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

Contents

• Preamble
• 1.0  Background
• 2.0 Screening and triage
• 3.0 Infection prevention and control measures.
• 4.0 Collection of specimens for laboratory diagnosis
• 5.0 Management of mild COVID-19
• 6.0 Management of moderate COVID-19
• 7.0 Management of severe COVID-19
  • 7.1 Oxygen therapy and monitoring
  • 7.2 Treatment of co-infections
• 8.0 Management of critical COVID-19
  • 8.1 Acute respiratory distress syndrome (ARDS)
  • 8.2 Septic shock
  • 8.3 Prevention of complications
• 9.0 Special considerations
  • 9.1 Caring for pregnant women with COVID-19
  • 9.2 Caring for infants and mothers with COVID-19 to IPC and breastfeeding
  • 9.3 Caring for older persons with COVID-19
  • 9.4 Managing patients with COVID-19 in remote and isolated communities
  • 9.5 Palliative care and COVID-19
  • 9.6 Immunocompromised patients and COVID-19
• 10.0 Specific and adjunctive COVID-19 treatments and clinical research
• 11.0 Acknowledgments
• References

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:

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.

• National surveillance case definitions have been developed to standardize public health reporting. These case definitions, however, are not to be used for clinical purposes.^{Footnote 24}
• Early recognition of suspected patients allows for timely initiation of appropriate infection prevention and control measures (see the Infection prevention and control section). Table 1 below outlines the clinical syndromes most often associated with COVID-19.
• Detailed guidance on infection prevention and control in acute healthcare settings and in outpatient and ambulatory care settings is available on the Public Health Agency of Canada website.^{Footnote 25Footnote 26}
• Most people with COVID-19 have uncomplicated or mild illness (approximately 80%). Some will develop severe illness requiring oxygen therapy and up to 5% will develop critical illness requiring ICU treatment. Of those critically ill, many will require mechanical ventilation.^{Footnote 9Footnote 27Footnote 7Footnote 11Footnote 8}
• For those with mild illness, hospitalization is not required unless there is concern about rapid deterioration or inability to return promptly to hospital.
• Isolation is necessary to contain virus transmission. All patients cared for outside of the hospital (for example, at home) should be instructed to follow public health protocols for self-isolation and return to hospital if their symptoms worsen.
• Early identification of those with severe illness or pneumonia, allows for optimized supportive care treatments and safe, rapid referral and admission to a hospital.
• Older people and those with comorbidities (for example, cardiovascular disease, diabetes mellitus, obesity, pre-existing lung conditions) have increased risk of severe disease and mortality. While they may present with mild disease, they have a higher risk of deterioration and should be monitored closely.
• Goals of care discussions should be a component of care for all patients, especially those who are at risk for, or present with, severe disease. Whether or not patients receive intensive and organ-supportive care in severe illness, patients should receive symptom-based care (including dyspnea management) and palliative care should be offered as appropriate. Symptom-based care and palliative care can be provided alongside supportive and curative treatments, and do not compromise survival.

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 adults: Footnote 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:

• The patient was not infected at the time of the initial swab, but became infected from a later exposure.
• The patient is infected but is not yet shedding much virus in the upper respiratory tract.  Every infection has a "window period" during which time the virus incubating in the patient may be there in quantities that are too low to be detected by any diagnostic test.
• The patient is shedding virus but the sample collection was poor.  Proper collection technique is essential to ensure that an adequate amount of specimen is collected from the correct anatomical site.
• The patient’s infection is manifesting outside the upper respiratory tract. In symptomatic people with mild infection, we know that the virus is shed just before or soon after symptom onset and in high numbers in the upper respiratory tract, lasting for at least 5-7 days.^{Footnote 40} However, in patients who have pneumonia, the most sensitive specimen is from the lungs.

