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COVID-19 Critical Care

Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Dec.09.2024

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
Around 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% are reported ^r1^r2^r3
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 ^r4^r5
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 ^r4^r5^r6
Corticosteroids and immunomodulators are the primary drug treatments for critically ill patients
The most common complications are acute respiratory distress syndrome, shock, acute cardiac injury, acute kidney dysfunction, and thrombotic events (both venous and arterial) ^r4
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 recently recognized coronavirus, SARS-CoV-2, which has spread globally, causing a pandemic ^r7^d1^d1^d1^d1^d1^d1^d1^d1
Illness ranges in severity from asymptomatic or mild to severe; around 5% of diagnosed cases require critical care to manage severe manifestations and complications, including acute respiratory distress syndrome, myocardial dysfunction, and shock ^r4
Among ICU patients with COVID-19, estimated mortality rate is approximately 34% ^r2^r3
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 classification: SARS-CoV-2 is a betacoronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) ^r8
- Classified as a member of the species Severe acute respiratory syndrome–related coronavirus, designated SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)
- Variants
  - Since late 2020, numerous variants with potential impact on transmission, clinical disease, and immune protection have been recognized and tracked ^r9^r10
  - The Omicron variant (B.1.1.529 and descendant lineages) emerged in November 2021 in South Africa; since early 2022, is the only variant circulating in the United States and the world, with numerous lineages including many subvariants ^r9
Illness classification: illness may be classified as asymptomatic, mild, moderate, severe, or critical ^r4^r5
- Critical disease is defined by any complication that requires intensive care, such as respiratory failure, septic shock, or multiple organ dysfunction

Diagnosis

Clinical Presentation

History

Mean incubation period for Omicron variants is 3 days; incubation for more than 14 days occurs in a small percentage of patients ^r11
- Patients may or may not report close contact with an infected person; the high transmissibility of Omicron variants contributes to the number of cases with unknown exposure history
Critical illness typically develops 10 to 12 days from symptom onset ^r5
Common presenting complaints include fever, cough (which may or may not be productive), fatigue, anorexia, shortness of breath, myalgia, sore throat, nasal congestion, headache, nausea, vomiting, diarrhea, loss of smell or taste ^r4^r12^r13^r14^r15^r16
- Likelihood of certain symptoms has changed depending on variants and prior immunity due to vaccination and prior infection ^r17
  - Fever and shortness of breath are less common, while sore throat, rhinorrhea, nasal congestion, and sneezing are more common
Patients with moderate to severe disease often complain of dyspnea; however, some patients with severe hypoxemia do not perceive dyspnea ^r14^r18
- Hemoptysis has been reported in a small percentage of patients ^r14
- Pleuritic chest pain has been reported ^r19
Patients with severe or critical disease most commonly have pulmonary disease; however, cardiac, vascular, and neurologic manifestations may accompany pulmonary disease ^c1^c2^c3^c4
- The most common symptoms among severe or critically ill patients are fever, cough, dyspnea, chest tightness, and fatigue ^r20

Physical examination

Physical findings may include systemic, neurologic, dermatologic, gastrointestinal, or others, but clinicians should be particularly attuned to pulmonary and hemodynamic indicators of critical illness
- Patients with severe disease may appear quite ill, with tachypnea and labored respirations ^c5^c6
- Patients in apparent distress require immediate assessment of airway, breathing, and circulation
- Clinicians should be aware of the COVID-19–related phenomenon of silent (or "happy") hypoxemia: absence of signs of respiratory distress may be misleading ^r18^r21^c7
- Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry) ^r4
  - Pulse oximetry has been demonstrated to be less effective in patients with darker skin tones of all ages, with risk of occult hypoxemia (arterial oxygen saturation less than 88% with concurrent pulse oximetry reading of 92% or more) being highest in Black patients ^r22^r23^r24^r25
- Tachyarrhythmias may be noted on auscultation or cardiac monitor ^r26^c8
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 ^r14^r17^c9
Conjunctival secretions, injection, and chemosis have been reported ^r27
Signs of arterial or deep venous thrombosis may be detected (eg, stroke, pulmonary embolism, acute limb ischemia, deep venous thrombosis) ^r28^r29
Other reported neurologic findings in severe disease include hyperactive deep tendon reflexes, ankle clonus, and positive Babinski sign ^r30^c10^c11^c12
Patients may be agitated, confused, or poorly responsive ^r30^c13^c14
A variety of skin changes have been described, including purpura^r32 and petechiae^r33; vesicular^r34 and nonspecific erythematous exanthems^r35 typical of viral infections; and acral lesions^r36^r37 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 ^r31^c15^c16^c17
Hypotension, tachycardia, and cool/clammy extremities suggest shock ^c18^c19^c20
- In children, manifestations of shock include: ^r4
  - Hypotension (systolic blood pressure less than 5th percentile or 2 standard deviations below the lower reference limit for age)
  - Altered mental status ^c21
  - Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children) ^c22
  - Prolonged capillary refill (more than 2 seconds) ^c23
  - Weak pulse, or warm vasodilation and bounding pulses
  - Tachypnea ^c24
  - Mottled or cool skin, petechiae, or purpura ^c25^c26^c27
  - Oliguria ^c28
  - Hyperthermia or hypothermia ^c29^c30

Causes and Risk Factors

Causes

Infection due to SARS-CoV-2 ^c31
- Person to person transmission occurs primarily through exposure to infectious respiratory droplets and aerosols of various sizes (eg, inhalation, contact of mucous membranes) during close contact, but other modes are also possible: long-distance airborne transmission, transmission via infected surfaces and fomites, transmission from infected animals, in utero transmission, and transmission through nonrespiratory fluids ^r19^r38

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 ^r5
- For example, using data from the United States, compared with persons aged 18 to 29 years, those aged 75 to 84 years have 140 times the risk of death and those aged 85 years or older have 340 times the risk of death ^r39

Sex

Outside the earliest months of the pandemic, more hospitalizations (per 100,000 population) have occurred among females and more deaths among males in the United States; males in most parts of the world experienced higher mortality than females ^r40^r41^r42^r43

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 ^r5
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 ^r44

Other risk factors/associations

Numerous medical conditions are associated with higher risk for severe disease; CDC periodically updates a list based on evidence ^r39^d1
However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities ^r39^r45^r46
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 ^r39
Being unvaccinated (compared with being fully up to date) confers substantially higher risk for infection, hospitalization, and death, even among those with prior infection ^r39^r46^r47

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 ^r48
- Upper respiratory tract samples include nasopharyngeal, nasal midturbinate, anterior nasal, nasopharyngeal wash or aspirate, or oropharyngeal specimens
- Lower respiratory tract samples include bronchoalveolar lavage fluid, tracheal aspirate, pleural fluid, lung biopsy specimen, and sputum
- Care must be taken to minimize risks associated with aerosolization during specimen collection. Clinicians should not attempt to induce sputum, because the process may increase aerosolization and risk of transmission
- Commercial, institutional, and public health laboratories may have different requirements and should be consulted for questions about collection site, swabs, transport media, or handling
Serologic testing is not recommended for routine use in diagnosis, but it may be useful in the diagnosis of multisystem inflammatory syndrome because patients might present as critically ill with no prior diagnosis of COVID-19 ^r49^d2
Other testing should be performed concurrently, if indicated, to identify alternative pathogens (eg, influenza, respiratory syncytial, and other viruses; bacterial pathogens) ^r4^d3^d3^d3^d3^d3^d3^d3^d3
- Coinfections occur, but bacterial coinfection at presentation is uncommon, from 0 to 6% ^r5^r50^r51
- Influenza may be clinically indistinguishable from COVID-19, and coinfection occurs ^r5^r52
  - 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 ^r16^r53
- During the initial outbreak in Wuhan, China, CT scan was considered a surrogate diagnostic modality, based on the following factors: greater sensitivity compared with chest radiographs; the observation that CT may find characteristic abnormalities even in the absence of a positive molecular test result; the high prevalence of COVID-19 in that geographic area at the time; and the public health goal of detecting and isolating all infected persons ^r54
- In patients with moderate to severe disease, chest imaging is essential to document extent and severity of lung involvement and to serve as a baseline against which to compare should respiratory status worsen ^r16^r54^c32^c33
  - In patients with severe disease, CT may offer an advantage over plain radiographs in distinguishing progression of infection from heart failure due to myocarditis or from pulmonary embolism (both commonly associated with COVID-19) ^r54
Routine blood work should be ordered as appropriate for clinical management based on disease severity (eg, CBC, coagulation studies, chemistry panel including tests of hepatic and renal function and—if sepsis is suspected—lactate level and blood cultures) ^r4^d4^d4^d4^d4^d4^d4^d4^d4
Public health reporting requirements vary by jurisdiction; clinicians should consult local authorities. In some regions, public health authorities may be able to facilitate testing and undertake contact tracing and monitoring

