Clinical management of patients with COVID-19: Second interim guidance

August 17, 2020

This guidance document has been endorsed by: Canadian Critical Care Society and Association of Medical Microbiology and Infectious Disease (AMMI) Canada.

Contents

Preamble

This guidance has been adapted for Canadian use from the WHO document entitled Clinical management of COVID-19: interim guidance, 27 May 2020.

This guidance is informed by currently available scientific evidence, expert opinion, and a multidisciplinary panel of health care providers with experience in the clinical management of patients with COVID-19 and other viral infections (including other severe respiratory infections due to coronaviruses such as SARS and MERS) as well as sepsis and acute respiratory distress syndrome (ARDS).Footnote 1Footnote 2 The information presented is subject to change as new information becomes available.

This guidance provides clinicians with interim advice on timely, effective, and safe supportive management of adults, children and youth with suspected or confirmed acute COVID-19. It is not meant to replace clinical judgment or specialist consultation, but rather to strengthen the clinical management of these patients. Best practices for triage and optimized supportive care are included.

In the guidelines, these symbols are used to flag interventions:

Do to the intervention is beneficial (strong recommendation) or the intervention is a best practice statement

Don’t to the intervention is known to be harmful.

Consider to the intervention may be beneficial in selected patients (conditional recommendation) or be careful when considering this intervention.

1.0 Background

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus that was first recognized in Wuhan, China in December 2019. Genetic sequencing of the virus determined that it is a betacoronavirus closely related to the SARS-CoV-1 virus, named Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2).Footnote 3Footnote 4

It has been estimated that up to half of persons infected with SARS-CoV-2 will remain pauci-symptomatic or asymptomatic. While most people that develop COVID-19 present with mild or uncomplicated illness, up to 15% of patients may develop severe disease requiring hospitalization and oxygen support and up to 5% may require admission to an intensive care unit (ICU).Footnote 5Footnote 4Footnote 6Footnote 7Footnote 8 In severe cases, COVID-19 can be complicated by respiratory failure, acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism and multiorgan failure, including acute kidney injury and cardiac injury.Footnote 9 Older age and co-morbid disease are risk factors for severe disease and death.

Clinical presentation and symptoms of COVID-19 vary in frequency and severity. Symptoms absent at the onset of illness may develop over time with disease progression. Clinical diagnosis should therefore always be confirmed by laboratory testing, and patients should always be encouraged to seek medical consultation if experiencing new or worsening symptoms.Footnote 7Footnote 10

The current estimates of the incubation period range from 1-14 days with median estimates of 5-6 days between infection and the onset of clinical symptoms of the disease. People infected with SARS-CoV-2 may be infectious before symptom onset.Footnote 7 The risk of infection from most patients at more than 8 days post symptom onset is likely to be low.Footnote 11Footnote 12

There are few data on the clinical presentation of COVID-19 in specific populations, such as children and pregnant women. Relatively few infant COVID-19 cases have been reported and in children with COVID-19, the symptoms are usually less severe than adults.Footnote 7 However, although severe forms of COVID-19 are much less frequent than in adults, many countries have reported some pediatric ICU admissions and deaths related to COVID-19.Footnote 13 Clinicians should also be aware of very rare complications that have been associated with COVID-19 infection. A severe multisystem inflammatory syndrome in children (MIS-C) has been reported to share features of typical or atypical Kawasaki disease or toxic shock syndrome.Footnote 14Footnote 15Footnote 16Footnote 17Footnote 18Footnote 19Footnote 20Footnote 21Footnote 22

Pregnant women might be at increased risk for severe COVID-19 illness; experience with severe viral respiratory illness from other etiologies emphasizes the need for unique appreciation of pregnancy-related critical illness.Footnote 23

2.0 Screening and triage

The primary objective of the COVID-19 response is to slow and stop transmission, find, isolate and test every suspect case, and provide timely, culturally sensitive and appropriate care of patients with COVID-19. The recommended location of care will depend on the patient’s severity of illness, patient and cohabitant safety, and patient ability to return to care in the event of worsening illness.

Screening and triage to screen and isolate all patients with suspected COVID-19 at the first point of contact with the health care system (such as the emergency department or outpatient department/clinic). Consider COVID-19 as a possible etiology in patients presenting with acute respiratory illness and place all patients suspected to have COVID-19 under Droplet and Contact Precautions, with the addition of Airborne Precautions if performing any aerosol-generating medical procedures. Triage patients using standardized triage tools and manage initial presentations accordingly.

Table 1: Clinical syndromes associated with COVID-19
Syndrome Details

Asymptomatic/
presymptomatic

Patients will be tested for SARS-CoV2 and have positive results without ever having symptoms or prior to the development of symptoms.Footnote 10

Mild illness

Patients with uncomplicated upper respiratory tract viral infection typically present with some signs or symptoms of COVID-19 but without shortness of breath or dyspnea or abnormal imaging. These patients may have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, conjunctivitis, loss/alteration of smell and taste, or headache. Patients may also present with diarrhea, abdominal pain, nausea and vomiting.Footnote 7Footnote 28Footnote 29Footnote 30 Many are afebrile or have low-grade fever.

The elderly and immunocompromised may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, for example, dyspnea, fever, GI symptoms or fatigue, may overlap with COVID-19 symptoms.

Pneumonia

Adult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygen.

Child with non-severe pneumonia who has cough or difficulty breathing plus tachypnea (in breaths per minute): < 2 months: ≥ 60; 2 to 11 months: ≥ 50; 1 to 5 years: ≥ 40), and no signs of severe pneumonia.