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}

• In admitted patients with suspected COVID-19, the diagnosis should be first attempted with an upper respiratory specimen, preferably a nasopharyngeal swab. However, a mid-turbinate and/or throat swab can be collected as an alternative if nasopharyngeal swabs are not available. For admitted patients with suspected COVID-19, if the upper respiratory swab is negative and there remains a high degree of clinical suspicion a repeat swab should be collected. In severely ill patients whose upper respiratory tract specimen is negative but a COVID-19 diagnosis is still suspected, a lower respiratory tract specimen consisting of sputum, or closed system suctioned endotracheal aspirate should also be collected when possible (for example, if the patient is producing sputum or they are already ventilated). Once a patient has a positive laboratory test, further testing for diagnostic purposes is not necessary.^{Footnote 42}
• Patients can be infected with more than one virus at the same time. Coinfections with other respiratory viruses in people with COVID-19 have been reported. Therefore, identifying infection with one respiratory virus does not exclude SARS-CoV-2 virus infection, and vice-versa.

5.0 Management of mild COVID-19

• In children signs and symptoms of clinical deterioration requiring urgent re-evaluation include difficulty breathing/fast or shallow breathing (for infants: grunting, inability to breastfeed), blue lips or face, chest pain or pressure, new confusion, inability to awaken/not interacting when awake, inability to drink or keep down liquids, extreme weakness).

6.0 Management of moderate COVID-19

• The decision regarding the location of care should be made on a case-by-case basis and will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household.
• For patients at high risk for deterioration, admission to hospital should be considered.
• The median time to acute respiratory distress syndrome (ARDS) ranges from 8 to 12 days.
• Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high CRP, and high ferritin levels may be associated with greater illness severity.^{Footnote 43}

7.0 Management of severe COVID-19

7.1 Oxygen therapy and monitoring

• Adults with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy. Initiate oxygen therapy at 5 L/min and titrate flow rates to reach target SpO₂ ≥ 94% during resuscitation; or use face mask with reservoir bag (at 10-15 L/min) if the patient is in critical condition. Once the patient is stable, the target is > 90% SpO₂ in non-pregnant adults and ≥ 92 to 95% in pregnant patients.
• In adults, techniques such as positioning, for example, high supported sitting may help to optimize oxygenation, ease breathlessness and reduce energy expenditure.^{Footnote 44} Prone position for awake, spontaneously breathing patients may also improve oxygenation and the ventilation/perfusion ratio, but evidence is lacking and should be done under clinical trial protocols to assess efficacy and safety. Children with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy during resuscitation to target SpO₂ ≥ 94%; otherwise, the target SpO₂ is ≥ 90%.^{Footnote 45} The use of a nasal cannula is preferred in young children, as it may be better tolerated.
• All areas where patients with severe acute respiratory infection are cared for should be equipped with pulse oximeters, functioning oxygen systems and disposable, single-patient use, oxygen-delivering interfaces (nasal cannula, face mask and mask with reservoir bag).

• Patients hospitalized with COVID-19 require regular monitoring of vital signs and, where possible, use of early warning scores (for example, NEWS2) that facilitate early recognition and escalation of care for a deteriorating patient.^{Footnote 46} Deterioration in adults is often sudden and may occur in the second week of illness.
• Patients with COVID-19 who have signs or symptoms suggestive of venous or arterial thromboembolism, (for example, stroke, deep venous thrombosis, pulmonary embolism or acute coronary syndrome) should be diagnosed (using laboratory tests and/or imaging) and treated according to hospital protocols. In pregnant women, sepsis is harder to assess. Use of a modified sepsis score, such as the modified early assessment warning system (MEOWS) is recommended.^{Footnote 47}
• In adults, a complete blood count with differential, electrolytes, creatinine, liver enzymes, liver function tests and lactate as well as other clinically indicated diagnostics (for example, blood tests, chest imaging and an ECG), should be performed at admission and as clinically indicated, to monitor for complications such as acute liver injury, acute kidney injury, acute cardiac injury or shock. Paediatric patients should have testing done as indicated by clinical judgement. Consider developing electronic order sets or pre-printed orders.
• Application of timely, effective and safe supportive therapies is the cornerstone of therapy for patients who develop severe manifestations of COVID-19.
• After resuscitation and stabilization of a pregnant patient, fetal well-being should be monitored.

