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Dec.05.2022

COVID-19 Critical Care

Synopsis

Key Points

  • COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
  • About 2% to 5% of diagnosed cases require critical care to manage severe manifestations and complications. Among patients with COVID-19 who are critically ill, mortality rates of 34% to 36% are reported r1r2r3r4
  • Intensive supportive care remains the cornerstone of care in critically ill patients; it includes oxygenation and ventilation strategies, hemodynamic control, conservative fluid administration, and prevention of complications such as thromboembolic events
  • In patients with increasing hypoxemia, high-flow nasal oxygen or noninvasive ventilation are advised but should not delay intubation in those with indications for mechanical ventilation r4r5r6r7
  • Pharmacologic support may be necessary in patients with shock whose hemodynamic parameters do not respond to fluids and oxygen; most guidelines favor norepinephrine as the initial agent for adults, and epinephrine in children r4r6r7
  • Corticosteroids and immunomodulators are the primary drug treatments for critically ill patients, with use of remdesivir in some patients
  • The most common complications are acute respiratory distress syndrome, shock, acute cardiac injury, acute kidney dysfunction, and thrombotic events (both venous and arterial) r5
  • In the critical care setting, infection control strategies are essential to prevent infection of staff and other patients, with most guidelines recommending standard, contact, and airborne precautions

Urgent Action

  • Patients with respiratory distress require prompt administration of supplemental oxygen; patients with respiratory failure require intubation and mechanical ventilation
  • Patients in shock require urgent but conservative fluid resuscitation with assessment of fluid responsiveness and addition of vasopressors as needed

Pitfalls

  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Terminology

Clinical Clarification

  • COVID-19 (coronavirus disease 2019) is a systemic infection with a predilection for the respiratory system; it is caused by a newly recognized coronavirus, SARS-CoV-2 r8d1d1d1d1d1d1d1d1
    • SARS-CoV-2 spread rapidly from the point of origin in China, and COVID-19 was officially declared by WHO to be a pandemic on March 11, 2020
  • Illness ranges in severity from asymptomatic or mild to severe; about 2% to 5% of diagnosed cases require critical care to manage severe manifestations and complications, including acute respiratory distress syndrome, myocardial dysfunction, and shock r4
  • Most patients with severe COVID-19 seem to have a bimodal illness, where there is initial improvement before worsening with severe or critical illness. This may be related to the immunologic role in the sepsis seen with COVID-19
  • Among ICU patients with COVID-19, estimated mortality rate is 34% to 36% r1r2r3
  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Classification

  • Pathogen is a betacoronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) r9
    • Classified as a member of the species Severe acute respiratory syndrome–related coronavirusr10
    • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) r10
  • Variants
    • Since late 2020, variants with potential impact on transmission, clinical disease, and immune protection have been recognized r11
      • CDC classifies them as variants of concern, variants being monitored, or variants of interest; the category of variants of high consequence exists in reserve, in case of future need r12
        • Classification is based on potential for increased transmissibility, greater severity of disease, reduction in protective effect of antibodies generated by previous disease or vaccination, reduced efficacy of available treatments or public health countermeasures, or reduced sensitivity of testing modalities
    • CDC COVID Data Tracker maintains information about geographical distribution of variants; at this time, circulating virus in the United States is Omicron variant, predominantly Omicron subvariant BA.5 r13
      • Omicron (B.1.1.529 and BA lineages): first detected in South Africa; the dominant variant in the United States and across the globe r11r13
        • More easily transmitted than other variants, and less susceptible to certain monoclonal antibody treatments; vaccination remains effective against hospitalization and death r4r12