While the diagnosis of pneumonia can be made on clinical grounds; chest imaging (radiograph, CT scan, ultrasound) may assist in diagnosis and identify or exclude pulmonary complications.

Severe pneumonia

Adolescent or adult: fever or suspected respiratory infection, plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air (adapted).Footnote 31

Child with cough and/or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2 < 90%; severe respiratory distress (for example, grunting, marked chest indrawing); signs of pneumonia with: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions.Footnote 32  Other signs of pneumonia may be present: fast breathing (in breaths/min) < 2 months: ≥ 60; 2 to 11 months: ≥ 50; 1 to 5 years: ≥ 40.Footnote 33 Chest imaging may identify some pulmonary complications.

Acute respiratory distress syndrome (ARDS)
Footnote 34Footnote 35Footnote 36

Onset: within 1 week of a known clinical insult or new or worsening respiratory symptoms.

Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules.

Origin of pulmonary infiltrates: respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (for example, echocardiography) to exclude hydrostatic cause of infiltrates/edema if no risk factor present.

Oxygenation impairment in adultsFootnote 34Footnote 36

  • mild ARDS: 200 mmHg < PaO2/FiO2Footnote a ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O, or non-ventilated)
  • moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated)
  • severe ARDS: PaO2/FiO2 ≤ 100 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated)
  • when PaO2 is not available, SpO2/FiO2 ≤ 315 suggests ARDS (including in non-ventilated patients)

Oxygenation impairment in children: Note OI = Oxygenation Index and OSI = Oxygenation Index using SpO2. Use PaO2-based metric when available. If PaO2 not available, wean FiO2 to maintain SpO2 at 92-97% to calculate OSI or SpO2/FiO2 ratio:

  • bilevel NIV or CPAP ≥ 5 cmH2O via full face mask: PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 264
  • mild ARDS (invasively ventilated): 4 ≤ OI < 8 or 5 ≤ OSI < 7.5
  • moderate ARDS (invasively ventilated): 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3
  • severe ARDS (invasively ventilated): OI ≥ 16 or OSI ≥ 12.3

Multi-system Inflammatory Syndrome in Children (MIS-C)

This is a syndrome that has been described in children and adolescents that presents with hyper- inflammatory markers with features of Kawasaki syndrome or septic shock. It is temporally related to COVID-19 outbreaks in several jurisdictions. Diagnostic criteria and characterization of this syndrome are evolving. A full discussion of this syndrome is beyond the scope of this document.

Sepsis
Footnote 1Footnote 2

Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction includeFootnote b: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia.Footnote 37Footnote 1

Children: suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count for age.

Septic shock
Footnote 1Footnote 2

Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥ 60-65 mmHg and serum lactate level > 2 mmol/L.

Children: any hypotension (SBP < 5th centile or > 2 SD below normal for age) or 2 or 3 of the following: altered mental state; tachycardia or bradycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia.Footnote 38 Children often have tachycardia before rapid onset of hypotension occurs.

Table 1 Footnote a

If altitude is higher than 1000m, then correction factor should be calculated as follows: PaO2/FiO2 x barometric pressure/760.

Table 1 Return to footnote a referrer

Table 1 Footnote b

The SOFA score ranges from 0 to 24 and includes points related to six organ systems: respiratory (hypoxemia defined by low PaO2/FiO2); coagulation (low platelets); liver (high bilirubin); cardiovascular (hypotension); central nervous system (low level of consciousness defined by Glasgow Coma Scale); and renal (low urine output or high creatinine).

Sepsis is defined by an increase in the sepsis-related SOFA score of ≥ 2 points. Assume the baseline score is 0 if data are not available.Footnote 39

Table 1 Return to footnote b referrer

Abbreviations: ARI acute respiratory infection; BP blood pressure; bpm beats per minute; CPAP continuous positive airway pressure; FiO2 fraction of inspired oxygen; MAP mean arterial pressure; NIV non-invasive ventilation; OI oxygenation Index; OSI oxygenation Index using SpO2; PaO2 partial pressure of oxygen; PEEP positive end-expiratory pressure; SBP systolic blood pressure; SD standard deviation; SIRS systemic inflammatory response syndrome; SOFA sequential organ failure assessment; SpO2 oxygen saturation.

3.0 Infection prevention and control measures

Infection prevention and control (IPC) is a critical and integral part of the clinical management of patients suspected or confirmed to have COVID-19.

Detailed national IPC guidance for COVID-19 in acute health care settings is available from the Public Health Agency of Canada (PHAC). Some provinces and territories have also issued IPC guidance for their jurisdiction, which complement existing regional and institutional policies. IPC guidance documents are revised and updated as new evidence becomes available therefore refer to the guidance documents directly.

Every effort should be made to allow support persons and essential visitors to visit patients.  This is perhaps particularly important for persons with disabilities and older persons, as well as at-risk patients and those nearing the end of life, in order to support the emotional burden and stress of both patients and loved ones. Visitation may be dependent upon sufficient local supply of PPE and the epidemiology of the virus in the local community. Visitors should receive in-time education, training, and monitoring for compliance with IPC measures, including practice with putting on and taking off appropriate PPE. Institutions will need to ensure that there are policies in place for PPE supply procurement and use. Health care settings should refer to the relevant local and jurisdictional public health guidance.

4.0 Collection of specimens for laboratory diagnosis

Testing criteria recommendations change as the situation evolves in regions.  All patients who are clinically suspected of infection with COVID-19 should be tested.

