical illness, antibody testing is most likely to be useful in the diagnosis of MIS-C or MIS-A (ie, multisystem inflammatory syndrome in children or adults, respectively); antibody testing is not indicated for routine diagnosis of COVID-19
• Routine blood work is not diagnostic or predictive of disease severity, but information from patients with severe or critical illness shows common patterns ^r20r55
  • Most such patients have had elevated C-reactive protein and D-dimer levels (83.5% and 73.3%, respectively)
  • Many such patients had WBC count abnormalities; most common were lymphopenia (70.3%), leukocytosis (21.7%), and leukopenia (18.2%), but 56.9% had normal WBC counts
  • Other common findings were liver function test abnormalities (39.8%), elevated procalcitonin level (36.6%), and thrombocytopenia (19.0%)
    • Elevated levels of procalcitonin were associated with significantly higher risk of severe infection ^r56
  • Lactate level of 2 mmol/L or higher suggests presence of septic shock ^r4
  • Markers most associated with mortality are troponin levels, interleukin-6 level, estimated GFR, neutrophil to lymphocyte ratio, B-type natriuretic peptide level, and D-dimer level (elevated in patients who died compared with those who survived); also, urea and lactate dehydrogenase levels (lower in those who died compared with those who survived) ^r57

Imaging

• Chest imaging (eg, plain radiography, CT, ultrasonography) is sensitive but not highly specific to COVID-19 ^r53
• Chest imaging findings are abnormal in most patients; imaging usually shows bilateral involvement, varying from consolidation in more severely ill patients to ground-glass opacities in less severe and recovering pneumonia ^{r14r16r19r58r59c34}
  • CT scan findings in more than 40% of patients include ground-glass opacities (more than 80%), ground-glass opacities mixed with consolidation, pleural thickening, consolidation, interlobular septal thickening, and air bronchograms ^r60
• CT is more sensitive^r54r53r61 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19^r62
  • Certain chest CT findings suggest more severe disease: bronchial wall thickening, crazy paving (thickened interlobular septa and intralobular lines superimposed on diffuse ground-glass changes), linear opacity (typical of interstitial lung disease), and ground-glass opacity (hazy increased lung opacity which is less opaque than consolidation), as well as bilateral involvement compared with unilateral ^r63
• Utilize bedside ultrasonography where appropriate to monitor progression of pulmonary infiltrates, to assess cardiac function and fluid status, and to detect deep vein thrombosis or vascular catheter thrombosis ^r5r64
  • Higher lung ultrasound scores are associated with decreasing PaO₂/FIO₂ ratio, and lung ultrasound scores were found to be higher in critically ill patients who died compared with survivors ^r65