Diagnosis

Clinical Presentation

History

  • Incubation period is typically within 14 days of exposure, and within 5 days in most patients. Incubation for more than 14 days occurs in a small percentage of patients r14r15
    • Patients may or may not report close contact with an infected person; the high transmissibility of the Omicron variant contributes to the number of cases with unknown exposure history
  • In symptomatic patients, illness may evolve over the course of a week or longer, beginning with mild symptoms that progress in some cases to the point of respiratory distress and shock r16
    • Median time from symptom onset to pneumonia is 5 days; time to severe hypoxemia is 7 to 12 days r5
  • The most common complaints in unvaccinated people are fever/chills and cough, which may or may not be productive r16r17r18
    • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) r16
    • Myalgia, headache, and fatigue are common; fatigue may be profound r16r18
    • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections r18
    • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections r16r18
    • Lack of smell (anosmia) and lack of taste (ageusia) are less common but highly suggestive r18r19r20
  • When COVID-19 is acquired after vaccination, a shift in the most common symptoms has been reported: rhinorrhea, headache, sneezing, sore throat, and persistent cough are most prominent, whereas shortness of breath and fever are less common than in unvaccinated people r21
  • Patients with moderate to severe disease often complain of dyspnea;r16 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnear22r18r23
    • Hemoptysis has been reported in a small percentage of patients r16
    • Pleuritic chest pain has been reported r14
  • 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 r24
      • It is unclear whether these symptoms have shifted significantly with vaccination, because among populations with access to vaccination, many who progress to severe or critical illness are unvaccinated r25

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 (eg, pulses, blood pressure)
    • Clinicians should be aware of the COVID-19–related phenomenon of silent (or "happy") hypoxemia: absence of signs of respiratory distress may be misleading r22r23c7
    • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry) r6
      • Pulse oximetry has been demonstrated to be less effective in patients with darker skin tones of all ages, with risk of occult hypoxemia being highest in Black patients (occult hypoxemia defined as arterial oxygen saturation less than 88% with concurrent pulse oximetry reading of 92% or more) r26r27r28r29
    • Tachyarrhythmias may be noted on auscultation or cardiac monitor r30c8
  • 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 r16r21c9
  • Conjunctival secretions, injection, and chemosis have been reported r31
  • Signs of arterial or deep venous thrombosis may be detected
    • Large-vessel stroke with associated neurologic deficit has been described as the presenting clinical event r32c10c11
  • Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign r33c12c13c14
  • Patients may be agitated, confused, or poorly responsive r33c15c16
  • A variety of skin changes have been described, including purpurar35 and petechiaer36; vesicularr37 and nonspecific erythematous exanthemsr38 typical of viral infections; and acral lesionsr39r40 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 r34c17c18c19
  • Hypotension, tachycardia, and cool/clammy extremities suggest shock c20c21c22
    • In children, manifestations of shock include: r6
      • Hypotension (systolic blood pressure less than 5th percentile or 2 standard deviations below the lower reference limit for age)
      • Altered mental status c23
      • 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) c24
      • Prolonged capillary refill (more than 2 seconds) c25
      • Weak pulse, or warm vasodilation and bounding pulses
      • Tachypnea c26
      • Mottled or cool skin, petechiae, or purpura c27c28c29
      • Oliguria c30
      • Hyperthermia or hypothermia c31c32

Causes and Risk Factors

Causes

  • Infection due to SARS-CoV-2 c33
    • Person to person transmission has been documentedr14 and occurs through exposure to infectious respiratory fluids (droplet and aerosols of various sizes) through inhalation, direct contact of fluids with mucous membranes (splashes or sprays, such as being coughed on), or touching mucous membranes with hands contaminated by respiratory fluids r41
      • Highest risk of exposure appears to be contact within 6 feet, but transmission may occur at farther than 6 feet; factors that increase risk of transmission include poor ventilation, prolonged contact, and/or increased exhalation of the infectious person (such as from singing or exercise) r41
      • Infection through contact with infected surfaces and fomites is possible but is not the primary mode of transmission r41
    • Many animals (eg, pets, livestock, wildlife) may acquire SARS-CoV-2 from humans or from one another, and cases of animal to human transmission have been reported. The extent to which humans may acquire infection from animals is low, to date r42c34
    • There is currently no evidence for transmission via food or water