Laboratory

Positive identification of SARS-CoV-2 RNA by nucleic acid amplification test is considered confirmation of diagnosis
- Reverse transcription polymerase chain reaction is the most common nucleic acid amplification test, but isothermal amplification methods are also available (eg, loop-mediated isothermal amplification)
- Laboratory-based polymerase chain reaction testing has high sensitivity and high specificity and is thus the reference standard. Point of care polymerase chain reaction testing has moderate sensitivity and high specificity ^r49
- False-negative results have been reported and may be due to a variety of factors, including inadequate sensitivity, poor or unrepresentative specimen, or time course of disease. Repeated sampling should be done if suspicion for COVID-19 is high and initial result is negative ^r49
Antigen tests are also available for use in diagnosis, and they have the advantage of rapid turnaround ^r49
- In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent
  - False-positive results are uncommon but do occur; they are more likely in a low-prevalence setting
  - False-negative results are common, depending on the test. A negative result may warrant retesting with polymerase chain reaction, or repeated antigen testing, if there is a high suspicion for infection based on clinical or epidemiologic indicators
For patients with severe or critical illness, antibody testing is most likely to be useful in the diagnosis of MIS-C or MIS-A (ie, multisystem inflammatory syndrome in children or adults, respectively); antibody testing is not indicated for routine diagnosis of COVID-19
Routine blood work is not diagnostic or predictive of disease severity, but information from patients with severe or critical illness shows common patterns ^r20^r55
- Most such patients have had elevated C-reactive protein and D-dimer levels (83.5% and 73.3%, respectively)
- Many such patients had WBC count abnormalities; most common were lymphopenia (70.3%), leukocytosis (21.7%), and leukopenia (18.2%), but 56.9% had normal WBC counts
- Other common findings were liver function test abnormalities (39.8%), elevated procalcitonin level (36.6%), and thrombocytopenia (19.0%)
  - Elevated levels of procalcitonin were associated with significantly higher risk of severe infection ^r56
- Lactate level of 2 mmol/L or higher suggests presence of septic shock ^r4
- Markers most associated with mortality are troponin levels, interleukin-6 level, estimated GFR, neutrophil to lymphocyte ratio, B-type natriuretic peptide level, and D-dimer level (elevated in patients who died compared with those who survived); also, urea and lactate dehydrogenase levels (lower in those who died compared with those who survived) ^r57

Imaging

Chest imaging (eg, plain radiography, CT, ultrasonography) is sensitive but not highly specific to COVID-19 ^r53
Chest imaging findings are abnormal in most patients; imaging usually shows bilateral involvement, varying from consolidation in more severely ill patients to ground-glass opacities in less severe and recovering pneumonia ^r14^r16^r19^r58^r59^c34
- CT scan findings in more than 40% of patients include ground-glass opacities (more than 80%), ground-glass opacities mixed with consolidation, pleural thickening, consolidation, interlobular septal thickening, and air bronchograms ^r60
CT is more sensitive^r54^r53^r61 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19^r62
- Certain chest CT findings suggest more severe disease: bronchial wall thickening, crazy paving (thickened interlobular septa and intralobular lines superimposed on diffuse ground-glass changes), linear opacity (typical of interstitial lung disease), and ground-glass opacity (hazy increased lung opacity which is less opaque than consolidation), as well as bilateral involvement compared with unilateral ^r63
Utilize bedside ultrasonography where appropriate to monitor progression of pulmonary infiltrates, to assess cardiac function and fluid status, and to detect deep vein thrombosis or vascular catheter thrombosis ^r5^r64
- Higher lung ultrasound scores are associated with decreasing PaO₂/FIO₂ ratio, and lung ultrasound scores were found to be higher in critically ill patients who died compared with survivors ^r65

Differential Diagnosis

Most common

Influenza ^c35^d5^d5^d5^d5^d5^d5^d5^d5
- Presentation includes fever, coryza, sore throat, dry cough, and myalgias; unlike COVID-19, influenza usually has fairly sudden onset
- Most cases are self-limited, but older adults (eg, those aged 65 years or older) or those with significant comorbidities often require hospitalization
- Usually occurs in winter months in temperate climates but is less seasonal in equatorial regions
- Patients with severe disease may have abnormal chest radiographic findings suggesting influenzal pneumonia or secondary bacterial pneumonia
- Positive result on rapid influenza diagnostic test confirms influenza diagnosis with high specificity during typical season; negative result does not rule out influenza
- Influenza may be clinically indistinguishable from COVID-19, and coinfection can occur ^r52
  - Test for both viruses when both are circulating in the community and positive results will change management (eg, in patients requiring hospitalization, or in patients who qualify for influenza antiviral treatment)
  - CDC recommends nucleic acid detection over antigen testing (multiplex or individual assays) for patients requiring hospitalization; use either nucleic acid or antigen testing when hospitalization is not required
Respiratory syncytial virus infection ^d6
- Presentation includes upper or lower respiratory tract symptoms, often clinically indistinguishable from other viruses
- Physical examination may include fever, tachypnea, crackles, wheezing, prolonged expiratory phase
- Diagnosis is often clinical, in the setting of typical symptoms during the usual season
- Differentiate with laboratory confirmation: polymerase chain reaction testing (single or multiplex assay, which may include SARS-CoV-2, influenza, and/or other common viral pathogens) or rapid antigen testing
MIS (multisystem inflammatory syndrome), in either children (MIS-C) or adults (MIS-A) ^d2
- Clinical presentation may be similar to that of acute, severe COVID-19
- Gastrointestinal, mucocutaneous, and cardiovascular involvement and shock are more common in MIS; respiratory involvement is more common in COVID-19
- Patients with MIS-C or MIS-A tend to be younger and have fewer comorbidities
- Differentiate with exposure history: COVID-19 onset is days after exposure; MIS occurs after weeks
- Laboratory tests may also differentiate: acute COVID-19 will more likely have positive antigen or nucleic acid amplification test result and moderately elevated inflammatory marker levels, whereas MIS will more likely have positive antibody test result and extremely elevated inflammatory marker levels
Bacterial pneumonia ^c36^d3^d3^d3^d3^d3^d3^d3^d3
- Presentation includes fever, cough, and dyspnea; pleuritic pain occurs in some cases
- Physical examination may find signs of consolidation (eg, dullness to percussion, auscultatory rales, tubular breath sounds)
- Chest radiography usually shows lobar consolidation or localized patchy infiltrate
- Sputum examination may find abundant polymorphonuclear leukocytes and a predominant bacterial organism
- Pneumococcal or legionella antigens may be detectable in urine; sputum culture may find those or other pathogens
Other viral pneumonias ^c37^d3^d3^d3^d3^d3^d3^d3^d3
- 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)

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 ^r5
- 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 ^r4
- 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

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

Treatment Options

Current standard treatment options include infection control measures, routine supportive care, and medications

Many drugs of different classes are being used under clinical trial and compassionate use protocols; consult ClinicalTrials.gov ^r66
Select drugs according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process ^r5
- Anti-inflammatory drugs and immunomodulators are more likely to be effective in critical illness, the stage characterized by a hyperinflammatory response
- In most cases, avoid antivirals, which will no longer be effective by the stage of critical illness
Given extensive potential medication interactions, clinicians are advised to use a drug interactions checker (eg, University of Liverpool) ^r67
Recommendations below summarize major treatment guidelines from NIH, WHO, Surviving Sepsis Campaign, and Infectious Diseases Society of America ^r4^r5^r6^r68^r69
- Evidence to support recommendations is found in each guideline
Evidence for treatment of critically ill pediatric patients is more limited than for adult patients, but guidance incorporates information from treatment of adults with COVID-19 and from treatment of children with other diseases, such as:
- Surviving Sepsis Campaign septic shock guideline ^r70
- Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children ^r71
- Pediatric Acute Lung Injury Consensus Conference recommendations ^r72

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 or cohorted with others with the same pathogen(s), 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 if resources do not allow, 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
- Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures ^r4