• Determine which chronic therapies should be continued and which should be stopped temporarily.
  • Monitor for drug interactions
  • Revisit the need for any held medications when clinically appropriate
• Metered dose inhalers with a spacer are preferred to nebulizers to reduce the potential to generate respiratory aerosols.
• Antihypertensive drugs should not routinely be stopped in patients with COVID-19, but therapy may need to be adjusted based on general considerations for patients with acute illness, with particular reference to maintaining normal blood pressure and renal function.
• Patients with psychiatric and neurological manifestations should be assessed for any underlying causes, including the monitoring of oxygenation and fluid status, correcting metabolic or endocrine abnormalities, addressing co-infections, minimizing the use of medications that may cause or worsen delirium, treating withdrawal from substances, understanding and minimizing the effects of any harmful drug-drug interactions and maintaining normal sleep cycles as much as possible.
• To reduce delirium in patients who are receiving invasive ventilation, consideration should be given to minimize continuous or intermittent sedation, targeting specific titration endpoints (light sedation unless contraindicated) or with daily interruption of continuous sedative infusions.
• In patients experiencing agitation (defined as marked restlessness or excessive motor activity, often accompanied by anxiety), calming communication strategies (to reorient the person) should be attempted. Acute pain due to physical illness or air hunger should be considered as triggers for agitation and need to be addressed immediately. While non-pharmacologic strategies are preferred, in case they are unsuccessful or distress is severe, psychotropic medications may need to be trialed alongside non-pharmacologic interventions.

• Patients with severe acute respiratory disease should be treated cautiously with intravenous fluids, because aggressive fluid resuscitation may worsen oxygenation, especially in settings where there is limited availability of mechanical ventilation.^{Footnote 48} This applies to the care of both children and adults.

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.

• Empiric antibiotic treatment should be based on the clinical diagnosis (for example, community-acquired pneumonia, health care-associated pneumonia or sepsis), local epidemiology and susceptibility data. The Infectious Disease Society of America and the American Thoracic Society have published treatment guidelines for community-acquired pneumonia.

• Regularly review the possibility of switching of intravenous to oral route of administration
• If antimicrobials are continued, this should be for the shortest recommended duration (for most indications 5-7 days)
• When there is ongoing local circulation of influenza, empiric therapy with a neuraminidase inhibitor should be considered for the treatment of influenza viruses in patients with or at risk for severe disease.^{Footnote 50}

8.0 Management of critical COVID-19

8.1 Acute respiratory distress syndrome (ARDS)

• Patients may continue to have increased work of breathing or hypoxemia even when oxygen is delivered via a face mask with reservoir bag (flow rates of 10 to 15 L/min, which is typically the minimum flow required to maintain bag inflation; FiO₂ 0.60 to 0.95). Hypoxemic respiratory failure in ARDS commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation.^{Footnote 1}

• Patients with ARDS, especially young children or those who are obese or pregnant, may desaturate quickly during intubation. Pre-oxygenate with 100% FiO₂ for 5 minutes, via a face mask with reservoir bag, bag-valve mask. The utilization of video laryngoscopy to increase chance of intubation at first attempt should be considered. Rapid sequence intubation is appropriate after an airway assessment that identifies no signs of difficult intubation, avoiding manual ventilation as a means to avoid aerosol generation, where possible and safe for patient care.^{Footnote 51Footnote 52Footnote 53}

• This guidance is not meant to replace clinical judgment or specialist consultation.
• There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering its use in this population.