Risk factors and/or associations

Age
  • All age groups are susceptible to COVID-19, but the risk of severe disease and death increases with age r4
    • In data from the United States, those aged 85 years or older have 10 times the risk of hospitalization and 330 times the risk of death compared with persons aged 18 to 29 years r43
    • Age distribution of cases has shifted substantially during the pandemic, as vaccinations and public health responses have changed
      • Despite the change in case rates in the United States, those aged 75 years or older, 65 to 74 years, and 50 to 64 years have remained the age groups with the most deaths per 100,000 population throughout the pandemic r44
        • Approximately 76% of the total mortality due to COVID-19 in the United States is among those aged 65 years or older
        • Even though age confers significantly higher risk, a substantial number of deaths (over 263,000 deaths as of September 2022) have occurred in those younger than 65 years
Sex
  • Overall, where sex or gender data are available, it appears that females are more often affected, but disease is more severe in males r44
    • Male sex may be a risk factor for severe disease; in a series of 5700 hospitalized patients with COVID-19, 60.3% were male; among ICU patients, 66.5% were male r45c35
Ethnicity/race
  • In the United States, persons in racial and ethnic minority groups, including Black, Hispanic, and Native American populations, have been disproportionately affected by COVID-19, including increased risk of infection, severe disease, and death; this risk is mediated through complex inequities and not genetic or biologic factors r46
  • Similarly, in the United Kingdom, Black people, those with Asian ethnicity, and other ethnic groups have had increased disease severity and mortality compared with White people r47
Other risk factors/associations
  • Various underlying medical conditions have been associated with increased risk for severe disease, and many conditions are under investigation r48
  • Conditions which have been associated with higher risk for severe outcome (based on systematic review or meta-analysis): r48
    • Asthma
    • Cerebrovascular disease
    • Chronic kidney disease
    • Specific chronic lung diseases: interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, chronic obstructive pulmonary disease
    • Specific chronic liver diseases: cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis
    • Serious cardiac conditions (eg, heart failure, coronary artery disease, cardiomyopathy)
    • Cystic fibrosis
    • Diabetes mellitus, type 1 and type 2
    • Malignancy
    • Pregnancy and recent pregnancy
    • Obesity (BMI of 30 kg/m² or higher, or 95th percentile or more in children)
    • Smoking, current and former
    • Specific mental health disorders: mood disorders, including depression and anxiety; schizophrenia spectrum disorders
    • Disabilities including attention-deficit/hyperactivity disorder, cerebral palsy, congenital malformations, intellectual and developmental disabilities, learning disabilities, spinal cord injuries, and limitations of activities of daily living
    • Dementia
    • HIV disease
    • Primary immunodeficiencies and use of immunosuppressive medications including glucocorticoids
    • Solid organ or blood cell transplant
    • Tuberculosis
    • Physical inactivity
  • Conditions which are suggestive of higher risk for severe outcomes (based on cohort, case-control, or cross-sectional studies): r48
    • Overweight (BMI more than 25 kg/m² but less than 30 kg/m²)
    • Sickle cell disease
    • Substance use disorders
    • Thalassemia
  • Conditions which might be associated with higher risk for severe disease (based on mixed evidence): r48
    • Hypertension
    • Hepatitis B
    • Hepatitis C
    • Bronchopulmonary dysplasia
    • Alpha₁-antitrypsin deficiency
  • However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities r48
  • Residents of nursing homes and long-term care facilities are at high risk for acquiring infection and for severe disease, probably owing to a combination of heightened transmission in a close-quarters community and prevalence of compromised health status r4
  • In areas where vaccines are widely available, being unvaccinated (compared with being fully vaccinated) confers substantially higher risk for infection, hospitalization, and death r25