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) ^r4

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 ^r4
- 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 ^r4^r5
COVID-19 is associated with inflammation and prothrombotic state, including macrovascular and microvascular thromboembolism in both the venous and arterial vessels, as well as disseminated intravascular coagulation. Multiple guidelines address antithrombotic therapy, including NIH, International Society of Thrombosis and Haemostasis, American Society of Hematology, and American College of Chest Physicians. Recommendations for critically ill patients are summarized below: ^r4^r5^r6^r28^r74^r75^r76
- Use prophylactic dose over intermediate dose or therapeutic dose anticoagulation
  - Switch from therapeutic dose to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
- Avoid adding antiplatelet medications to prophylactic dose anticoagulation
- Select heparins (low-molecular-weight heparin preferred, or unfractionated heparin) over oral agents
- Continue anticoagulation or antiplatelet therapy for those on therapeutic doses for another indication
- Monitor 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
- Patients on extracorporeal membrane oxygenation or continuous renal replacement therapy should have the same anticoagulation as patients on those therapies without COVID-19
Surviving Sepsis Campaign, NIH, and WHO treatment guidelines provide guidance specific to treatment of shock in patients with COVID-19, summarized below: ^r4^r5^r6^d4^d4^d4^d4^d4^d4^d4^d4
- WHO definitions for septic shock: ^r4
  - 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
- Target a mean arterial pressure of 60 to 65 mm Hg as the hemodynamic goal for adults
- Choose conservative fluid resuscitation over liberal fluid strategy, owing to risk of volume overload
  - Utilize crystalloids for fluid resuscitation
    - Avoid starches, gelatins, and albumin
    - Some evidence suggests use of balanced crystalloids over normal saline for critically ill children ^r5
- Use vasopressors if fluid administration does not restore adequate perfusion
  - In adults for whom vasopressors are needed, begin with norepinephrine; use epinephrine or vasopressin as second line over dopamine if norepinephrine is unavailable
  - In children, use epinephrine or norepinephrine as first line agents ^r4^r5
    - Select a target mean arterial pressure either between the 5th and 50th percentile, or above the 50th percentile, for age ^r5^r70
    - Evidence is insufficient to recommend for or against use of inodilators (eg, dobutamine or milrinone) in children with cardiac dysfunction and hypoperfusion despite fluid resuscitation and vasopressors ^r5
  - For adults with COVID-19 and refractory shock despite fluid and norepinephrine:
    - Consider adding vasopressin rather than further titrating norepinephrine, or to lower the dose of norepinephrine required ^r5^r6
    - Add dobutamine for patients with evidence of cardiac dysfunction ^r5
  - For adults and children with refractory septic shock who have completed a course of steroids for COVID-19, add low-dose corticosteroids ("shock-reversal therapy") ^r5

Use corticosteroid therapy for all critically ill patients ^r5^r6^r68^r69

Use dexamethasone (when available) over alternatives
In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used

Immunomodulators are used in conjunction with steroids for mitigation of excessive inflammatory response

Evidence for efficacy is strongest for patients with elevated inflammatory markers ^r5^r68^r69
Baricitinib (a Janus kinase inhibitor) ^r5^r68^r69
- Use baricitinib as a preferred second immunomodulator with dexamethasone for hospitalized patients with severe or critical disease requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation
  - Guidelines generally recommend against combination of baricitinib with interleukin-6 inhibitors or other potent immunosuppressants, except WHO guideline advises corticosteroids, baricitinib, and an interleukin-6 inhibitor may all be used concurrently ^r68
- Baricitinib has a stronger evidence base than other JAK inhibitors
- Baricitinib has FDA approval for treatment of adults and emergency use authorization for treatment of children aged 2 years and older for hospitalized patients with COVID-19 on oxygen supplementation (including noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation) ^r77^r78
Tocilizumab (a monoclonal interleukin-6 receptor blocker) ^r79^r80
- Use tocilizumab as an alternative second immunomodulator with dexamethasone for hospitalized patients with severe or critical disease requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation when baricitinib is unavailable or contraindicated
  - Guidelines generally recommend against combination of interleukin-6 inhibitors with baricitinib or other potent immunosuppressants, except WHO guideline advises corticosteroids, baricitinib, and an interleukin-6 inhibitor may all be used concurrently
- Tocilizumab has a stronger evidence base than other IL-6 inhibitors
- Tocilizumab 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 corticosteroids who require oxygen supplementation (including noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation) ^r79^r80
Sarilumab (a monoclonal interleukin-6 receptor blocker) ^r5^r68^r69
- Use sarilumab as an alternative second immunomodulator with dexamethasone for hospitalized patients with severe or critical disease requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation when baricitinib is unavailable or contraindicated
  - Guidelines generally recommend against combination of interleukin-6 inhibitors with baricitinib or other potent immunosuppressants, except that the WHO guideline advises that corticosteroids, baricitinib, and an interleukin-6 inhibitor may all be used concurrently
- Evidence base for baricitinib and tocilizumab is stronger than for sarilumab
- Sarilumab, which is FDA approved for use in rheumatoid arthritis and other indications, has been used off-label for COVID-19 treatment ^r81
Tofacitinib (a Janus kinase inhibitor)
- Use tofacitinib as an alternative second immunomodulator with dexamethasone for hospitalized patients with severe or critical disease requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation when baricitinib, tocilizumab, sarilumab are all unable to be used
- Evidence base for baricitinib, tocilizumab, and sarilumab is stronger than for tofacitinib
- Tofacitinib, which has FDA approval for several indications including rheumatoid arthritis and ulcerative colitis, has been used off-label for COVID-19 treatment ^r82
Additional immunomodulators are being investigated; not all guidelines address use of these medications as alternatives ^r5
- Abatacept (cytotoxic T-lymphocyte–associated antigen 4 agonist)
  - Consider use of abatacept as an alternative second immunomodulator with dexamethasone for patients requiring high-flow oxygen or noninvasive ventilation when baricitinib and tocilizumab are unavailable or unable to be used, according to NIH guidelines; avoid use in patients requiring mechanical ventilation or extracorporeal membrane oxygenation
  - IDSA and WHO guidelines do not address abatacept
  - Abatacept, which is FDA approved for use in rheumatoid arthritis and other indications, has been used off-label for COVID-19 treatment ^r83
- Infliximab (tumor necrosis factor α inhibitor)
  - Consider use of infliximab as an alternative second immunomodulator with dexamethasone for patients requiring high-flow oxygen or noninvasive ventilation when baricitinib and tocilizumab are unavailable or unable to be used, according to NIH guidelines; avoid use in patients requiring mechanical ventilation or extracorporeal membrane oxygenation
  - IDSA and WHO guidelines do not address infliximab
  - Infliximab, which is FDA approved for use in inflammatory bowel disease, rheumatoid arthritis, and other indications, has been used off-label for COVID-19 treatment ^r84
- Vilobelimab (a monoclonal antibody which binds to factor C5a of the complement cascade)
  - FDA emergency use authorization was granted in April 2023 for use in hospitalized adults (aged 18 years or older) within 48 hours of initiation of mechanical ventilation or extracorporeal membrane oxygenation for COVID-19 ^r85
  - A randomized, double blinded, placebo-controlled phase 3 trial of 368 patients from 46 hospitals in 9 countries showed a significant decrease in 28-day mortality in patients on vilobelimab compared with placebo (absolute risk reduction, 11%; number needed to treat, 9 patients to prevent 1 death) ^r86
    - All patients were aged 18 years or older and also received standard of care (eg, corticosteroids, antithrombotic drugs, tocilizumab, baricitinib) in addition to vilobelimab or placebo initiated within 48 hours of invasive mechanical ventilation
    - 28-day mortality was 31.7% in the vilobelimab group compared with 41.6% in the placebo group (hazard ratio, 0.67), and all-cause mortality benefit persisted through 60 days (end of follow-up)
    - Adverse effects were similar between treatment groups (including pneumonia, sepsis, and acute kidney injury)
    - Notably, given the time span in which patients were enrolled (ie, October 2020 through October 2021), many patients were unvaccinated and few patients were infected with the Omicron variant
  - Guidelines do not yet address use of vilobelimab due to insufficient evidence

Antiviral remdesivir

In general, patients who have critical illness no longer benefit from antiviral medications ^r68^r69
Consider remdesivir in addition to immunomodulators for select hospitalized patients requiring high-flow oxygen or noninvasive ventilation who may have ongoing viral replication (eg, immunocompromised, within 10 days of symptoms onset, continued positive antigen test) ^r5
Avoid initiating remdesivir for patients requiring mechanical ventilation or extracorporeal membrane oxygenation; complete a course of remdesivir if already initiated ^r5^r68^r69

Medications including other antivirals, 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 ^d1

In addition, many medications with a mechanism of action which may affect patients with COVID-19 are being investigated; avoid use outside clinical trials
Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists ^r5