Recommendations for mechanically ventilated adult and pediatric patients with ARDS

• Adults: This is a strong recommendation from a clinical guideline for patients with ARDS, and is suggested for patients with sepsis-induced respiratory failure who do not meet ARDS criteria.^{Footnote 1} The initial tidal volume is 6 mL/kg PBW; tidal volume up to 8 mL/kg PBW is allowed if undesirable side-effects occur (for example, dyssynchrony, pH < 7.15). Permissive hypercapnia is permitted. Ventilator protocols are available.^{Footnote 54} The use of deep sedation may be required to control respiratory drive and achieve tidal volume targets.
• Children: A lower level of plateau pressure (< 28 cmH₂O) is targeted, and a lower pH target is permitted (7.15 to 7.30). Tidal volumes should be adapted to disease severity: 3 to 6 mL/kg PBW in the case of poor respiratory system compliance, and 5 to 8 mL/kg PBW with better preserved compliance.^{Footnote 53} Slightly higher Plateau pressures (30-32 cmH₂O) can be tolerated in case of poor chest wall compliance.

• Application of prone ventilation should be considered for adult patients, preferably for 16 hours per day, and may be considered for paediatric patients with severe ARDS but requires sufficient human resources and expertise to be performed safely.^{Footnote 33Footnote 34} Protocols (including videos) are available.
• Pregnant women should not be placed in a prone position but in the supine position with a wedge placed under the right hip to decrease aortocaval obstruction, or placed in lateral decubitus position.

• This is a strong recommendation for both adults and children; the main effect is to shorten the duration of ventilation ^{Footnote 1}. See reference ^{Footnote 55} for a sample protocol.

• PEEP titration requires consideration of benefits (reducing atelectrauma and improving alveolar recruitment) vs risks (end-inspiratory overdistension leading to lung injury and higher pulmonary vascular resistance). Tables are available to guide PEEP titration based on the FiO₂ required to maintain SpO₂.^{Footnote 54} Although high driving pressure (plateau pressure minus PEEP) may more accurately predict increased mortality in ARDS compared with high tidal volume or plateau pressure, data from RCTs of ventilation strategies that target driving pressure are not currently available.^{Footnote 56}
• Recruitment manoeuvres (RMs) can be delivered as episodic periods of high continuous positive airway pressure (CPAP) (30 to 40 cmH₂O), progressive incremental increases in PEEP with constant driving pressure, or high driving pressure; considerations of benefits vs risks are similar. PEEP and RMs were both conditionally recommended in a clinical practice guideline. For PEEP, the guideline considered an individual patient data meta-analysis of three RCTs.^{Footnote 57} However, a subsequent RCT of high PEEP and prolonged high-pressure RMs showed harm, suggesting that the protocol in this RCT should be avoided.^{Footnote 58} Monitoring of patients to identify those who respond to the initial application of higher PEEP or a different RM protocol, and stopping these interventions in non-responders are suggested, noting that patients with hypoxic respiratory failure without strong suspicion or evidence of alveolar de-recruitment are less likely to benefit from RMs but may still be at risk of side-effects.^{Footnote 59}

• While one trial found that this strategy improved survival in adult patients with severe ARDS (PaO₂/FiO₂ < 150) without causing significant weakness, results of a recent larger trial found that use of neuromuscular blockage with high PEEP strategy was not associated with a survival benefit when compared with a light sedation strategy without neuromuscular blockade.^{Footnote 60Footnote 61} Continuous neuromuscular blockade may still be considered in patients, both adults and children, with ARDS in certain situations, such as ventilator dyssynchrony despite sedation, such that tidal volume limitation cannot be reliably achieved; refractory hypoxemia; or hypercapnia.