Diagnostic Procedures

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 r4r49
    • Upper respiratory tract samples include nasopharyngeal, nasal midturbinate, anterior nasal, nasopharyngeal wash or aspirate, oropharyngeal, or saliva specimens
      • Nasopharyngeal samples are preferred, with anterior nares, midturbinate, or oropharyngeal areas being common alternative sites r4
    • 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 r50
    • CDC provides instructions for collection and handling of specimens. Commercial, institutional, and public health laboratories may have different requirements and should be consulted for questions about collection site, swabs, transport media, or handling r50
  • Serologic testing is not recommended for routine use in diagnosis, but it may be useful in the diagnosis of MIS-C or MIS-A (ie, multisystem inflammatory syndrome in children or adults, respectively) because patients might present as critically ill with no prior diagnosis of COVID-19 r4
  • Other testing should be performed concurrently, if indicated, to identify alternative pathogens (eg, influenza, respiratory syncytial, and other viruses; bacterial pathogens) r6d2d2d2d2d2d2d2d2
    • Coinfections have been reported, but the overall frequency is unknown; bacterial coinfection at presentation appears to be uncommon, from 0 to 6% r4r51r52
    • Circulation of common respiratory viruses has been altered by public health measures to prevent COVID-19; be alert for off-season circulation and for increases in transmission when COVID-19 mitigation measures are relaxed r53
    • Influenza may be clinically indistinguishable from COVID-19, and coinfection can occur r4r54
      • 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 r17r55
    • 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 r56
    • 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 r17r56c36c37
      • 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) r56
  • 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) r6d3d3d3d3d3d3d3d3
  • 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 r5r49
    • 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 r4
  • Antigen tests are also available for use in diagnosis, and they have the advantage of rapid turnaround r57
    • 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 (preferably within 2 days) 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, but a pattern of typical abnormalities is known
    • In reports of patients with varying severity of illness: r14r16r17
      • Abnormalities of blood cell counts are common: leukopenia, relative lymphopenia, anemia, thrombocytopenia, and thrombocytosis r14r16r17
      • Laboratory indicators of inflammation, such as acute phase reactant levels, are frequently elevated: C-reactive protein, erythrocyte sedimentation rate, ferritin, fibrinogen
      • COVID-19–induced abnormal coagulability may be reflected in prolonged prothrombin time, elevated D-dimer level, or elevated fibrinogen level r14r16r17r58
      • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common c38
      • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection r16
      • Troponin or B-type natriuretic peptide levels are often elevated (not necessarily signifying complete myocardial infarction or heart failure) and are correlated with mortality r5r59r60
    • Information from patients with severe or critical illness similarly shows common patterns r24
      • 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 r61
      • Lactate level of 2 mmol/L or higher suggests presence of septic shock r6
      • 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) r60

Imaging

  • Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 r55
  • 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 r9r14r16r17r62c39
    • 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 r63
  • CT appears to be more sensitiver64r56r55 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19r65
    • Certain chest CT findings may 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 r66
  • Bedside ultrasonography is widely used to monitor progression of pulmonary infiltrates, and to assess cardiac function and fluid status; it may also be used to detect deep vein thrombosis or vascular catheter thrombosis, which appear to be common in patients with COVID-19 r5r67

Differential Diagnosis

Most common

  • Influenza c40d4d4d4d4d4d4d4d4
    • 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
      • Mitigation measures for COVID-19 may alter the timing and amount of circulating respiratory viruses, including influenza virus r53
    • 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; additionally, coinfection can occur. Therefore, 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 r4r54
      • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
  • Other viral pneumonias c41d2d2d2d2d2d2d2d2
    • 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)
    • As with influenza virus, timing and amount of circulating respiratory viruses may be altered by COVID-19 mitigation measures r53
  • Bacterial pneumonia c42d2d2d2d2d2d2d2d2
    • 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

Treatment

Goals

  • Ensure adequate oxygenation and hemodynamic support during acute phase of illness
  • Prevent complications where possible (eg, thromboses); monitor for and treat unavoidable complications (eg, myocardial dysfunction)

Disposition

Admission criteria

Criteria for ICU admission
  • NIH COVID-19 treatment guidelines describe the spectrum of clinical illness as asymptomatic/presymptomatic, mild, moderate, severe, or critical r4
    • Severe illness is defined as SpO₂ less than 94% (room air, sea level), PaO₂/FIO₂ ratio less than 300 mm Hg, respiratory rate more than 30 breaths per minute, or lung infiltrates more than 50%
      • Rapid clinical deterioration is possible; thus, admission to ICU may be indicated if needed for close monitoring or in patients with risk factors for more severe disease, where resources allow
    • Critical illness is defined by presence of respiratory failure, shock, or multiple organ dysfunction
  • WHO guidelines describe the spectrum of clinical illness as mild, moderate, severe, or critical r6
    • Severe illness is defined by presence of any of the following:
      • Oxygen saturation less than 90% (room air)
      • Respiratory rate more than 30 breaths per minute (or age-appropriate tachypnea equivalent)
      • Signs of severe respiratory distress
        • In children, signs may include accessory muscle use, inability to complete full sentences, very severe chest wall retractions, grunting, central cyanosis, or presence of any other pediatric danger signs (eg, inability to breastfeed or drink, lethargy, reduced level of consciousness)
    • Critical illness is defined by the criteria for acute respiratory distress syndrome, sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation (invasive or noninvasive) or vasopressor therapy