Drug therapy

Immunomodulators
- Corticosteroids
  - For treatment of severe COVID-19 in patients requiring supplemental oxygen
    - Dexamethasone ^c38
      - Dexamethasone Sodium Phosphate Solution for injection; Children and Adolescents: 0.15 mg/kg/dose (Max: 6 mg/dose) IV once daily for up to 10 days.
      - Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge, whichever comes first.
    - Methylprednisolone ^c39
      - Methylprednisolone Sodium Succinate Solution for injection; Adults: 32 mg/day IV divided every 6, 12, or 24 hours for up to 10 days or until hospital discharge, whichever comes first.
    - Prednisone ^c40
      - Prednisone Oral solution; Adults: 40 mg/day PO divided once or twice daily for up to 10 days or until hospital discharge, whichever comes first.
  - For treatment of COVID-19–related septic shock refractory to vasopressors and fluids
    - Hydrocortisone ^c41
      - Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 8 hours or 160 mg/day IV in 2 to 4 divided doses for up to 10 days or until hospital discharge, whichever comes first.
- Janus kinase inhibitors
  - Baricitinib ^c42
    - Baricitinib Oral tablet; Children 2 to 8 years†: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Baricitinib Oral tablet; Children and Adolescents 9 to 17 years†: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  - Tofacitinib
    - Tofacitinib Oral tablet; Adults: 10 mg PO twice daily for up to 14 days or until hospital discharge, whichever comes first. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Interleukin-6 receptor inhibitors
  - Sarilumab ^c43
    - Sarilumab Solution for injection; Adults: 400 mg IV once.
  - Tocilizumab ^c44
    - Tocilizumab Solution for injection; Children and Adolescents 2 to 17 years weighing less than 30 kg†: 12 mg/kg/dose IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
    - Tocilizumab Solution for injection; Children and Adolescents 2 to 17 years weighing 30 kg or more†: 8 mg/kg/dose (Max: 800 mg) IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
    - Tocilizumab Solution for injection; Adults: 8 mg/kg/dose (Max: 800 mg) IV once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
- Complement factor 5a inhibitor
  - Vilobelimab
    - Vilobelimab Solution for injection; Adults: 800 mg IV for up to 6 doses while hospitalized. Give first dose within 48 hours of intubation (Day 1), followed by doses on Days 2, 4, 8, 15, and 22.
- Cytotoxic T-lymphocyte–associated antigen 4 agonist
  - Abatacept
    - Abatacept Solution for injection; Adults: 10 mg/kg/dose (Max: 1,000 mg) IV once, using actual body weight.
- Tumor necrosis factor inhibitor
  - Infliximab
    - Infliximab (Murine) Solution for injection; Adults: 5 mg/kg/dose once, using actual body weight.
Antivirals
- Remdesivir
  - Remdesivir Solution for injection; Adults: 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
  - Remdesivir Solution for injection; Children and Adolescents: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
Vasopressors
- Norepinephrine ^c45
  - Norepinephrine Bitartrate Solution for injection; Neonates†: 0.1 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate dose every 30 minutes based on clinical response. Usual Max: 2 mcg/kg/minute.
  - Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion, initially. Titrate dose as needed based on clinical response. Usual Max: 2 mcg/kg/minute.
  - Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate dose by 0.02 mcg/kg/minute (or more in emergency cases) every 2 to 5 minutes based on clinical response. Usual dose: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.
- Epinephrine ^c46
  - Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate dose as needed based on clinical response.
  - Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate dose by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes based on clinical response.
- Vasopressin ^c47
  - Vasopressin Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 8 milliunits/kg/minute continuous IV infusion; reserve for catecholamine-resistant shock, dosage range not well established.
  - Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion, initially; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
Inotropes
- Dobutamine ^c48
  - Dobutamine Hydrochloride Solution for injection; Neonates: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion, initially. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute.
  - Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion, initially. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute.
  - Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate dose every few minutes based on clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
Anticoagulants
- Dalteparin
  - For thrombosis prophylaxis
    - Dalteparin Sodium (Porcine) Solution for injection; Infants†, Children†, and Adolescents†: 75 to 125 units/kg/dose (Max: 5,000 units/dose) subcutaneously once daily; adjust dose to maintain an anti-factor Xa concentration of 0.2 to 0.4 units/mL.
    - Dalteparin Sodium (Porcine) Solution for injection; Adults with severely restricted mobility during acute illness: 5,000 units subcutaneously once daily.
  - For treatment of suspected or proven thromboembolism
    - Dalteparin Sodium (Porcine) Solution for injection; Infants and Children 1 to 23 months: 150 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
    - Dalteparin Sodium (Porcine) Solution for injection; Children 2 to 7 years: 125 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
    - Dalteparin Sodium (Porcine) Solution for injection; Children and Adolescents 8 to 17 years: 100 units/kg/dose subcutaneously twice daily, initially. Adjust dose by 25 units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 unit/mL.
    - Dalteparin Sodium (Porcine) Solution for injection; Adults: 100 units/kg/dose subcutaneously every 12 hours or 200 units/kg/dose subcutaneously once daily. Max: 18,000 units/day.
- Enoxaparin ^c49
  - For thrombosis prophylaxis
    - Enoxaparin Sodium (Porcine) Solution for injection; Infants† 1 month: 0.75 mg/kg/dose subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
    - Enoxaparin Sodium (Porcine) Solution for injection; Infants†, Children†, and Adolescents† 2 months to 17 years: 0.5 mg/kg/dose subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
    - Enoxaparin Sodium (Porcine) Solution for injection; Adults with severely restricted mobility during acute illness: 40 mg subcutaneously once daily.
  - For treatment of suspected or proven thromboembolism
    - Enoxaparin Sodium (Porcine) Solution for injection; Infants 1 to 2 months†: 1.5 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.8 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours post-dose or 0.5 to 0.8 units/mL 2 to 6 hours post-dose.
    - Enoxaparin Sodium (Porcine) Solution for injection; Infants 3 to 11 months†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.5 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    - Enoxaparin Sodium (Porcine) Solution for injection; Children 1 to 5 years†: 1 mg/kg/dose subcutaneously every 12 hours, or alternatively, 1.2 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    - Enoxaparin Sodium (Porcine) Solution for injection; Children and Adolescents 6 to 17 years†: 1 mg/kg/dose subcutaneously every 12 hours, initially. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
    - Enoxaparin Sodium (Porcine) Solution for injection; Adults: 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours.
Sedatives (for mechanically ventilated patients)
- Dexmedetomidine ^c50
  - Dexmedetomidine Hydrochloride Solution for injection; Term Neonates†: 0.05 to 0.5 mcg/kg/dose IV loading dose, followed by 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Titrate dose as needed until target level of sedation is attained. Loading doses are often bypassed. Max: 2.5 mcg/kg/hour.
  - Dexmedetomidine Hydrochloride Solution for injection; Infants†: 0.5 to 1 mcg/kg IV loading dose, followed by 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate dose by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
  - Dexmedetomidine Hydrochloride Solution for injection; Children† and Adolescents†: 0.5 to 1 mcg/kg IV loading dose, followed by 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate dose by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.
  - Dexmedetomidine Hydrochloride Solution for injection; Adults: 1 mcg/kg IV loading dose, followed by 0.2 to 0.7 mcg/kg/hour continuous IV infusion, initially. Titrate dose until target level of sedation is attained. Loading doses are often bypassed. Max: 1.5 mcg/kg/hour.
- Propofol ^c51
  - Propofol Emulsion for injection; Adolescents 17 years: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
  - Propofol Emulsion for injection; Adults: 5 mcg/kg/minute continuous IV infusion, initially; titrate by 5 to 10 mcg/kg/minute every 5 to 10 minutes to clinical response. Usual dose: 5 to 50 mcg/kg/minute. Do not exceed 4 mg/kg/hour unless the benefits outweigh the risks. May use 10 to 20 mg IV bolus if needed to rapidly increase sedation depth in patients where hypotension is unlikely to occur.
Neuromuscular blockers (for mechanically ventilated patients)
- Rocuronium ^c52
  - Intermittent IV dosage (preferred over continuous infusion, where clinically possible)
    - Rocuronium Bromide Solution for injection; Neonates: 0.45 to 0.6 mg/kg/dose IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg/dose IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg/dose IV once, followed by 0.1 to 1 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  - Continuous IV infusion dosage
    - Rocuronium Bromide Solution for injection; Neonates: 0.6 mg/kg/dose IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Rocuronium Bromide Solution for injection; Infants, Children, and Adolescents: 0.6 mg/kg/dose IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    - Rocuronium Bromide Solution for injection; Adults: 0.6 to 1 mg/kg/dose IV bolus, followed by 8 to 12 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Usual dosage range: 4 to 16 mcg/kg/minute. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Nondrug and supportive care