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

• Adult HFNO systems can deliver 60 L/min of gas flow and FiO₂ up to 1.0. Pediatric circuits generally only handle up to 25 L/min, and many children will require an adult circuit to deliver adequate flow.
• Compared with standard oxygen therapy, HFNO reduces the need for intubation.^{Footnote 62} Patients with hypercapnia (exacerbation of obstructive lung disease, cardiogenic pulmonary edema), hemodynamic instability, multiorgan failure, or abnormal mental status should generally not receive HFNO, although emerging data suggest that HFNO may be safe in patients with mild-moderate and non-worsening hypercapnia.^{Footnote 62Footnote 63Footnote 64} Patients receiving HFNO should be in a monitored setting and cared for by experienced personnel capable of endotracheal intubation in case the patient acutely deteriorates or does not improve after a short trial (about 1 hour). Evidence-based guidelines on the treatment of patients with COVID-19 with HFNO do not exist, and reports on HFNO in other coronavirus-infected patients are limited.^{Footnote 64}
• NIV guidelines make no recommendation for use in hypoxemic respiratory failure (apart from cardiogenic pulmonary edema and post-operative respiratory failure) or pandemic viral illness.^{Footnote 1} Risks include delayed intubation, large tidal volumes, and injurious transpulmonary pressures. Limited data suggest a high failure rate in patients with other viral infections such as MERS who receive NIV.^{Footnote 65}
• Patients receiving a trial of NIV should be in a monitored setting and cared for by experienced personnel capable of endotracheal intubation in case the patient acutely deteriorates or does not improve after a short trial (about 1 hour). Patients with haemodynamic instability, multiorgan failure, or abnormal mental status should likely not receive NIV in place of other options such as invasive ventilation.
• In situations where mechanical ventilation may not be available, bubble nasal CPAP may be used. for newborns and children with severe hypoxemia.^{Footnote 66}
• Because of uncertainty around the potential for aerosolization, HFNO, NIV, including bubble CPAP, should be used with airborne precautions until further evaluation of safety can be completed. If these interventions are performed outside of private rooms in ICUs with appropriate ventilation systems installed, then cohorting of patients requiring these interventions in designated wards, where possible, will facilitate the implementation of airborne precautions. All staff entering in the immediate vicinity of patients receiving potentially aerosol generating medical procedures must wear PPE appropriate for the procedures.

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

• An RCT of ECMO for adult patients with ARDS was stopped early and found no statistically significant difference in the primary outcome of 60-day mortality between ECMO and standard medical management (including prone positioning and neuromuscular blockade).^{Footnote 67} However, ECMO was associated with a reduced risk of the composite outcome of mortality and crossover to ECMO, and a post hoc Bayesian analysis of this RCT showed that ECMO is very likely to reduce mortality across a range of prior assumptions.^{Footnote 67Footnote 68} In patients with MERS, ECMO vs conventional treatment was associated with reduced mortality in a cohort study.^{Footnote 69} ECMO should ideally be offered in expert centres with a sufficient case volume to maintain expertise and that can apply the IPC measures required for adult and pediatric COVID-19 patients.^{Footnote 70Footnote 71}

8.2 Septic shock

• In the absence of a lactate measurement, use blood pressure (for example, MAP) and clinical signs of perfusion to define shock.
• Standard care includes early recognition and the following treatments within 1 hour of recognition: antimicrobial therapy and initiation of fluid bolus and vasopressors for hypotension.^{Footnote 1} The use of central venous and arterial catheters should be based on resource availability and individual patient needs. Detailed guidelines are available for the management of septic shock in adults and children.^{Footnote 1Footnote 2Footnote 33} Alternate fluid regimens are suggested when caring for adults and children in resource-limited settings.^{Footnote 72Footnote 73}