Currently, PCR-based molecular testing is predominantly being used in Canada. Since the sensitivity and specificity are linked to the viral load in the specimen, test performance varies during the course of the illness and by specimen type and quality of specimen collection. The virus is detected at high levels in the upper respiratory tract early in infection, and declines with time, usually over a 7 to 10 day period, although a prolonged period of shedding has been observed in recovering patients. In patients that develop a lower respiratory tract infection, detection from upper respiratory tract specimens (nasopharyngeal or nose/throat specimens) can be variable. In patients who are intubated, a lower respiratory tract specimen should be obtained, if possible. If there is a high suspicion of COVID-19 even after a negative swab of either type, individuals should be re-tested and have imaging of their lungs.

False negative test results/interpretations can occur when:

While it is very unusual to get a false positive result due to the cross reactivity with another RNA virus, PCR testing can sometimes give non-specific reactions or contamination within the laboratory can occur. Expert interpretation may be required in such cases.

Further guidance on appropriate testing and specimen collection for COVID-19 is available from the Public Health Agency of Canada, the Canadian Public Health Laboratory Network and from provincial/territorial public health laboratories.Footnote 10Footnote 41

Collect specimens for COVID-19 testing as recommended by your local or provincial public health laboratory.

Collect blood cultures for bacteria where clinically indicated based on the presenting syndrome, for example, sepsis or severe pneumonia, ideally before antimicrobial therapy. Do not delay antimicrobial therapy to collect blood cultures.  Blood cultures should be done in children if clinically indicated.

SARS-CoV-2 antibody tests are not recommended for diagnosis of current SARS-CoV-2 infection, but they may be useful in post-infectious syndromes.

5.0 Management of mild COVID-19

Patients with mild disease do not require hospitalization, unless there is concern for rapid deterioration or an inability to return promptly to hospital.

Isolation is necessary to contain virus transmission. All patients cared for outside hospital should be instructed to follow public health protocols for self-isolation and return to hospital if symptoms worsen. Self-isolation protocols are available from PHAC and provincial/territorial and local public health departments.

Provide patients with mild COVID-19 information on symptomatic treatment.

Counsel patients with mild COVID-19 and their caregivers about the signs and symptoms of complications that should prompt urgent care. If they develop symptoms like difficulty breathing, pain or pressure in the chest, confusion, drowsiness, or weakness, they should seek follow-up care.

Antibiotics should not be prescribed to patients with suspected or confirmed mild COVID-19 unless there is clinical suspicion of a bacterial infection.

6.0 Management of moderate COVID-19

Patients with moderate suspected or confirmed COVID-19 (for example, with clinical signs of pneumonia but no signs of severe pneumonia, including SpO2 ≥ 90% on room air) who are not determined to be at high risk of deterioration may not require hospitalization, but they should be isolated.

Antibiotics should not be prescribed to patients with suspected or confirmed moderate COVID-19 unless there is clinical suspicion of a bacterial infection.

7.0 Management of severe COVID-19

7.1 Oxygen therapy and monitoring

Give supplemental oxygen therapy immediately to patients with COVID-19 who have severe acute respiratory infection and respiratory distress, hypoxaemia or shock, and target saturations of 90-96% SpO2 during resuscitation.

Closely monitor patients with COVID-19 for signs of clinical deterioration, such as rapidly progressive respiratory failure or shock and respond immediately with supportive care interventions.

Understand the patient’s co-morbid conditions and tailor management accordingly.

Use conservative fluid management in patients with severe acute respiratory infection when there is no evidence of shock.

7.2 Treatment of co-infections

The prevalence of acute co-infections or secondary infections coinciding with COVID-19 has not been adequately described but appears to be low.Footnote 49 Antibiotic overuse increases the risk of emergence and transmission of multidrug-resistant bacteria. Infections with multidrug- resistant bacteria are more difficult to treat and are associated with increased morbidity and mortality.

Give empiric antimicrobials to treat all likely pathogens causing severe acute respiratory infection and sepsis as soon as possible, within 1 hour of initial patient assessment for patients with sepsis.

Frequently re-evaluate and de-escalate empiric therapy where possible on the basis of microbiology results and clinical judgment.

8.0 Management of critical COVID-19

8.1 Acute respiratory distress syndrome (ARDS)

Recognize severe hypoxemic respiratory failure when a patient with respiratory distress is failing standard oxygen therapy and prepare to provide advanced oxygen/ventilatory support.

Endotracheal intubation should be performed by a trained and experienced provider using airborne precautions.

Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until off oxygen or discharge if earlier) or equivalent glucocorticoid dose.

Recommendations for mechanically ventilated adult and pediatric patients with ARDS

Implement mechanical ventilation using lower tidal volumes (4 to 8 mL/kg predicted body weight [PBW]) and lower inspiratory pressures (plateau pressure < 30 cmH2O).

In adult patients with severe ARDS, prone ventilation for 12- 16 hours per day should be considered.

Use a conservative fluid management strategy for ARDS patients without tissue  hypoperfusion.

In patients with moderate or severe ARDS, higher PEEP instead of lower PEEP is  suggested.

In patients with moderate-severe ARDS (PaO2/FiO2 < 150), neuromuscular blockade by continuous infusion should not be routinely used.

Avoid disconnecting the patient from the ventilator, which results in loss of PEEP and atelectasis.

Use in-line catheters for airway suctioning and clamp the endotracheal tube when disconnection is required (for example, transfer to a transport ventilator).

Recommendations for adult and pediatric patients with ARDS who are treated with non-invasive or high flow oxygen systems

High-flow nasal oxygen (HFNO) and non-invasive ventilation (NIV) should be considered. Patients treated with either HFNO or NIV should be closely monitored for clinical deterioration.

Recommendations for adult and paediatric patients with ARDS in whom a lung protective ventilation strategy fails

In settings with access to expertise in extracorporeal membrane oxygenation (ECMO), consider referral of patients who have refractory hypoxemia despite lung protective ventilation.