Most common

• Influenza ^{c35d5d5d5d5d5d5d5d5}
  • Presentation includes fever, coryza, sore throat, dry cough, and myalgias; unlike COVID-19, influenza usually has fairly sudden onset
  • Most cases are self-limited, but older adults (eg, those aged 65 years or older) or those with significant comorbidities often require hospitalization
  • Usually occurs in winter months in temperate climates but is less seasonal in equatorial regions
  • Patients with severe disease may have abnormal chest radiographic findings suggesting influenzal pneumonia or secondary bacterial pneumonia
  • Positive result on rapid influenza diagnostic test confirms influenza diagnosis with high specificity during typical season; negative result does not rule out influenza
  • Influenza may be clinically indistinguishable from COVID-19, and coinfection can occur ^r52
    • Test for both viruses when both are circulating in the community and positive results will change management (eg, in patients requiring hospitalization, or in patients who qualify for influenza antiviral treatment)
    • CDC recommends nucleic acid detection over antigen testing (multiplex or individual assays) for patients requiring hospitalization; use either nucleic acid or antigen testing when hospitalization is not required
• Respiratory syncytial virus infection ^d6
  • Presentation includes upper or lower respiratory tract symptoms, often clinically indistinguishable from other viruses
  • Physical examination may include fever, tachypnea, crackles, wheezing, prolonged expiratory phase
  • Diagnosis is often clinical, in the setting of typical symptoms during the usual season
  • Differentiate with laboratory confirmation: polymerase chain reaction testing (single or multiplex assay, which may include SARS-CoV-2, influenza, and/or other common viral pathogens) or rapid antigen testing
• MIS (multisystem inflammatory syndrome), in either children (MIS-C) or adults (MIS-A) ^d2
  • Clinical presentation may be similar to that of acute, severe COVID-19
  • Gastrointestinal, mucocutaneous, and cardiovascular involvement and shock are more common in MIS; respiratory involvement is more common in COVID-19
  • Patients with MIS-C or MIS-A tend to be younger and have fewer comorbidities
  • Differentiate with exposure history: COVID-19 onset is days after exposure; MIS occurs after weeks
  • Laboratory tests may also differentiate: acute COVID-19 will more likely have positive antigen or nucleic acid amplification test result and moderately elevated inflammatory marker levels, whereas MIS will more likely have positive antibody test result and extremely elevated inflammatory marker levels
• Bacterial pneumonia ^{c36d3d3d3d3d3d3d3d3}
  • Presentation includes fever, cough, and dyspnea; pleuritic pain occurs in some cases
  • Physical examination may find signs of consolidation (eg, dullness to percussion, auscultatory rales, tubular breath sounds)
  • Chest radiography usually shows lobar consolidation or localized patchy infiltrate
  • Sputum examination may find abundant polymorphonuclear leukocytes and a predominant bacterial organism
  • Pneumococcal or legionella antigens may be detectable in urine; sputum culture may find those or other pathogens
• Other viral pneumonias ^{c37d3d3d3d3d3d3d3d3}
  • Presentations include fever, dry cough, and dyspnea
  • Physical examination may find scattered rales
  • Chest radiography usually shows diffuse patchy infiltrates
  • Diagnosis is usually clinical. Testing for specific viral causes may be done; multiplex panels can test simultaneously for various common viral respiratory pathogens (eg, respiratory syncytial virus, adenoviruses, others)

Admission criteria

Recommendations for specialist referral

• Consult critical care specialist to manage fluids, mechanical ventilation, and hemodynamic support as needed
• Consult pulmonologist to aid in obtaining deep specimens for diagnosis and managing mechanical ventilation if necessary
• Consult infectious disease specialist to coordinate diagnosis and management as needed
• All patients should be managed according to local public health guidance