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

• Crystalloids include normal saline and Ringer’s lactate, with a preference for Ringer’s lactate.
• Determine need for additional fluid boluses (500-1000 mL in adults or 10 to 20 mL/kg in children) based on clinical response and improvement of perfusion targets. Perfusion targets include MAP (≥ 60-65 mmHg or age-appropriate targets in children), urine output (> 0.5 mL/kg/hr in adults, 1 mL/kg/hr in children), and improvement of skin mottling and extremity perfusion, capillary refill, heart rate, level of consciousness, and lactate.
• Consider dynamic indices of volume responsiveness to guide volume administration beyond initial resuscitation based on local resources and experience.^{Footnote 1} These indices include passive leg raises, fluid challenges with serial stroke volume measurements, or variations in systolic pressure, pulse pressure, inferior vena cava size, or stroke volume in response to changes in intrathoracic pressure during mechanical ventilation.
• In pregnant women, compression of the inferior vena cava can cause a decrease in venous return and cardiac preload and may result in hypotension. For this reason, pregnant women should be cared for with a wedge under their right hip and may need to be placed in a lateral decubitus position to off-load the inferior vena cava.^{Footnote 74}
• Clinical trials conducted in resource limited settings comparing aggressive versus conservative fluid regimens suggest higher mortality in patients treated with aggressive fluid regimes for other severe infections.^{Footnote 72Footnote 73}

• Starches are associated with an increased risk of death and acute kidney injury compared with crystalloids. The effects of gelatins are less clear, but they are more expensive than crystalloids.^{Footnote 1Footnote 75} Hypotonic (vs isotonic) solutions are less effective at increasing intravascular volume. Surviving Sepsis also suggests albumin for resuscitation when patients require substantial amounts of crystalloids, but this conditional recommendation is based on low-quality evidence.^{Footnote 1}

• there are signs of shock such as 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 seconds) or feeble pulses;
• tachypnea; mottled cool skin or petechial or purpuric rash; increased lactate; persisting oliguria; or
• age-appropriate blood pressure targets are not achieved

• Vasopressors (for example, norepinephrine, epinephrine, vasopressin, and dopamine) are most safely given through a central venous catheter at a strictly controlled rate, but it is also possible to administer them safely via peripheral vein and intraosseous needle.^{Footnote 76} Monitor blood pressure frequently and titrate the vasopressor to the minimum dose necessary to maintain perfusion and prevent side effects.
• Norepinephrine is considered first-line in adult patients; epinephrine or vasopressin can be added to achieve the MAP target. Because of the risk of tachyarrhythmia, reserve dopamine for selected patients with low risk of tachyarrhythmia or those with bradycardia.
• In children, epinephrine is considered first-line treatment, while norepinephrine can be added if shock persists despite optimal dose of epinephrine.
• No RCTs have compared dobutamine with placebo for clinical outcomes
• See the Specific and adjunctive COVID-19 treatments and clinical research section for remarks on corticosteroids and sepsis.

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.

• Evidence of increased adverse maternal or neonatal outcomes is uncertain. Some literature has reported higher rates of stillbirth and many reports suggest higher rates of preterm birth but recent (August 5, 2020 - Living Systematic Reviews from the WHO collaborating centre for global women’s health COVID-19 in Pregnancy (PregCOV-19LSR)), found a cumulative rate of preterm birth in 14,210 women from 49 cohort studies of 17%.  In addition, there are reports of higher rates of fetal distress in labour particularly associated with maternal infection in the third trimester.^{Footnote 81Footnote 82}. Until more evidence becomes available, pregnant women with COVID-19 need to be observed closely for severe illness.

• Prevention of complications as described earlier, also apply to pregnant and recently pregnant women including those with miscarriage, late pregnancy fetal loss and postpartum/post-abortion women.
• The mode of delivery should be individualized based on obstetric indications.
• Multidisciplinary consultations from obstetric, perinatal, neonatal, infectious disease and intensive care specialists should be provided as required.
• Access to reproductive health care including termination of pregnancy should be ensured throughout the pandemic.

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.

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.

• Physiological changes with age lead to declines in intrinsic capacity such as malnutrition, cognitive decline, depressive symptoms, and those conditions interact at several levels.
• Hearing and vision impairments become more prevalent among older adults and may pose a communication barrier, especially when masks prevent lip reading and decrease vocal clarity. Cognitive decline may also need to be considered when communicating with older patients.
• Older people who experience COVID-19, including those admitted to ICU and/or treated with protracted oxygen therapy and bed rest, are more likely to experience pronounced functional decline and may require coordinated rehabilitation care after acute hospitalization.