8.2 Septic shock

Recognize septic shock in adults when infection is suspected or confirmed AND vasopressors are needed to maintain mean arterial pressure (MAP) ≥ 60-65 mmHg AND lactate is ≥ 2 mmol/L, in absence of hypovolemia.

Recognize septic shock in children with any hypotension (systolic blood pressure [SBP] < 5th centile or 2 SD below normal for age) or two or more of the following: altered mental state; bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or feeble pulses; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia.

Recommendations for resuscitation strategies for adult and paediatric patients with septic shock

In resuscitation for septic shock in adults, give 250-500 mL crystalloid fluid as a rapid bolus in the first 15- 30 minutes and reassess for signs of fluid overload after each bolus.

In resuscitation for septic shock in children, give 10-20 mL/kg crystalloid fluid as a rapid bolus in the first 30-60 minutes and reassess for signs of fluid overload after each bolus. 

Fluid resuscitation may lead to volume overload, including respiratory failure, particularly with ARDS. If there is no response to fluid loading or signs of volume overload appear (for example, jugular venous distension, crackles on lung auscultation, pulmonary edema on imaging, or hepatomegaly in children), then reduce or discontinue fluid administration. This step is particularly important in patients with hypoxemic respiratory failure.

Do not use hypotonic crystalloids, starches or gelatins for resuscitation.

In adults, administer vasopressors when shock persists during or after fluid resuscitation. The blood pressure target should be MAP ≥ 60-65 mmHg in adults and improvement of markers of perfusion.

In children administer vasopressors if signs of fluid overload are apparent or the following persist after two fluid boluses:

If central venous catheters are not available, vasopressors can be given through a peripheral IV, but use a large vein and monitor closely for signs of extravasation and local tissue necrosis. If extravasation occurs, stop the infusion and consider local injection of phentolamine. Vasopressors can also be administered through intraosseous needles.

If signs of poor perfusion and cardiac dysfunction persist despite achieving the MAP target with fluids and vasopressors, consider an inotrope such as dobutamine.

8.3 Prevention of complications

Implement the interventions shown in Table 2 below to prevent complications associated with critical illness. These interventions are based on Surviving Sepsis and other guidelines and are considered to be feasible and based on high quality evidence.Footnote 1Footnote 77Footnote 78Footnote 79Footnote 80

Careful consideration should be given to the numerous, clinically significant side-effects of medications that may be used in the context of COVID-19, as well as drug-drug interactions between medications, both of which may affect COVID-19 symptomatology (including effects on respiratory, cardiac, immune and mental and neurological function). Both pharmacokinetic and pharmacodynamic effects should be considered.

Table 2: Prevention of complications in critically ill patients
Anticipated outcome Interventions

Reduce days of invasive mechanical ventilation

  • Use weaning protocols that include daily assessment for readiness to breathe spontaneously;
  • Minimize continuous or intermittent sedation, targeting specific titration endpoints (sedation score targeted light sedation unless contraindicated) or with daily interruption of continuous sedative infusions;
  • Early mobilization;
  • Implementation of the above as a bundle of care (such as the Awakening and Breathing Coordination, Delirium assessment/management, and Early mobility [ABCDE]) may also reduce delirium.

Reduce incidence of ventilator-associated pneumonia

  • Oral intubation is preferable to nasal intubation in adolescents and adults;
  • Keep patient in semi-recumbent position (head of bed elevation at 30 to 45o);
  • Use a closed suctioning system; periodically drain and discard condensate in tubing;
  • Continue regular oral care
  • Use a new ventilator circuit for each patient; once patient is ventilated, change circuit if it is soiled or damaged, but not routinely;
  • Change heat moisture exchanger when it malfunctions, when soiled, or every 5 to 7 days.

Reduce incidence of venous thromboembolism

  • Use pharmacological prophylaxis (low molecular-weight heparin [preferred] or heparin subcutaneously twice daily) in children, adolescents and adults without contraindications, and based on an assessment of individual risk factors for both thrombosis and bleeding. For those with contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices).

Reduce incidence of catheter-related bloodstream infection

  • Use a checklist with completion verified by a real-time observer as a reminder of each step needed for sterile insertion and as a daily reminder to remove catheter if no longer needed.

Reduce incidence of pressure ulcers

  • Turn patient every 2 hours.

Reduce incidence of stress ulcers and gastrointestinal bleeding

  • Give early enteral nutrition (within 24 to 48 hours of admission);
  • Consider administering histamine-2 receptor blockers or proton-pump inhibitors in patients with risk factors for GI bleeding. Risk factors for gastrointestinal bleeding include mechanical ventilation for ≥ 48 hours, coagulopathy, renal replacement therapy, liver disease, multiple comorbidities, and higher organ failure score. Stress ulcer prophylaxis should be reassessed as the patient’s condition improves and as enteral feeding is established.

Reduce incidence of ICU-related weakness

  • Actively mobilize the patient early in the course of illness when safe to do so.

Reduce the development of antimicrobial resistance

  • Utilize de-escalation protocols as soon as patient is clinically stable and there is no evidence of bacterial infection.

Promote appropriate antimicrobial prescribing and use during the COVID- 19 pandemic

  • Do not prescribe antibiotics to suspected or confirmed COVID-19 patients with low suspicion of a bacterial infection, to avoid short-term side-effects of antibiotics and negative long-term consequences of increased antimicrobial resistance.