Excellent supportive care is critical for treatment ^c53

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

Oxygenation and ventilation ^c54^c55
- Begin supplemental oxygen therapy when SpO₂ (peripheral oxygen saturation) falls below 90% to 92% for nonpregnant patients, or below 95% for pregnant patients
  - Specific target SpO₂ is not definitively known
    - WHO guidelines suggest initial target during resuscitation of 94% or more in all patients, and once stable, a target of more than 90% SpO₂ in nonpregnant adults and children and at least 92% to 95% in pregnant patients ^r4
    - NIH guidelines suggest a target SpO₂ of 92% to 96% for nonpregnant adults, 95% or more in pregnant patients, and 92% to 97% for children; consider target less than 92% in children with severe acute respiratory distress syndrome to minimize exposure to high FIO₂ (fraction of inspired oxygen) ^r5
    - Surviving Sepsis recommends that SpO₂ be maintained no higher than 96% for adults ^r6
  - Conventional oxygenation may use a variety of delivery methods (eg, nasal cannula at 5 L/minute, face mask with reservoir bag at 10 to 15 L/minute) ^r4^c56
- Use high-flow nasal cannula for patients with persistent respiratory failure despite conventional oxygen therapy ^r5^r87^c57^c58
  - Initiate high-flow nasal cannula over noninvasive positive pressure ventilation for adults; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation with close monitoring may be used if high-flow nasal oxygen is not available ^r5^r6
  - For infants and children not needing intubation, a trial of high-flow oxygen or noninvasive ventilation is recommended, with insufficient evidence to recommend one method over another ^r5
  - WHO guideline recommends high-flow oxygen, CPAP (continuous positive airway pressure), or other noninvasive ventilation over standard oxygen therapy for patients with severe or critical disease and acute hypoxemic respiratory failure not needing emergent intubation; no recommendation is given for one over another, owing to lack of evidence ^r4
- Use noninvasive positive pressure ventilation, such as CPAP and BPAP, in monitored settings with immediate availability of endotracheal intubation if needed; if indications for endotracheal intubation are already present, high-flow nasal cannula or noninvasive positive pressure ventilation should not be used to delay needed mechanical ventilation ^r4
  - Given the potential for noninvasive ventilation techniques to aerosolize the virus, airborne precautions are recommended ^r4^r5
  - Guidelines do not advise on method of delivery (eg, helmet, face mask) for noninvasive ventilation, owing to limited evidence comparing one with another
- Use awake prone positioning to improve oxygenation in patients requiring high-flow oxygen or noninvasive ventilation ^r4^r5^c59
  - Do not attempt prone positioning to avert the need for mechanical ventilation in patients who otherwise require it (eg, respiratory distress, hemodynamic instability)
  - Pregnant patients may be placed in left lateral decubitus or fully prone position, as tolerated ^r5
  - The optimal duration of prone positioning is not known; limited evidence suggests more significant protective effect on mechanical ventilation and mortality for patients spending 8 hours per day in prone position ^r88
- Utilize mechanical ventilation for patients in whom oxygenation targets cannot be met with less invasive measures or who cannot maintain the work of breathing; indications for intubation are the same as for non–COVID-19 conditions (eg, PaO₂/FIO₂ ratio less than 300 mm Hg, coma) ^c60
  - Categorization of degree of acute respiratory distress syndrome in adults, by PaO₂/FIO₂ ratio (mm Hg): ^r4
    - Mild: PaO₂/FIO₂ ratio less than 300 but more than 200, with PEEP or CPAP at 5 cm H₂O or more
    - Moderate: PaO₂/FIO₂ ratio of 200 or less but more than 100, with PEEP at 5 cm H₂O or more
    - Severe: PaO₂/FIO₂ ratio of 100 or less, with PEEP at 5 cm H₂O or more
  - Categorization of degree of acute respiratory distress syndrome in children: ^r4
    - Indices:
      - Oxygenation index is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by PaO₂ (mm Hg)
      - Oxygen saturation index is a noninvasive surrogate for oxygenation index and is calculated as FIO₂ multiplied by mean airway pressure (mm Hg), divided by SpO₂ (peripheral oxygen saturation as measured by pulse oximetry)
    - Mild (invasively ventilated): oxygenation index from 4 to less than 8 or oxygen saturation index from 5 to less than 7.5
    - Moderate (invasively ventilated): oxygenation index from 8 to less than 16 or oxygen saturation index from 7.5 to less than 12.3
    - Severe (invasively ventilated): oxygenation index of 16 or more or oxygen saturation index of 12.3 or more
  - Intubation should be performed by experienced personnel, using video laryngoscopy where available; N95 respirators or comparable, along with eye protection, gown, and gloves, are recommended for use during intubation and other aerosol-generating procedures and when caring for mechanically ventilated patients, to prevent exposure during unexpected ventilator circuit disruptions ^r5^r6
    - WHO additionally recommends against disconnection from ventilators, which risks exposing health care workers, and suggests consideration of airway clearance techniques for excessive secretions only with strict infection control practices ^r4
    - For children, cuffed endotracheal tubes are recommended over uncuffed ^r5
  - Choose lower tidal volume of 4 to 8 mL/kg (predicted body weight) over higher tidal volumes and plateau pressures less than 30 cm H₂O for adults ^r5^r6^r68
    - 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) ^r4^r5
  - Select a higher PEEP strategy over lower PEEP, with close monitoring for barotrauma and with consideration of risks (eg, overdistention, higher pulmonary vascular resistance) and benefits (eg, improved alveolar recruitment) ^r4^r5^r6^c61^d7^d7^d7^d7^d7^d7^d7^d7
  - In children, allow permissive hypercapnia (pH 7.2 to 7.3) if needed to maintain the above lung-protective ventilation strategies, unless the patient has a condition that would be worsened by acidosis (eg, pulmonary hypertension, ventricular dysfunction, intracranial hypertension) ^r5
  - For patients with moderate to severe acute respiratory distress syndrome on mechanical ventilation, use prone positioning for 12 to 16 hours/day ^r4^r5^r6^c62
    - Lateral decubitus position may be used for pregnant patients, especially in the third trimester ^r4
  - Sedation with or without neuromuscular blockade may be necessary for comfort and optimal ventilation; the Society of Critical Care Medicine offers guidance on appropriate agents and monitoring for adults and children ^r71^r89
    - Select intermittent neuromuscular blockade as needed (eg, rocuronium) rather than continuous infusion ^r4^r5^r6^c63^c64
      - 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 ^r5^r6
  - 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 ^r5^r6
  - Similarly, in patients on mechanical ventilation with persistent hypoxemia despite all other measures, recruitment maneuvers (eg, brief high PEEP or CPAP) are suggested except incremental (staircase) PEEP
  - Tracheostomy may be required; it should be performed for indications similar to those in patients without COVID-19 (eg, prolonged mechanical ventilation, secretion management, failed extubation, inability to protect airway)
    - Current evidence does not reveal whether early tracheostomy offers any benefit or harm compared with late tracheostomy ^r90
- Consider extracorporeal membrane oxygenation if all other measures have not alleviated refractory hypoxemia ^r4^r6^r14^c65
  - WHO definition of refractory hypoxemia is: PaO₂/FIO₂ ratio of less than 50 mm Hg for 3 hours, or less than 80 mm Hg for more than 6 hours
  - Limited evidence suggests that extracorporeal membrane oxygenation may reduce mortality, although bleeding complications are high ^r4^r91
- Evidence is insufficient to recommend for or against high frequency oscillatory ventilation in children with severe acute respiratory distress syndrome and refractory hypoxemia ^r5
Fluid management
- Avoid overhydration, which may precipitate or exacerbate acute respiratory distress syndrome; use conservative rather than aggressive fluid management ^r4^r5^r6
- 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) ^r4^r5
  - An increase in cardiac output (by echocardiography or transpulmonary thermodilution) after 1 minute of passive leg raise has been shown to be a reliable predictor of response and helps to avoid overhydration in patients unlikely to respond ^r92
  - Physical examination findings may be less accurate predictors of fluid responsiveness ^r92
  - Based on non–COVID-19 patient data, early lactate clearance–guided resuscitation may be beneficial compared with central venous oxygen saturation–guided therapy ^r5
- To monitor resuscitation in children, a combination of serial clinical assessments, cardiac ultrasonography or echocardiography, and/or laboratory markers (including lactate levels) is recommended ^r5
- In patients with shock:
  - Choose crystalloids for resuscitation over starches, gelatins, or albumin; whether use of balanced crystalloids is superior to normal saline is unknown ^r4^r5
    - Adults: administer 250 to 500 mL over the first 15 to 30 minutes; goal is mean arterial pressure of 60 to 65 mm Hg^r6 (if invasive pressure monitoring is available)
    - Children: 10 to 20 mL/kg bolus over the first 30 to 60 minutes
    - If there is no response to fluid bolus or if signs of fluid overload exist, discontinue or reduce fluid administration
    - For patients who respond to initial bolus and are without evidence of fluid overload, titrate continued fluid to achieve improvement in clinical signs (capillary refill, heart rate, tactile temperature of extremities, palpable pulses), urine output (0.5 mL/kg/hour in adults, 1 mL/kg/hour in children), and hemodynamic parameters (mean arterial pressure more than 65 mm Hg in adults)
  - Administer vasopressors in adults if shock persists after fluid bolus, and in children after 2 fluid boluses, or if there are signs of fluid overload

Procedures

Extracorporeal membrane oxygenation ^c66

General explanation

Heart-lung bypass is a technique in which blood is circulated from patient through bypass machine, where transmembrane exchange of oxygen and carbon dioxide occurs before blood is returned to patient; method can also be used to support arterial blood pressure

Indication

Refractory hypoxemia with or without hemodynamic compromise despite standard supportive measures
May be helpful if resources and expertise are available ^r6

Contraindications

Neurologic impairment
Severe preexisting disease

Complications

Limb ischemia distal to vascular access catheters

Comorbidities

Severe COVID-19 has been associated with many underlying conditions (eg, diabetes, hypertension); overall treatment of critically ill patients does not differ for those with specific conditions with few exceptions ^r39^c67^c68
- For patients with immunocompromise due to medications, immunomodulatory drug regimens may need to be adjusted to reduce the risk of drug-drug interactions, overlapping toxicities, and secondary infections; any dosage changes should be done in consultation with appropriate specialists ^r5
- Pay close attention to drug-drug interactions, and do not discontinue or adjust current medications (eg, chemotherapy, antiretroviral therapy) without appropriate specialist consultation, in patients with comorbid conditions such as active malignancy and HIV ^r5