Drug therapy

• Immunomodulators
  • Corticosteroids
    • For treatment of severe COVID-19 in patients requiring supplemental oxygen
      • Dexamethasone ^c38
        • 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.
        • Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge, whichever comes first.
      • Methylprednisolone ^c39
        • Methylprednisolone Sodium Succinate Solution for injection; Adults: 32 mg/day IV divided every 6, 12, or 24 hours for up to 10 days or until hospital discharge, whichever comes first.
      • Prednisone ^c40
        • Prednisone Oral solution; Adults: 40 mg/day PO divided once or twice daily for up to 10 days or until hospital discharge, whichever comes first.
    • For treatment of COVID-19–related septic shock refractory to vasopressors and fluids
      • Hydrocortisone ^c41
        • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 8 hours or 160 mg/day IV in 2 to 4 divided doses for up to 10 days or until hospital discharge, whichever comes first.
  • Janus kinase inhibitors
    • Baricitinib ^c42
      • Baricitinib Oral tablet; Children 2 to 8 years†: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. 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. 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Tofacitinib
      • Tofacitinib Oral tablet; Adults: 10 mg PO twice daily for up to 14 days or until hospital discharge, whichever comes first. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Interleukin-6 receptor inhibitors
    • Sarilumab ^c43
      • Sarilumab Solution for injection; Adults: 400 mg IV once.
    • Tocilizumab ^c44
      • Tocilizumab Solution for injection; Children and Adolescents 2 to 17 years weighing less than 30 kg†: 12 mg/kg/dose IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
      • Tocilizumab Solution for injection; Children and Adolescents 2 to 17 years weighing 30 kg or more†: 8 mg/kg/dose (Max: 800 mg) IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
      • Tocilizumab Solution for injection; Adults: 8 mg/kg/dose (Max: 800 mg) IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
  • Complement factor 5a inhibitor
    • Vilobelimab
      • Vilobelimab Solution for injection; Adults: 800 mg IV for up to 6 doses while hospitalized. Give first dose within 48 hours of intubation (Day 1), followed by doses on Days 2, 4, 8, 15, and 22.
  • Cytotoxic T-lymphocyte–associated antigen 4 agonist
    • Abatacept
      • Abatacept Solution for injection; Adults: 10 mg/kg/dose (Max: 1,000 mg) IV once, using actual body weight.
  • Tumor necrosis factor inhibitor
    • Infliximab
      • Infliximab (Murine) Solution for injection; Adults: 5 mg/kg/dose once, using actual body weight.
• Antivirals
  • Remdesivir
    • Remdesivir Solution for injection; Adults: 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; Children and Adolescents: 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.
• Vasopressors
  • Norepinephrine ^c45
    • Norepinephrine Bitartrate Solution for injection; Neonates†: 0.1 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate dose every 30 minutes based on 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, initially. Titrate dose as needed based on 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 dose by 0.02 mcg/kg/minute (or more in emergency cases) every 2 to 5 minutes based on clinical response. Usual dose: 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 ^c46
    • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate dose as needed based on clinical response.
    • Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate dose by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes based on clinical response.
  • Vasopressin ^c47
    • Vasopressin Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 8 milliunits/kg/minute continuous IV infusion; reserve for catecholamine-resistant shock, dosage range not well established.
    • 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.
• Inotropes
  • Dobutamine ^c48
    • Dobutamine Hydrochloride Solution for injection; Neonates: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion, initially. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute.
    • Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion, initially. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute.
    • Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
• Anticoagulants
  • Dalteparin
    • For thrombosis prophylaxis
      • Dalteparin Sodium (Porcine) Solution for injection; Infants†, Children†, and Adolescents†: 75 to 125 units/kg/dose (Max: 5,000 units/dose) subcutaneously once daily; adjust dose to maintain an anti-factor Xa concentration of 0.2 to 0.4 units/mL.
      • Dalteparin Sodium (Porcine) Solution for injection; Adults with severely restricted mobility during acute illness: 5,000 units subcutaneously once daily.
    • For treatment of suspected or proven thromboembolism
      • Dalteparin Sodium (Porcine) Solution for injection; Infants and Children 1 to 23 months: 150 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
      • Dalteparin Sodium (Porcine) Solution for injection; Children 2 to 7 years: 125 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
      • Dalteparin Sodium (Porcine) Solution for injection; Children and Adolescents 8 to 17 years: 100 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
      • Dalteparin Sodium (Porcine) Solution for injection; Adults: 100 units/kg/dose subcutaneously every 12 hours or 200 units/kg/dose subcutaneously once daily. Max: 18,000 units/day.
  • Enoxaparin ^c49
    • For thrombosis prophylaxis
      • Enoxaparin Sodium (Porcine) Solution for injection; Infants† 1 month: 0.75 mg/kg/dose 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/dose 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; Adults with severely restricted mobility during acute illness: 40 mg subcutaneously once daily.
    • For treatment of suspected or proven thromboembolism
      • 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.
• Sedatives (for mechanically ventilated patients)
  • Dexmedetomidine ^c50
    • Dexmedetomidine Hydrochloride Solution for injection; Term Neonates†: 0.05 to 0.5 mcg/kg/dose IV loading dose, followed by 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Titrate dose as needed 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 loading dose, followed by 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate dose 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 loading dose, followed by 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate dose 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 loading dose, followed by 0.2 to 0.7 mcg/kg/hour continuous IV infusion, initially. Titrate dose until target level of sedation is attained. Loading doses are often bypassed. Max: 1.5 mcg/kg/hour.
  • Propofol ^c51
    • 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 ^c52
    • Intermittent IV dosage (preferred over continuous infusion, where clinically possible)
      • Rocuronium Bromide Solution for injection; Neonates: 0.45 to 0.6 mg/kg/dose 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/dose 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/dose 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 IV infusion dosage
      • Rocuronium Bromide Solution for injection; Neonates: 0.6 mg/kg/dose 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/dose 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/dose 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 is critical for treatment ^c53

WHO,^r4NIH,^r5 and Surviving Sepsis Campaign^r6 provide specific guidance for oxygenation, ventilation, hemodynamics, fluid management, and prevention of complications in COVID-19