9.0 Special considerations

9.1 Caring for pregnant women with COVID-19

The Society for Obstetrician and Gynecologists Canada (SOGC) has published COVID-19 resources on obstetric and perinatal care to assist obstetricians in Canada.  To date, there are limited data on clinical presentation and perinatal outcomes after COVID-19 during pregnancy or the post-partum period. There is no solid evidence that pregnant women present with different signs or symptoms or are at higher risk of severe illness. The literature is mixed regarding whether pregnant women are at higher risk of severe illness, however it appears that the rates are not significantly higher, with reports of 4% or women requiring ICU admission and 3% requiring mechanical ventilation, which are similar to the non-pregnant population.

The section below on COVID-19 and pregnancy builds on existing recommendations and provides additional remarks for the management of pregnant and recently pregnant women.

Pregnant and recently pregnant women with suspected or confirmed COVID-19 should be isolated and treated with the supportive and management therapies previously described for other adults, taking into account the immunologic and physiologic adaptations occurring during and after pregnancy.

Pregnant women with a suspected, probable or confirmed COVID-19 infection, including women who may need to spend time in isolation, should have access to woman-centred, respectful skilled care, including obstetric, foetal medicine and neonatal care, as well as mental health and psychosocial support, with readiness to care for maternal and neonatal complications.

All recently pregnant women with COVID-19 infection or who have recovered from COVID-19 should be provided with counselling on safe infant feeding, including recommendations for breast feeding and appropriate infection prevention measures to prevent COVID-19 transmission (see section 9.2 below).

Pregnant and recently pregnant women who have recovered from COVID-19 should be encouraged to attend enhanced antenatal, postpartum or other obstetrical care as appropriate. Enhanced fetal surveillance is recommended for women with COVID-19 illness.

9.2 Caring for infants and mothers with COVID-19 to IPC and breastfeeding

Relatively few cases have been reported of infants confirmed with COVID-19 infection. At this time there is no clear evidence that vertical transmission occurs. Breast milk samples from the mothers after the first lactation were negative for SARS CoV-2.Footnote 81Footnote 82 Although recommendations for infant feeding varies around the world, Canadian recommendations are found below.  Additional guidance on feeding and caring for infants and young children of mothers with COVID-19 is available on the WHO website.

Infants born to mothers with suspected, probable, or confirmed COVID-19 should be fed according to standard infant feeding guidelines, primarily breast feeding while providing necessary infection prevention precautions.

Symptomatic mothers who are breastfeeding should practice respiratory hygiene, including during feeding (for example, use of a mask when near a child if the mother has respiratory symptoms), perform hand hygiene before and after contact with the child, and routinely clean and disinfect surfaces with which the symptomatic mother has been in contact.

In situations when severe illness in a mother due to COVID-19 or other complications prevents her from caring for her infant or prevents her from continuing direct breastfeeding, mothers should be encouraged and supported to express milk, and safely provide breast milk to the infant, while applying appropriate IPC measures.

Mothers and infants should be allowed to remain together and to practice rooming-in if desired, especially during establishment of breastfeeding, whether they or their infants have suspected, probable or confirmed COVID-19.

Parents and caregivers who may need to be separated from their children, and children who may need to be separated from their primary caregivers, should have access to appropriately trained health or non-health workers for mental health and psychosocial support. 

9.3 Caring for older persons with COVID-19

Older age and comorbid conditions such as diabetes and cardiovascular disease have been reported as risk factors for death in persons with COVID-19.Footnote 40 Because older persons are at highest risk for severe disease and fatality and are one of the most vulnerable populations, they should be screened for COVID-19 at the first point of access to the health system, be diagnosed promptly if they are suspected to have COVID-19 and treated appropriately. As older patients may present with atypical symptoms, health workers should take this into account during the screening process.

Identify if there is an advance care plan for patients with COVID-19 and ensure the care plan takes into consideration their priorities and preferences. Tailor the care plan to be in line with the patient’s expressed wishes (refer to section 9.5 for additional guidance on palliative care)

For older persons with probable or suspected COVID-19, in addition to a conventional history the assessment should include an understanding of the person’s life, values, priorities and preferences for health management.

Ensure multidisciplinary collaboration (physicians, nurses, pharmacists and other health professionals) in the decision-making process to address multimorbidity and functional decline.

Early detection of inappropriate medication prescriptions is recommended to prevent adverse drug events and drug interactions in those being treated for COVID-19.

Where appropriate, involve caregivers and family members in decision-making and goal setting throughout the management of older COVID-19 patients.

Symptom-based and palliative care should be provided, as appropriate, even for patients with supportive or curative goals of care.

9.4 Managing patients with COVID-19 in remote and isolated communities

While primary health care services are available in most remote and isolated communities, there is limited capacity to provide acute care and they may lack appropriate medical equipment, supplies and services (for example, ventilators, access to specialists) to treat patients with severe illness. In many remote and isolated communities, a nurse-led health care team can provide emergency resuscitation and stabilization, emergency ambulatory care and outpatient non-urgent services. Access to physician services is available remotely via telehealth or teleconference, but much variation exists from community to community regarding the availability and frequency of physicians. Severely ill patients requiring complex emergency medical care are evacuated to a secondary or tertiary hospital or facility.

Treatment considerations for these remote and isolated settings include the following measures:

9.5 Palliative care and COVID-19

We recommend identifying, in all patients with COVID-19, if they have an advance care plan for COVID-19 (such as desires for intensive care support) and to discuss goals of care in the setting of acute illness. Patient priorities and preferences should be respected and their care plan tailored to allow the provision of the best care irrespective of treatment choice.

Palliative care services should be made accessible at each institution that provides care for persons with COVID-19, and symptomatic treatments (for example, management of dyspnea) should be provided even for patients with supportive or curative goals of care.

9.6 Immunocompromised patients and COVID-19

Patients living with HIV Infection should be offered standard of care.