Special populations

Pregnant patients
- NIH guidelines contain a summary of considerations for pregnant and breastfeeding patients; American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine also have guidance regarding pregnant patients with COVID-19 ^r5^r93^r94
- 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 ^r5^r93^r94
- COVID-19 in pregnancy is associated with increased risk for complications such as preterm birth, stillbirth, and hypertensive disorders of pregnancy ^r5^r93^r94
- In general, therapeutic management of pregnant patients should be the same as for nonpregnant patients; potentially effective treatments for COVID-19 should not be withheld because of theoretical concerns related to the safety of using those drugs in pregnancy ^r5
Pediatric patients
- Evidence to guide treatment in pediatric populations is more limited than for adults ^r5
- General management of critically ill children is also based on guidance for non-COVID critical illness, such as Surviving Sepsis Campaign septic shock guideline,^r70Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children,^r71 and Pediatric Acute Lung Injury Consensus Conference recommendations^r72

Monitoring

Standard critical care monitoring, including oxygen saturation and hemodynamic measures, is appropriate ^c69^c70
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: ^r4^r60
- Acute respiratory distress syndrome ^c71^d7^d7^d7^d7^d7^d7^d7^d7
  - 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 ^r95^r96
  - In a global analysis, 62% of critically ill patients required mechanical ventilation ^r3
  - In a meta-analysis covering more than 58,000 patients, 6.9% received extracorporeal membrane oxygenation; in-hospital mortality of such patients was 39% ^r97
- Shock ^c72^d4^d4^d4^d4^d4^d4^d4^d4
  - Need for vasopressors ranged from 26% to 66% in 2 hospital systems in the United States ^r96
- Acute cardiac injury, including myocardial infarction, myocarditis, heart failure, Takotsubo cardiomyopathy, and arrhythmias including atrial fibrillation ^c73^c74^d8^d8^d8^d8^d8^d8^d8^d8
  - Estimates of myocardial infarction are 2.5% to 8%; new-onset atrial fibrillation is approximately 10% ^r98^r99
- Acute kidney injury ^c75^d9^d9^d9^d9^d9^d9^d9^d9
  - Between 9% and 31% of critically ill patients (without preexisting renal disease) required acute renal replacement therapy in US samples ^r96
- Neurologic complications are reported in more than 12% of critically ill patients ^r100
  - Most common are ischemic stroke (2.9%), intracranial hemorrhage (2.8%), and seizures (2.6%) ^r100
  - Altered mental status (33% of patients in one US hospital system, almost 15% in another study) ^r60^r95
- Thromboembolic events are common (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) ^r60^r101
- Secondary infections, including ventilator-associated pneumonia and catheter infections, appear to be less common than initially thought ^r5^c76^c77
  - In a series of more than 700 critically ill patients in Italy, 46% had hospital-acquired infections ^r102
  - In a meta-analysis of more than 3000 patients, bacterial coinfection was estimated at 6.9% overall, and slightly higher in critically ill patients ^r103
- Multiorgan failure
Multisystem inflammatory syndrome (MIS-C in children younger than 21 years, and MIS-A in adults age 21 years or older) frequently requires critical care ^d2
- MIS-C and MIS-A are characterized by fever, elevated laboratory markers of inflammation, and evidence of organ dysfunction in cardiac, hematologic, gastrointestinal, and dermatologic systems, along with linkage to COVID-19
- In children, MIS-C may present similarly to other pediatric hyperinflammatory syndromes such as Kawasaki disease and toxic shock syndrome
  - Common clinical features in children include fever, hypotension/shock, abdominal pain, vomiting, diarrhea, conjunctivitis, rash, and headache
- Common features in adults with MIS-A include fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation

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 ^r14^r16^r95
Laboratory markers associated with mortality include troponin, interleukin-6, estimated GFR, neutrophil to lymphocyte ratio, B-type natriuretic peptide, and D-dimer ^r57
Recent review of 142,291 critically ill patients worldwide calculated a pooled estimate of mortality 34% ^r3
Survivors of COVID-19 are reported to have decreased quality of life and various persistent symptoms; patients with critical illness have an increased risk compared with those with noncritical illness ^r104^r105^r106^r107^r108^r109
- A majority of patients have symptoms consistent with post–intensive care syndrome; prevalence of symptoms decreases over time ^r107^r110
  - Studies report abnormalities such as fatigue, pain, weakness, and dyspnea in one-quarter to one-third of patients at 12 months ^r104^r106^r107
  - At 2 years after discharge in one study, fewer than one-quarter of patients completely returned to pre-COVID baseline, with persistent neurocognitive effect, sleep impairment, dyspnea, and fatigue the most common complaints ^r108
- Patients with severe or critical illness have increased risk for long COVID ^r111
  - 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
- Studies have reported increased risk of cardiovascular adverse outcomes, gastrointestinal and hepatic conditions, connective tissue disorders, cognitive decline, new-onset diabetes, respiratory adverse outcomes, and death up to 1 year after diagnosis of COVID-19; many report increased risk in critically ill patients ^r112^r113^r114^r115^r116^r117^r118^r119^r120^r121

Screening and Prevention

Screening ^c78

Prevention

Prevention or mitigation of COVID-19 infection by vaccination remains the most effective way of preventing critical illness ^d1^d1^d1^d1^d1^d1^d1^d1
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) ^r73^c79^c80^c81^c82^c83
- Universal personal protective equipment in healthcare settings includes standard precautions and transmission-based precautions
  - Recommended personal protective equipment for healthcare personnel working with COVID-19 patients includes N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection
  - Source control is recommended for all individuals with suspected COVID-19 or exposure; universal source control is recommended for higher-risk situations (such as for particular departments or procedures, working with certain patient populations, or during outbreaks)
    - Take measures to reduce leakage around oxygen masks and from ventilator tubing in critically ill patients
- Place patient in a single room with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange) if available; if resources do not allow, 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
  - 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
Discontinue transmission-based precautions for critically ill patients: ^r73
- For patients without moderate to severe immunocompromise:
  - 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:
  - Use a test-based strategy
    - Results are negative from at least 2 consecutive respiratory specimens collected 48 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), and
    - Fever should be resolved at least 24 hours, without fever-reducing medicines, and
    - Symptoms have improved
  - Consider consultation with an infectious disease specialist

Haase N et al: Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19--a nationwide, observational study in Denmark. Acta Anaesthesiol Scand. 66(8):987-95, 2022

35781689

Leazer S et al: Outcomes associated with intensive care and organ support among patients with COVID-19: a systematic review and meta-analysis. Mil Med. ePub, 2022

35639913

Gebremeskel GG et al: Mortality and morbidity in critically ill COVID-19 patients: A systematic review and meta-analysis. J Infect Public Health. 17(10):102533, 2024

39243690

WHO: Clinical Management of COVID-19: Living Guideline, version 7.0. MagicApp website. Updated August 17, 2023. Accessed November 12, 2024. https://app.magicapp.org/#/guideline/6915https://app.magicapp.org/#/guideline/6915NIH: COVID-19 Treatment Guidelines. Updated February 29, 2024. Accessed November 12, 2024. https://web.archive.org/web/20240229211748/https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf https://web.archive.org/web/20240229211748/https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdfAlhazzani W et al: Surviving Sepsis Campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med. 49(3):e219-34, 2021

33555780

WHO: Coronavirus Disease 2019 (COVID-19): Situation Report--51. WHO website. Published March 11, 2020. Accessed November 12, 2024. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdfhttps://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdfCoronaviridae Study Group of the International Committee on Taxonomy of Viruses: The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 5(4):536-44, 2020

32123347

CDC: COVID Data Tracker: Variant Proportions. CDC website. Updated November 9, 2024. Accessed November 12, 2024. https://covid.cdc.gov/covid-data-tracker/#variant-proportionshttps://covid.cdc.gov/covid-data-tracker/#variant-proportionsWHO: Tracking SARS-CoV-2 Variants. WHO website. Updated September 25, 2024. Accessed November 12, 2024. https://www.who.int/activities/tracking-SARS-CoV-2-variants/https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/Wu Y et al: Incubation Period of COVID-19 Caused by Unique SARS-CoV-2 Strains: A Systematic Review and Meta-analysis. JAMA Netw Open. 5(8):e2228008, 2022

35994285

Stokes EK et al: Coronavirus disease 2019 case surveillance--United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 69(24):759-65, 2020

32555134

Sudre CH et al: Anosmia, ageusia, and other COVID-19-like symptoms in association with a positive SARS-CoV-2 test, across six national digital surveillance platforms: an observational study. Lancet Digit Health. 3(9):e577-86, 2021