Recommendations for specialist referral

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

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) r6

  • Appropriate testing (eg, blood cultures in those with severe or critical illness) and treatment for other pathogens (eg, influenza, malaria) should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r6
    • Evidence does not support routine use of antibiotics for all patients with COVID-19, especially in those with low suspicion of bacterial infection. If empiric coverage is begun, use antibiotic de-escalation protocols (eg, daily reassessment of need for antibiotics) when patient's clinical status has been stabilized and there is no evidence of bacterial coinfection r4r6
  • 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 r4r74r75r78
    • Where specified, heparins are preferred over oral anticoagulants and low-molecular-weight heparin is preferred over unfractionated heparin r4r6r7r76
    • 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 r4r6
    • 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,r7NIH,r4 and WHOr6 treatment guidelines provide guidance specific to treatment of shock in patients with COVID-19 d3d3d3d3d3d3d3d3
    • WHO definitions for septic shock: r6
      • Adults: suspected or confirmed infection; 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 r4r7
      • 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) r4r7
        • 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 r6r81
    • 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 r7
    • 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 r7
    • 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 r4r6
      • 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 r4r7r71r72

  • 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 r7
  • 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 r4r91
  • 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 r4r7r71r72
    • 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 one 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, then 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 2.5 mcg/kg/hour.
      • Dexmedetomidine Hydrochloride Solution for injection; Infants†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
      • Dexmedetomidine Hydrochloride Solution for injection; Children† and Adolescents†: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
      • Dexmedetomidine Hydrochloride Solution for injection; Adults: 1 mcg/kg IV, then 0.2 to 0.7 mcg/kg/hour continuous IV infusion, initially. Titrate until target level of sedation is attained. Loading doses are often bypassed. Max: 1.5 mcg/kg/hour.
    • Propofol 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,r6NIH,r4 and Surviving Sepsis Campaignr7 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 r6
        • 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 r7
    • 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) r6c62
    • 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 r4r7
      • 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 r6
    • Noninvasive positive pressure ventilation, such as CPAP and BPAP, may be used in monitored settings with immediate availability of endotracheal intubation if needed; if indications for endotracheal intubation are already present, high-flow nasal cannula or noninvasive positive pressure ventilation should not be used to delay needed mechanical ventilation r6
      • Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended r4r6
      • 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): r6
        • 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: r6
        • 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 r4r7
        • WHO additionally recommends against disconnection from ventilators, which risks exposing health care workers, and suggests consideration of airway clearance techniques for excessive secretions only with strict infection control practices r6
        • 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 r4r7r71
        • 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) r4r6
      • 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 r6
      • Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate 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 r4r7
      • 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 r4r7
      • 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) r4r6
      • 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: r6
        • Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hgr7 (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 r7
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 childrenr99

Monitoring

  • Standard critical care monitoring, including oxygen saturation and hemodynamic measures, is appropriate c75c76
  • Patients who are undergoing a trial of high-flow oxygen or noninvasive ventilation require especially close attention pending sustained improvement or decision to intubate