In solid organ transplant patients, the risk of COVID 19 infection from a living donor or deceased donor is unknown at this time and such decisions on transplantation are to be made with expert advice.

In Hematopoietic Stem Cell Transplantation (HSCT) patients, it is recommended that all recipients should have a negative COVID 19 PCR test prior to start of conditioning.

10.0 Specific and adjunctive COVID-19 treatments and clinical research

There are many ongoing clinical trials testing various potential medical treatments. Until specific therapies become available, any medication should be given as part of a randomized controlled trial.

Collect standardized clinical data on all hospitalized patients to improve our understanding of the natural history of disease.

Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose.

 Consider the use of Remdesivir, either as a therapy or preferably as part of a randomized controlled trial.

 Do not use hydroxychloroquine or ritonavir/lopinavir outside of a clinical trial.

Use of investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials.

11.0 Acknowledgments

This guidance document was prepared by: Dr. R. Fowler, Dr. T. Hatchette, Dr. M. Salvadori, Dr. O. Baclic, Dr. C. Volling, Dr. S. Murthy, Dr. G. Emeriaud, Dr. D. Money, Dr. T. Yeung, Dr. G Poliquin, Dr. J. Brooks, ML Decou and Dr. M. Ofner

The guidance document has been endorsed by: Canadian Critical Care Society and Association of Medical Microbiology and Infectious Disease (AMMI) Canada

Canadian Critical Care Society reviewers: Dr. K. Burns, Dr. F. D’Aragon, Dr. J. Downar, Dr. C. Farrell, Dr. S. Murthy & Dr. J. Waechter

Association of Medical Microbiology and Infectious Disease (AMMI) Canada reviewers: Dr. G. Evans, Dr. S. Forgie, Dr. S. Hota, Dr. S. Mubareka, Dr. J. Papenburg

References

Footnote 1

A. Rhodes, L. Evans, W. Alhazzani, L. Mitchell and M. Antonelli, "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016," Intensive Care Medicine, vol. 43, no. 3, pp. 304-377, 18 01 2017.

Return to footnote 1 referrer

Footnote 2

S. Weiss, M. Peters, W. Alhazzani, A. Michael, H. Flori and D. Inwald, "Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children," Pediatric Critical Care Medicine, vol. 21, no. 2, 02 2020.

Return to footnote 2 referrer

Footnote 3

Coronaviridae 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, vol. 5, pp. 536-544, 2020.

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X. Yang, Y. Yu, J. Xu, H. Shu, J. Xia, H. Liu, S. Pan, X. Zou, S. Yuan and Y. Shang, "Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.," Lancet Respiratory Medicine, no. 5, pp. 475-481, 28 02 2020.

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S. Riphagen, X. Gomez and C. Gonzalez-Martinez, "Hyperinflammatory shock in children during COVID-19 pandemic," Lancet, vol. 395, no. 10237, p. 1607 to 1608, 2020

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L. Feldstein, E. Rose and S. Horwitz, "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents," N Engl J Med, 2020.

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J. Cai, J. Xu, D. Lin, Z. Yang, L. Xu and Z. Qu, "A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features," Clinical Infectious Diseases, 28 02 2020.

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Footnote 26

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Footnote 27

Z. Wu and J. Mcgoogan, "Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention," JAMA, vol. 323, no. 13, p. 1239, 07 04 2020.

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Footnote 28

C. Huang, Y. Wang, X. Li, L. Ren, J. Zhao and Y. Hu, "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China," The Lancet, vol. 395, no. 10223, pp. 497-, 2020.

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E. Riviello, W. Kiviri, T. Twagirumugabe, A. Mueller, V. Banner-Goodspeed, L. Officer and V. Novack, "Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition," American Journal of Respiratory and Critical Care Medicine, vol. 193, no. 1, pp. 52-59, 01 2016.

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J. Vincent, R. Moreno, J. Takala, S. Willatts, A. Mendonça, H. Bruining, C. Reinhart, P. Suter and L. Thijs, "The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure," Intensive Care Medicine, vol. 22, no. 7, pp. 707-710, 07 1996.

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F. Zhou, T. Yu, R. du, G. Fan, Y. Liu, Z. Liu, J. Xiang, Y. Wang, B. Song, X. Gu, L. Guan, Y. Wei and H. Li, "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study," The Lancet, vol. 395, no. 10229, pp. 1054-1062, 2020.

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W. Park, L. Poon, S.-J. Choi, P. Choe, K.-H. Song, J. Bang, E. Kim and H. Kim, "Replicative virus shedding in the respiratory tract of patients with Middle East respiratory syndrome coronavirus infection," International Journal of Infectious Diseases, vol. 72, pp. 8-10, 07 2018.

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W. Edwards, S. Dore, J. van Schalkwyk and B. Armson, "Prioritizing Maternal Sepsis: National Adoption of an Obstetric Early Warning System to Prevent Morbidity and Mortality," Journal of Obstetrics and Gynaecology Canada, vol. 42, no. 5, pp. 640-643, 01 05 2020.

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M. Schultz, M. Dunser, A. Dondorp, N. Adhikari, S. Iyer, A. Kwizera, Y. Lubell, A. Papali and L. Pisani, "Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future," Intensive Care Medicine, vol. 43, no. 5, pp. 612-624, 27 03 2017.

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T. Rawson, L. Moore and N. Zhu, "Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing," Clin Infect Dis, 2020.

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P. Peng, P.-L. Ho and S. Hota, "Outbreak of a new coronavirus: what anaesthetists should know," British Journal of Anaesthesia, vol. 124, no. 5, pp. 497-501, 05 2020.