34305035

Huang C et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395(10223):497-506, 2020

31986264

Spinato G et al: Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. ePub, April 22, 2020

32320008

Chen N et al: Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. ePub, January 30, 2020

32007143

ZOE Health Study group: What are the most common COVID symptoms? United Kingdom survey update. ZOE Health Study website. Updated December 13, 2022. Accessed November 12, 2024. https://health-study.joinzoe.com/blog/covid-new-top-10-covid-symptomshttps://health-study.joinzoe.com/blog/covid-new-top-10-covid-symptomsBertran Recasens B et al: Lack of dyspnea in Covid-19 patients: another neurological conundrum? Eur J Neurol. ePub, April 17, 2020

32301553

Chan JFW et al: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 395(10223):514-23, 2020

31986261

Zhong Z et al: Clinical characteristics of 2,459 severe or critically ill COVID-19 patients: a meta-analysis. Medicine (Baltimore). 100(5):e23781, 2021

33592834

Tobin MJ et al: Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. ePub, June 15, 2020

32539537

Vesoulis Z et al: Racial discrepancy in pulse oximeter accuracy in preterm infants. J Perinatol. 42(1):79-85, 2022

34642469

Henry NR et al: Disparities in hypoxemia detection by pulse oximetry across self-identified racial groups and associations with clinical outcomes. Crit Care Med. 50(2):204-11, 2022

35100193

Andrist E et al: Association of race with pulse oximetry accuracy in hospitalized children. JAMA Netw Open. 5(3):e224584, 2022

35357460

Fawzy A et al: Racial and ethnic discrepancy in pulse oximetry and delayed identification of treatment eligibility among patients with COVID-19. JAMA Intern Med. 182(7):730-8, 2022

35639368

Atri D et al: COVID-19 for the cardiologist: a current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies. JACC Basic Transl Sci. ePub, April 10, 2020

32292848

Wu P et al: Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. ePub, March 31, 2020

32232433

Schulman S et al: 2023 ISTH update of the 2022 ISTH guidelines for antithrombotic treatment in COVID-19. J Thromb Haemost. 22(6):1779-97, 2024

38503600

Oxley TJ et al: Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. ePub, May 14, 2020

32343504

Helms J et al: Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 382(23):2268-70, 2020

32294339

Galván Casas C et al: Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. ePub, April 29, 2020

32348545

Magro C et al: Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. ePub, April 15, 2020

32299776

Joob B et al: COVID-19 can present with a rash and be mistaken for dengue. J Am Acad Dermatol. 82(5):e177, 2020

32213305

Marzano AV et al: Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol. ePub, April 16, 2020

32305439

Recalcati S: Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. ePub, March 26, 2020

32215952

Alramthan A et al: A case of COVID-19 presenting in clinical picture resembling chilblains disease: first report from the Middle East. Clin Exp Dermatol. ePub, April 17, 2020

32302422

Fernandez-Nieto D et al: Characterization of acute acro-ischemic lesions in non-hospitalized patients: a case series of 132 patients during the COVID-19 outbreak. J Am Acad Dermatol. ePub, April 24, 2020

32339703

Marks KM et al: COVID-19. Ann Intern Med. 176(10):ITC145-ITC160, 2023

37812774

CDC: COVID-19: Underlying Conditions and the Higher Risk for Severe COVID-19. CDC website. Updated July 30, 2024. Accessed November 12, 2024. https://www.cdc.gov/covid/hcp/clinical-care/underlying-conditions.htmlhttps://www.cdc.gov/covid/hcp/clinical-care/underlying-conditions.htmlRichardson S et al: Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. ePub, April 22, 2020

32320003

CDC: COVID Data Tracker. CDC website. Updated September 30, 2024. Accessed November 12, 2024. https://covid.cdc.gov/covid-data-tracker/#demographicsovertimehttps://covid.cdc.gov/covid-data-tracker/#demographicsovertimeTorres C et al: Identifying age- and sex-specific COVID-19 mortality trends over time in six countries. Int J Infect Dis. 128:32-40, 2023

36509336

Leong R et al: Global Temporal Patterns of Age Group and Sex Distributions of COVID-19. Infect Dis Rep. 13(2):582-596, 2021

34205538

Siddiq S et al: Clinical outcomes following COVID-19 infection in ethnic minority groups in the UK: a systematic review and meta-analysis. Public Health. ePub, 2022

35970621

Aparicio C et al: Risk Factors for Pediatric Critical COVID-19: A Systematic Review and Meta-Analysis. J Pediatric Infect Dis Soc. 13(7):352-362, 2024

38780125

Taylor CA et al: COVID-19-Associated Hospitalizations Among U.S. Adults Aged ≥65 Years - COVID-NET, 13 States, January-August 2023. MMWR Morb Mortal Wkly Rep. 72(40):1089-1094, 2023

37796744

Scobie HM et al: Monitoring incidence of COVID-19 cases, hospitalizations, and deaths, by vaccination status--13 U.S. jurisdictions, April 4-July 17, 2021. MMWR Morb Mortal Wkly Rep. 70(37):1284-90, 2021

34529637

CDC: COVID-19: Interim Guidelines for Collecting and Handling of Clinical Specimens for COVID-19 Testing. CDC website. Updated October 29, 2024. Accessed November 12, 2024. https://www.cdc.gov/covid/hcp/clinical-care/clinical-specimen-guidelines.htmlhttps://www.cdc.gov/covid/hcp/clinical-care/clinical-specimen-guidelines.htmlCDC: COVID-19: Overview of Testing for SARS-CoV-2. CDC website. Updated August 29, 2024. Accessed November 12, 2024. https://www.cdc.gov/covid/hcp/clinical-care/overview-testing-sars-cov-2.htmlhttps://www.cdc.gov/covid/hcp/clinical-care/overview-testing-sars-cov-2.htmlDing Q et al: The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol. ePub, March 20, 2020

32196707

Fan BE et al: COVID-19 and mycoplasma pneumoniae coinfection. Am J Hematol. 95(6):723-4, 2020

32173883

CDC: Influenza (Flu): Clinical Guidance for Hospitalized and Non-hospitalized Patients When SARS-CoV-2 and Influenza Viruses are Co-circulating. CDC website. Updated September 17, 2024. Accessed November 12, 2024. https://www.cdc.gov/flu/hcp/clinical-guidance/testing-guidance-for-clinicians.htmlhttps://www.cdc.gov/flu/hcp/clinical-guidance/testing-guidance-for-clinicians.htmlIslam N et al: Thoracic imaging tests for the diagnosis of COVID-19. Cochrane Database Syst Rev. 3:CD013639, 2021

33724443

Rubin GD et al: The role of chest imaging in patient management during the COVID-19 pandemic: a multinational consensus statement from the Fleischner Society. Chest. ePub, April 7, 2020

32275978

De Rop L et al: Accuracy of routine laboratory tests to predict mortality and deterioration to severe or critical COVID-19 in people with SARS-CoV-2. Cochrane Database Syst Rev. 8(8):CD015050, 2024

39105481

Lippi G et al: Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chim Acta. 505:190-1, 2020

32145275

Griffith LE et al: The complexity of examining laboratory-based biological markers associated with mortality in hospitalized patients during early phase of the COVID-19 pandemic: a systematic review and evidence map. PLoS One. 17(9):e0273578, 2022

36084120

Shi H et al: Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 20(4):425-434, 2020

32105637

Zhu N et al: A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 382(8):727-33, 2020

31978945

Bell TD: COVID-19 in the critically ill patient. Infect Dis Clin North Am. 36(2):365-77, 2022

35636905

Yoon SH et al: Chest radiographic and CT findings of the 2019 novel coronavirus disease (COVID-19): analysis of nine patients treated in Korea. Korean J Radiol. 21(4):494-500, 2020

32100485

Kanne JP: Chest CT findings in 2019 novel coronavirus (2019-nCoV) infections from Wuhan, China: key points for the radiologist. Radiology. 295(1):16-7, 2020

32017662

Hashemi-Madani N et al: Typical chest CT features can determine the severity of COVID-19: a systematic review and meta-analysis of the observational studies. Clin Imaging. 74:67-75, 2021

33444992

Peng QY et al: Using echocardiography to guide the treatment of novel coronavirus pneumonia. Crit Care. 24(1):143, 2020

32276598

Lai SY et al: Lung Ultrasound Score in COVID-19 Patients Correlates with PO(2)/FiO(2), Intubation Rates, and Mortality. West J Emerg Med. 25(1):28-39, 2024

38205982

US National Library of Medicine: ClinicalTrials.gov website. Accessed November 12, 2024. https://clinicaltrials.gov/https://clinicaltrials.gov/Liverpool Drug Interaction Group, University of Liverpool: COVID-19 Drug Interactions website. Accessed November 12, 2024. https://www.covid19-druginteractions.org/checkerhttps://www.covid19-druginteractions.org/checkerWHO: Therapeutics and COVID-19: Living Guideline. Version 14.1. MAGICapp website. Updated November 9, 2023. Accessed November 14, 2024. https://app.magicapp.org/#/guideline/7789https://app.magicapp.org/#/guideline/7789Bhimraj A et al: Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19. IDSA website. Updated August 12, 2024. Accessed November 14, 2024. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Weiss SL et al: Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med. 46(suppl 1):10-67, 2020