Complications and Prognosis

Complications

  • Among ICU patients, many complications have been noted:
    • Acute respiratory distress syndrome (60% to 70%) r5c77d5d5d5d5d5d5d5d5
      • In representative studies of critically ill patients in the United States, 68% to 79% required mechanical ventilation, 8% to 15% required tracheostomy, and about 3% required extracorporeal membrane oxygenation r104r105
      • In a meta-analysis covering more than 58,000 patients, 6.9% received extracorporeal membrane oxygenation; in-hospital mortality of such patients was 39% r106
    • Shock (30%) r5c78d3d3d3d3d3d3d3d3
      • Need for vasopressors ranged from 26% to 66% in 2 hospital systems in the United States r104
    • Acute cardiac injury, including cardiomyopathy, arrhythmias, and sudden cardiac death c79c80d6d6d6d6d6d6d6d6
      • Myocardial injury (initially reported up to 30%; 8% had myocardial infarction in another study) and arrhythmias (between 18% and 44%) r5r63
    • Acute kidney injury (10% to 30%) r5r63c81d7d7d7d7d7d7d7d7
      • Between 9% and 31% of critically ill patients (without preexisting renal disease) required acute renal replacement therapy in US samples r104
    • Altered mental status (33% of patients in one US hospital system, almost 15% in another study) r63r105
    • Liver dysfunction
    • Thromboembolic events are commonly reported (eg, pulmonary embolism, deep venous thrombosis, catheter-related thrombosis, ischemic stroke, arterial thromboembolism); one series of 184 ICU patients in the Netherlands found a cumulative adjusted incidence of 31% to 49%, of which pulmonary embolism was the most common (65 patients) r63r107
    • Secondary infections, including ventilator-associated pneumonia and catheter infections, appear to be less common than initially thought r4c82c83
      • In a series of more than 700 critically ill patients in Italy, 46% had hospital-acquired infections r108
      • In a meta-analysis of more than 3000 patients, bacterial coinfection was estimated at 6.9% overall, and slightly higher in critically ill patients r109
    • Multiorgan failure has been reported
  • Multisystem inflammatory syndrome (both MIS-C and MIS-A, in children or adults, respectively) is associated with COVID-19 d8
    • Case definition in children (MIS-C): a person younger than 21 years with fever, laboratory evidence of inflammation, and clinically severe illness requiring hospitalization, with involvement of 2 or more organ systems; plus no alternative diagnosis; plus current or recent COVID-19 or exposure within the past 4 weeks r110
      • Fever may be documented or reported subjectively, lasting 24 hours or more
      • Laboratory parameters include elevated C-reactive protein level and/or erythrocyte sedimentation rate; elevated levels of acute phase reactants or related proteins (eg, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, and/or interleukin-6); elevated neutrophil count; reduced lymphocyte count; and/or low albumin level
      • Organ systems involved may include cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic
      • Patients may meet partial or full criteria for Kawasaki disease but regardless should be reported if they meet case definition of MIS-C
    • Case definition in adults (MIS-A): a person aged 21 years or older with hospitalization for 24 hours or more, or an illness resulting in death, with clinical and laboratory criteria below, and with no alternative diagnosis: r111
      • Clinical: fever for 24 hours or more, and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion:
        • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash; and nonpurulent conjunctivitis
        • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
      • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive test result for SARS-CoV-2 (from polymerase chain reaction assay, antigen test, or serology)
    • Common features in children include persistent fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions, hypotension, and shock; however, a wide variety of symptoms and signs have been reported, including headache, swelling of hands and feet, lymphadenopathy, and elevated troponin or B-type natriuretic peptide levels r110
      • MIS-C may be difficult to distinguish from Kawasaki disease, toxic shock syndrome, and bacterial sepsis
      • NIH and American College of Rheumatology offer guidance on MIS-C (with some applicability to MIS-A) r4r112
    • In a systematic review covering 221 patients with MIS-A, the age range was 19 to 34 years; 70% of patients were male; and Black and Hispanic patients were disproportionately affected r113
      • Common features included fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation
      • Median number of organ systems involved was 5
      • Most patients (57%) required ICU care, and 7% died
    • There are no guidelines specific for treatment of MIS-A; clinicians are applying information from MIS-C to the young adult population