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M. Detsky, N. Jivraj, N. Adhikari, J. Friedrich, R. Pinto, D. Simel, D. Wijeysundera and D. Scales, "Will This Patient Be Difficult to Intubate? The Rational Clinical Examination Systematic Review," JAMA, vol. 321, no. 5, p. 493, 05 02 2019.

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P. Rimensberger and I. Cheifetz, "Ventilatory Support in Children With Pediatric Acute Respiratory Distress Syndrome: Proceedings from the pediatric acute lung injury consensus conference," Pediatric Critical Care Medicine, vol. 16, no. 5, pp. S51-S60, 06 2015.

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H. Wiedemann, A. Wheeler and G. Bernard, "Comparison of Two Fluid-Management Strategies in Acute Lung Injury," New England Journal of Medicine, vol. 354, no. 24, pp. 2564-2575, 2006.

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M. Amato, M. Meade, A. Slutsky, L. Brochard, E. Costa, D. Schoenfeld, T. Stewart, M. Briel and D. Talmor, "Driving Pressure and Survival in the Acute Respiratory Distress Syndrome," New England Journal of Medicine, vol. 372, no. 8, pp. 747-755, 19 02 2015.

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Footnote 57

M. Briel, M. Meade, A. Mercat, R. Brower, D. Talmor, S. Walter, A. Slutsky and E. Pullenayegum, "Higher vs Lower Positive End-Expiratory Pressure in Patients With Acute Lung Injury and Acute Respiratory Distress Syndrome," JAMA, vol. 303, no. 9, p. 865, 03 03 2010.

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A. Cavalcanti, É. Suzumura and L. Laranjeira, "Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome," JAMA, vol. 318, no. 14, pp. 1335-1345, 2017.

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Footnote 59

E. Goligher, B. Kavanagh, G. Rubenfeld, N. Adhikari, R. Pinto, E. Fan, L. Brochard, J. Granton and A. Mercat, "Oxygenation Response to Positive End-Expiratory Pressure Predicts Mortality in Acute Respiratory Distress Syndrome. A Secondary Analysis of the LOVS and ExPress Trials," American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 1, pp. 70-76, 2014.

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L. Papazian, J.-M. Forel, A. Gacouin, C. Penot-Ragon, G. Perrin, A. Loundou, S. Jaber, J.-M. Arnal and D. Perez, "Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome," New England Journal of Medicine, vol. 363, no. 12, pp. 1107-1116, 2010.

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Footnote 61

National Heart Lung and Blood Institute, "Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome," New England Journal of Medicine, vol. 380, no. 21, pp. 1997-2008, 2019.

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B. Rochwerg, L. Brochard, M. Elliott, D. Hess, N. Hill, S. Nava, P. Navalesi and M. Antonelli, "Official ERS/ATS clinical practice guidelines: noninvasive ventilation," European Respiratory Journal, vol. 50, no. 2, p. 1602426, 2017.

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M. Lee, J. Choi, B. Park, B. Kim, S. Lee, S.-H. Kim, S. Yong, E. Choi and W.-Y. Lee, "High flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure," The Clinical Respiratory Journal, vol. 12, no. 6, pp. 2046-2056, 2018.

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Y. Luo, R. Ou, Y. Ling and T. Qin, "[The therapeutic effect of high flow nasal cannula oxygen therapy for the first imported case of Middle East respiratory syndrome to China].," Zhonghua wei Zhong Bing ji jiu yi xue, vol. 27, no. 10, pp. 841-844, 30 09 2015.

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Footnote 65

Y. Arabi, A. Arifi, H. Balkhy, H. Najm, A. Aldawood, A. Ghabashi, H. Hawa, A. Alothman, K. Abdulaziz and B. Raiy, "Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection," Annals of Internal Medicine, vol. 160, no. 6, pp. 389-397, 2014.

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O. Ekhaguere, A. Mairami and H. Kirpalani, "Risk and benefits of Bubble Continuous Positive Airway Pressure for neonatal and childhood respiratory diseases in Low- and Middle-Income countries," Paediatric Respiratory Reviews, vol. 29, pp. 31-36, 2019.

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Footnote 67

A. Combes, D. Hajage, G. Capellier, A. Demoule, S. Lavoué, C. Guervilly, D. Silva, L. Zafrani and P. Tirot, "Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome," New England Journal of Medicine, vol. 378, no. 21, pp. 1965-1975, 2018.

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Footnote 68

E. Goligher, G. Tomlinson, D. Hajage, D. Wijeysundera, E. Fan, P. Jüni, D. Brodie, A. Slutsky and A. Combes, "Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial," JAMA, vol. 320, no. 21, pp. 2251-2259, 2018.

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Footnote 69

M. Alshahrani, A. Sindi, F. Alshamsi, A. Al-Omari, M. Tahan, A. Zein and B. Alahmadi, "Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus," Annals of Intensive Care, vol. 8, no. 1, 10 01 2018.

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Footnote 70

A. Combes, D. Brodie, R. Bartlett, L. Brochard, R. Brower, S. Conrad, D. Backer and E. Fan, "Position Paper for the Organization of Extracorporeal Membrane Oxygenation Programs for Acute Respiratory Failure in Adult Patients," American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 5, pp. 488-496, 01 09 2014.

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Footnote 71

L. Munshi, A. Walkey, E. Goligher, T. Pham, E. Uleryk and E. Fan, "Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis," The Lancet Respiratory Medicine, vol. 7, no. 2, pp. 163-172, 02 2019.

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B. Andrews, M. Semler, L. Muchemwa, P. Kelly, S. Lakhi, D. Heimburger, C. Mabula, M. Bwalya and G. Bernard, "Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension," JAMA, vol. 318, no. 13, pp. 1233-1240, 03 10 2017.