• Oxygenation and ventilation ^c54c55
  • Begin supplemental oxygen therapy when SpO₂ (peripheral oxygen saturation) falls below 90% to 92% for nonpregnant patients, or below 95% for pregnant patients
    • 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 ^r4
      • 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) ^r5
      • 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) ^r4c56
  • Use high-flow nasal cannula for patients with persistent respiratory failure despite conventional oxygen therapy ^r5r87c57c58
    • Initiate high-flow nasal cannula over noninvasive positive pressure ventilation for adults; 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 ^r5r6
    • 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 ^r5
    • WHO guideline recommends high-flow oxygen, CPAP (continuous positive airway pressure), or other noninvasive ventilation 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 ^r4
  • Use noninvasive positive pressure ventilation, such as CPAP and BPAP, 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 ^r4
    • Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended ^r4r5
    • Guidelines do not advise on method of delivery (eg, helmet, face mask) for noninvasive ventilation, owing to limited evidence comparing one with another
  • Use awake prone positioning to improve oxygenation in patients requiring high-flow oxygen or noninvasive ventilation ^r4r5c59
    • Do not attempt prone positioning 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 ^r5
    • The optimal duration of prone positioning is not known; limited evidence suggests more significant protective effect on mechanical ventilation and mortality for patients spending 8 hours per day in prone position ^r88
  • Utilize mechanical ventilation 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) ^c60
    • Categorization of degree of acute respiratory distress syndrome in adults, by PaO₂/FIO₂ ratio (mm Hg): ^r4
      • 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: ^r4
      • 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 ^r5r6
      • 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 ^r4
      • For children, cuffed endotracheal tubes are recommended over uncuffed ^r5
    • Choose 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 ^r5r6r68
      • 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) ^r4r5
    • Select 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) ^{r4r5r6c61d7d7d7d7d7d7d7d7}
    • In children, allow permissive hypercapnia (pH 7.2 to 7.3) 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) ^r5
    • For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, use prone positioning for 12 to 16 hours/day ^r4r5r6c62
      • Lateral decubitus position may be used for pregnant patients, especially in the third trimester ^r4
    • 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 ^r71r89
      • Select intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion ^r4r5r6c63c64
        • 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 ^r5r6
    • 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 ^r5r6
    • 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)
      • Current evidence does not reveal whether early tracheostomy offers any benefit or harm compared with late tracheostomy ^r90
  • Consider extracorporeal membrane oxygenation if all other measures have not alleviated refractory hypoxemia ^r4r6r14c65
    • 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
    • Limited evidence suggests that extracorporeal membrane oxygenation may reduce mortality, although bleeding complications are high ^r4r91
  • Evidence is insufficient to recommend for or against high frequency oscillatory ventilation in children with severe acute respiratory distress syndrome and refractory hypoxemia ^r5
• Fluid management
  • Avoid overhydration, which may precipitate or exacerbate acute respiratory distress syndrome; use conservative rather than aggressive fluid management ^r4r5r6
  • 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) ^r4r5
    • 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 ^r92
    • Physical examination findings may be less accurate predictors of fluid responsiveness ^r92
    • Based on non–COVID-19 patient data, early lactate clearance–guided resuscitation may be beneficial compared with central venous oxygen saturation–guided therapy ^r5
  • To monitor resuscitation in children, a combination of serial clinical assessments, cardiac ultrasonography or echocardiography, and/or laboratory markers (including lactate levels) is recommended ^r5
  • In patients with shock:
    • Choose crystalloids for resuscitation over starches, gelatins, or albumin; whether use of balanced crystalloids is superior to normal saline is unknown ^r4r5
      • Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hg^r6 (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

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 ^r39c67c68
  • For patients with immunocompromise 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 ^r5
  • 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 ^r5

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 ^r5r93r94
  • 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 ^r5r93r94
  • COVID-19 in pregnancy is associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy ^r5r93r94
  • 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 ^r5
• Pediatric patients
  • Evidence to guide treatment in pediatric populations is more limited than for adults ^r5
  • General management of critically ill children is also based on guidance for non-COVID critical illness, such as Surviving Sepsis Campaign septic shock guideline,^r70Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children,^r71 and Pediatric Acute Lung Injury Consensus Conference recommendations^r72