32030529

Smith HAB et al: 2022 Society of Critical Care Medicine clinical practice guidelines on prevention and management of pain, agitation, neuromuscular blockade, and delirium in critically ill pediatric patients with consideration of the ICU environment and early mobility. Pediatr Crit Care Med. 23(2):e74-110, 2022

35119438

Emeriaud G et al: Executive summary of the second international guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PALICC-2). Pediatr Crit Care Med. 24(2):143-68, 2023

36661420

CDC: COVID-19: Infection Control Guidance SARS-CoV-2. CDC website. Updated June 24, 2024. Accessed November 14, 2024. https://www.cdc.gov/covid/hcp/infection-control/index.htmlhttps://www.cdc.gov/covid/hcp/infection-control/index.htmlCuker A et al: American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients. Blood Adv. ePub, 2022

35503027

Cuker A et al: American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients Blood Adv. ePub, 2022

35748885

Moores LK et al: Thromboprophylaxis in patients with COVID-19: a brief update to the CHEST guideline and expert panel report. Chest. ePub, 2022

35167861

Eli Lilly and Company: Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of Baricitinib. FDA website. Updated May 2022. Accessed November 15, 2024. https://www.fda.gov/media/143823/downloadhttps://www.fda.gov/media/143823/downloadEli Lilly and Company: Olumiant (Baricitinib). Highlights of prescribing information. Updated June 2022. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/Genentech Inc: Actemra (Tocilizumab). Prescribing information. Updated September 2024. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/Genentech Inc: Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) for Actemra (tocilizumab). FDA website. Updated June 2021. Accessed November 15, 2024. https://www.fda.gov/media/150321/downloadhttps://www.fda.gov/media/150321/downloadSanofi-Aventis: Kevzara (Sarilumab). Prescribing information. Updated June 2024. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/Pfizer: Xeljanz (Tofacitinib). Prescribing information. Updated September 2024. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/Bristol Myers Squibb: Orencia (Abatacept). Prescribing information. Updated May 2024. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/Janssen Biotech Inc: Infliximab. Prescribing Information. Updated October 2021. Accessed November 15, 2024https://dailymed.nlm.nih.gov/dailymed/InflaRx Pharmaceuticals Inc: Fact Sheet for Healthcare Providers: Emergency Use Authorization for Gohibic (vilobelimab). Gohibic website. Updated May 2023. Accessed November 15, 2024. https://www.gohibic.com/uploads/pdf/Fact%20Sheet%20for%20Healthcare%20Providers_20230518%20(1).pdfhttps://www.gohibic.com/uploads/pdf/Fact%20Sheet%20for%20Healthcare%20Providers_20230518%20(1).pdfVlaar APJ et al: Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 10(12):1137-46, 2022

36087611

Murthy S et al: Care for critically ill patients with COVID-19. JAMA. 323(15):1499-500, 2020

32159735

Vásquez-Tirado GA et al: Conscious prone positioning in nonintubated COVID-19 patients with acute respiratory distress syndrome: systematic review and meta-analysis. Crit Care Sci. 36:e20240176en, 2024

38597483

Devlin JW et al: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 46(9):e825-73, 2018

30113379

Szafran A et al: Early versus late tracheostomy in critically ill COVID-19 patients. Cochrane Database Syst Rev. 11(11):CD015532, 2023

37982427

Wang L et al: Extracorporeal membrane oxygenation for COVID-19 and influenza associated acute respiratory distress syndrome: a systematic review. Expert Rev Respir Med. 17(10):951-959, 2023

37847592

Bentzer P et al: Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 316(12):1298-309, 2016

27673307

American College of Obstetricians and Gynecologists: COVID-19 FAQs for Obstetrician-Gynecologists, Obstetrics. ACOG website. Updated October 2023. Accessed November 15, 2024. https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetricshttps://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetricsSociety for Maternal-Fetal Medicine: Publications and Clinical Guidance for COVID-19. SMFM website. Updated September 14, 2023. Accessed November 15, 2024. https://www.smfm.org/covid-clinicalhttps://www.smfm.org/covidclinicalAnesi GL et al: Characteristics, outcomes, and trends of patients with COVID-19-related critical illness at a learning health system in the United States. Ann Intern Med. 174(5):613-21, 2021

33460330

Cummings MJ et al: Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 395(10239):1763-70, 2020

32442528

Bertini P et al: ECMO in COVID-19 patients: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 36(8 Pt A):2700-6, 2022

34906383

Krishna BA et al: Cardiovascular disease and covid-19: A systematic review. Int J Cardiol Heart Vasc. 54:101482, 2024

39189008

Shen NN et al: A pooled analysis of the incidence and mortality risk of atrial fibrillation in patients with COVID-19. PeerJ. 12:e18330, 2024

39430559

Ahmad SA et al: Neurological Complications and Outcomes in Critically Ill Patients With COVID-19: Results From International Neurological Study Group From the COVID-19 Critical Care Consortium. Neurohospitalist. 19418744241292487, 2024

39544265

Klok FA et al: Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 191:148-50, 2020

32381264

Grasselli G et al: Hospital-acquired infections in critically ill patients with COVID-19. Chest. 160(2):454-65, 2021

33857475

Langford BJ et al: Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 26(12):1622-1629, 2020

32711058

Didriksson I et al: Long-term recovery in critically ill COVID-19 survivors: A prospective cohort study. Acta Anaesthesiol Scand. 69(1):e14550, 2025

39540322

Neville TH et al: Survival after severe COVID-19: long-term outcomes of patients admitted to an intensive care unit. J Intensive Care Med. 8850666221092687, 2022

35382627

Gesser AF et al: Impact of COVID-19 critical illness on functional status, fatigue symptoms, and health-related quality of life one-year after hospital discharge: a systematic review and meta-analysis. Disabil Rehabil. 46(18):4086-4097, 2024

37818936

Fernández-Gonzalo S et al: Characterization of postintensive care syndrome in a prospective cohort of survivors of COVID-19 critical illness: a 12-month follow-up study. Can J Anaesth. 71(9):1282-1301, 2024

39251486

Berentschot JC et al: Long-term health outcomes of COVID-19 in ICU- and non-ICU-treated patients up to 2 years after hospitalization: a longitudinal cohort study (CO-FLOW). J Intensive Care. 12(1):47, 2024

39516956

Nandasena HMRKG et al: Quality of life of COVID 19 patients after discharge: systematic review. PLoS One. 17(2):e0263941, 2022

35171956

Maley JH et al: Six-month impairment in cognition, mental health, and physical function following COVID-19-associated respiratory failure. Crit Care Explor. 4(4):e0673, 2022

35372848

CDC: COVID-19: Clinical Overview of Long COVID. CDC website. Updated July 12, 2024. Accessed November 17, 2024. https://www.cdc.gov/covid/hcp/clinical-overview/index.htmlhttps://www.cdc.gov/covid/hcp/clinical-overview/index.htmlXie Y et al: Long-term cardiovascular outcomes of COVID-19. Nat Med. 28(3):583-590, 2022

35132265

Xie Y et al: Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes Endocrinol. ePub, 2022

35325624

Mainous AG 3rd et al: COVID-19 post-acute sequelae among adults: 12 month mortality risk. Front Med (Lausanne). 8:778434, 2021

34926521

Huang C et al: 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 397(10270):220-32, 2021

33428867

Lebbe A et al: New Onset of Acute and Chronic Hepatic Diseases Post-COVID-19 Infection: A Systematic Review. Biomedicines. 12(9), 2024

39335578

Tereshchenko LG et al: Risk of cardiovascular events after COVID-19. Am J Cardiol. 179:102-9, 2022

35843735

Prestes GDS et al: Respiratory outcomes after 6 months of hospital discharge in patients affected by COVID-19: a prospective cohort. Front Med (Lausanne). 9:795074, 2022

35321473

Shrestha A et al: The risk of cognitive decline and dementia in older adults diagnosed with COVID-19: A systematic review and meta-analysis. Ageing Res Rev. 101:102448, 2024

39127446

Heo YW et al: Long-Term Risk of Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19. JAMA Dermatol. ePub, 2024

39504045

Mohammed I et al: Gastrointestinal Sequelae of COVID-19: Investigating Post-Infection Complications--A Systematic Review. Viruses. 16(10), 2024

39459851

COVID-19 Critical Care

Synopsis

Key Points

Urgent Action

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Sex

Ethnicity/race

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Admission criteria

Criteria for ICU admission

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures

Extracorporeal membrane oxygenation c66

Comorbidities

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening c78

Prevention

Extracorporeal membrane oxygenation ^c66

Screening ^c78