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Footnote 73

K. Maitland, S. Kiguli, R. Opoka, C. Engoru, P. Olupot-Olupot, S. Akech, R. Nyeko, G. Mtove, H. Reyburn and T. Lang, "Mortality after Fluid Bolus in African Children with Severe Infection," New England Journal of Medicine, vol. 364, no. 26, pp. 2483-2495, 30 06 2011.

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R. Bridwell, B. Carius, B. Long, J. Oliver and G. Schmitz, "Sepsis in Pregnancy: Recognition and Resuscitation," Western Journal of Emergency Medicine, vol. 20, no. 5, pp. 822-832, 06 08 2019.

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Footnote 75

B. Rochwerg, W. Alhazzani, A. Sindi, D. Heels-Ansdell, L. Thabane, A. Fox-Robichaud, L. Mbuagbaw, W. Szczeklik and F. Alshamsi, "Fluid Resuscitation in Sepsis: a systematic review and network meta-analysis," Annals of Internal Medicine, vol. 161, no. 5, pp. 347-355, 02 07 2014.

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O. Loubani and R. Green, "A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters," Journal of Critical Care, vol. 30, no. 3, pp. 653.e9-653.e17, 22 01 2015.

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Footnote 77

M. Klompas, R. Branson, E. Eichenwald, L. Greene, M. Howell, G. Lee, S. Magill, L. Maragakis and G. Priebe, "Strategies to Prevent Ventilator-Associated Pneumonia in Acute Care Hospitals: 2014 Update," Infection Control & Hospital Epidemiology, vol. 35, no. 8, pp. 915-936, 09 2014.

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Footnote 78

J. Marschall, L. Mermel, M. Fakih, L. Hadaway, A. Kallen, N. O’Grady, A. Pettis, M. Rupp and T. Sandora, "Strategies to Prevent Central Line to Associated Bloodstream Infections in Acute Care Hospitals: 2014 Update," Infection Control & Hospital Epidemiology, vol. 35, no. 7, pp. 753-771, 07 2014.

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Footnote 79

J. Muscedere, P. Dodek, S. Keenan, R. Fowler, D. Cook and D. Heyland, "Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: Prevention," Journal of Critical Care, vol. 23, no. 1, pp. 126-137, 03 2008.

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Footnote 80

G. Schmidt, T. Girard, J. Kress, P. Morris, D. Ouellette, W. Alhazzani, S. Burns, S. Epstein and A. Esteban, "Official Executive Summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults," American Journal of Respiratory and Critical Care Medicine, vol. 195, no. 1, pp. 115-119, 2017.

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Footnote 81

H. Zhu, L. Wang, C. Fang, S. Peng, L. Zhang, G. Chang, S. Xia and W. Zhou, "Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia," Translational Pediatrics, vol. 9, no. 1, pp. 51-60, 02 2020.

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Footnote 82

H. Chen, J. Guo, C. Wang, F. Luo, X. Yu, W. Zhang, J. Li, D. Zhao and D. Xu, "Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records," The Lancet, vol. 395, no. 10226, pp. 809-815, 07 03 2020.

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Footnote 83

M. Holshue, C. Debolt, S. Lindquist, K. Lofy, J. Wiesman, H. Bruce, C. Spitters, K. Ericson and S. Wilkerson, "First Case of 2019 Novel Coronavirus in the United States," New England Journal of Medicine, vol. 382, no. 10, pp. 929-936, 05 03 2020.

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M. Fung and J. Babik, "COVID-19 in Immunocompromised Hosts: What We Know So Far," Clinical Infectious Diseases.

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"COVID-19 Treatment Guidelines: National Institutes of Health," 2020. [Online]. Available: https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf.

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D. Halpin, D. Singh and R. Hadfield, "Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective," Eur Respir J, vol. 55, no. 5, 2020.

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A. Bhimraj, R. Morgan and A. Shumaker, "Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19," Clin Infect Dis, 2020.

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C. Licskai, C. Yang and F. Ducharme, "Key highlights from the Canadian Thoracic Society's Position Statement on the Optimization of Asthma Management during the COVID-19 Pandemic," Chest, 2020.

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Footnote 90

Y. Licskai, F. Ducharme and D. Radhakrishnan, "Addressing therapeutic questions to help Canadian physicians optimize asthma management for their patients during the COVID-19 pandemic," Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, vol. 4, no. 2, pp. 73-76, 2020.

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Footnote 91

H. Bhutani, J. Bourbeau and G. Dechman., "KEY HIGHLIGHTS of the Canadian Thoracic Society's Position Statement on the Optimization of Chronic Obstructive Pulmonary Disease Management during the COVID-19 Pandemic," Chest, 2020.

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Footnote 92

M. Bhutani, J. Bourbeau and G. Dechman, "ddressing therapeutic questions to help Canadian health care professionals optimize COPD management for their patients during the COVID-19 pandemic," Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, vol. 4, no. 2, pp. 77-80, 2020.

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M. Patel, K. Steinberg and M. Suarez-Barcelo, "Chronic Obstructive Pulmonary Disease in Post-acute/Long-term Care Settings: Seizing Opportunities to Individualize Treatment and Device Selection," Am Med Dir Assoc, vol. 18, no. 6, pp. e17- e22, 2017.

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J. Beigel, K. Tomashek and L. Dodd., "Remdesivir for the Treatment of Covid-19 - Preliminary Report," N Engl J Med, 2020.

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P. Horby and M. Mafham, "Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.," medRxiv, 2020.

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Footnote 97

"No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY," [Online]. Available: https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery.

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