Prognosis

  • Patients who require hospital admission often require prolonged inpatient stay (interquartile range in one series was 7 to 25 days), and resulting deconditioning may be profound r16r17r105
  • Laboratory markers associated with mortality include troponin, interleukin-6, estimated GFR, neutrophil to lymphocyte ratio, B-type natriuretic peptide, and D-dimer r60
  • Reported mortality rates in critically ill patients are highly variable depending on location and time (10% to 90%); reviews of intensive care admissions through June 2021 estimate mortality in the 34% to 36% range r1r2r3
    • Mortality rates decreased from early 2020 to late 2020, a finding attributed to improved knowledge of critical care in COVID-19 (including increased use of proning, noninvasive ventilation, and therapeutics) and different patient populations over time (eg, predominance of older patients earlier in the pandemic, compared with younger patients later) r2r3
    • Limited evidence from later in the pandemic indicates a plateau in improvement r1r3
  • Survivors of COVID-19 are reported to have increased risk of numerous sequelae; although even mild cases can result in long-term complications, many studies document an increasing risk based on disease severity
    • Up to 80% of patients may have symptoms consistent with post–intensive care syndrome 6 months after discharge from an ICU stay for COVID-19, as found in a study r114
      • In that study, substantial proportions of patients had difficulties with cognition (42%), physical functioning (55%), and mental health (eg, 33% with posttraumatic stress disorder, 42% with depression, 38% with anxiety); nearly half had difficulties in more than 1 domain r114
      • How those rates compare with post–intensive care syndrome rates for non–COVID-19 illnesses is not known; however, prepandemic estimates for post–intensive care complications vary by patient population (cognitive impairment, 30%-80% of patients; psychiatric illnesses, 8%-57% of patients; physical impairment, 25%-80% of patients) r115
    • Patients with severe or critical illness appear to be at increased risk for long COVID, persistent symptoms and prolonged recovery (variously defined as more than 4 weeks or more than 12 weeks from onset of COVID-19). This syndrome is also known as postacute COVID-19, chronic COVID, or PASC (postacute sequelae of SARS-CoV-2 infection) r116
      • Common symptoms include fatigue, postexertional malaise, shortness of breath, chest pain, cognitive dysfunction, headache, and abdominal pain; numerous symptoms have been described
      • Research is ongoing to determine causes, prevalence, and treatment
    • Many studies have reported decreased quality of life for up to 12 months after COVID-19 diagnosis, with lower quality of life in those with ICU stays, prolonged ICU stays, and mechanical ventilation r117
      • Although one study reported that overall health-related quality of life measures for patients 6 months after ICU discharge were comparable to those in the US population as a whole for most domains (except physical function), almost one-quarter of the patients had substantial decreases in multiple domains, including anxiety, fatigue, pain, depression, social function, and physical function r118
    • Studies have reported increased risk of cardiovascular adverse outcomes, new-onset diabetes, respiratory adverse outcomes, and death up to 1 year after diagnosis of COVID-19 (with nearly 80% of deaths due to noncardiovascular, nonrespiratory causes) r119r120r121r122r123r124

Screening and Prevention

Screening c84

Prevention

  • Prevention of COVID-19 infection by vaccination remains the most effective way of preventing critical illness d1d1d1d1d1d1d1d1
  • In the critical care setting, infection control strategies are essential to prevent infection of staff and other patients (ie, standard, contact, and droplet or airborne precautions as resources permit, with strict attention to proper donning and doffing of personal protective equipment) r73c85c86c87c88c89
    • Universal personal protective equipment in healthcare settings includes all standard precautions and universal masking for source control; additional eye protection and N95 or equivalent respirators are recommended in locations with substantial or high transmission, during aerosol-generating procedures, in specific units of the facility with higher risk for exposure, or if there is higher risk of transmission (eg, unvaccinated patients, poor ventilation)
    • Patients should be placed in a single room, with the door closed, and ideally 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)
    • Persons entering the room of SARS-CoV-2 positive or suspect patients should wear gloves, gowns, eye protection, and a respirator at least as effective as an N95
    • Source control should be applied whenever possible; this consists of a face mask or cloth covering for nonintubated patients and measures to reduce leakage around oxygen masks and from ventilator tubing
    • Limit transport of patient from the room (eg, for studies or procedures). Arrange for portable studies and procedures if feasible; during aerosol-generating procedures, limit number of workers in room to those necessary
    • Equipment used for patient care should be single use (disposable) or should be disinfected between patients
  • Criteria for discontinuation of isolation precautions vary depending on severity of illness. CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Patients with severe or critical illness, or those with immunocompromise, may shed replication-competent virus for longer duration than others (for whom 10 days of transmission-based precautions are recommended) r125
    • For patients with severe or critical illness the following criteria apply:
      • At least 10 days and up to 20 days have passed since symptom onset and
      • At least 24 hours have passed since last fever without use of antipyretics and
      • Symptoms have improved
    • For moderately or severely immunocompromised patients:
      • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result
        • Fever should be resolved at least 24 hours, without fever-reducing medicines
        • Symptoms should be improved, except that loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation
      • Consultation with an infectious disease specialist and/or serial testing may be used to determine the end of isolation
        • Negative results from 2 consecutive respiratory specimens collected at least 24 hours apart (total of 2 negative specimens) tested using an antigen test (or nucleic acid amplification test such as polymerase chain reaction, with caveat that such tests may detect noninfectious virus for a prolonged period)
        • Retesting for SARS-CoV-2 infection is suggested if symptoms worsen or return after ending isolation and precautions
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