• Older patients are at greater risk of polypharmacy which increases the risk of negative health consequences. If medications are prescribed for mental and neurological manifestations of COVID-19 in older adults, this should be done with extreme caution given the increased susceptibility to drug side-effects and drug interactions with other prescribed medications.

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:

• Primary care providers or nursing stations, where available, should plan to provide triage and assessment, primary care treatment and monitoring.
• Mild disease, including uncomplicated pneumonia, should be managed within the community, with appropriate precautions in place.
• Alternate arrangements for self-isolation may be needed for persons in crowded living arrangements.
• Fluid management should be conservative when there is no evidence of shock, because aggressive fluid management may worsen oxygenation in settings without access to mechanical ventilation.
• Mild cases may progress to lower respiratory tract disease. Possible risk factors for progression to severe illness include older age and underlying chronic medical conditions such as lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, and pregnancy.^{Footnote 28Footnote 83}
• Patients should be carefully monitored for signs of impending deterioration so that transfer can be arranged before intubation is required. Clinicians should be aware of the potential for some patients to rapidly deteriorate 1 week after illness
• Anticipate delays in accessing hospital care (awaiting air-ambulance, weather issues). Therefore, a low threshold should be considered for medevac options, particularly for the elderly, persons with underlying medical conditions or persons with evidence of pneumonia.

9.5 Palliative care and COVID-19

9.6 Immunocompromised patients and COVID-19

• Case series of patients living with HIV and COVID-19 have not shown a higher COVID-19 infection rate or complication rate in patients with suppressed viral loads and CD4> 200. It is assumed that patients with CD4<200 or not receiving Antiretroviral therapy will be at increased risk of disease due to their immunosuppression.^{Footnote 84}

• In HSCT patients, if a donor has travelled to a high risk area for COVID 19 transmission or has had contact with a patient confirmed to have COVID-19, the donor must be excluded from donation for at least 28 days.

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.

• The recommendation is based on the data from a preliminary report of the RECOVERY trial comparing the use of 6 mg of dexamethasone given once daily for up to ten days. The primary outcome was 28-day mortality in more than 6,400 patients randomly allocated (1:2) to receive dexamethasone or usual care.^{Footnote 85}
• While the trial demonstrated benefit of dexamethasone use in patients who required supplemental oxygen or mechanical ventilation, it did not reduce mortality in patients who did not require respiratory support at randomization (17.8% vs. 14%, RR 1.18 [95% CI 0.91 to 1.55]).
• There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering use.
• If oral, IV and/or inhaled steroids are indicated for non-COVID-19 reasons (for example, asthma or COPD exacerbation, or stress dosing in someone on chronic steroids or with known adrenal insufficiency), they should not be avoided.^{Footnote 86Footnote 87Footnote 88Footnote 89Footnote 90Footnote 91Footnote 92Footnote 93}

• Data from a preliminary report of a multinational, randomized, placebo-controlled trial (the Adaptive COVID-19 Treatment Trial [ACTT]) of hospitalized patients with severe disease who received Remdesivir showed a shorter median time to clinical recovery compared to patients who received placebo (11 vs 15 days; rate ratio for recovery 1.32 [95% CI 1.12 to 1.55]).^{Footnote 94} The benefit of Remdesivir on reducing time to recovery was highest among patients who were not intubated but required supplemental oxygen. In mechanically ventilated patients who received Remdesivir there was no observed decrease in time to recovery.^{Footnote 95}  Health Canada has authorized the use of Remdesivir for adults and adolescents aged 12 and over, and clinical trials are presently underway in children.

• The use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients was recently reported in a large randomized, controlled, open-label, adaptive, platform trial (the RECOVERY trial). In the hydroxychloroquine arm of the trial, patients were randomised to receive either hydroxychloroquine (n=1,561) or usual care (n=3,155).^{Footnote 96} There was no significant difference in the primary endpoint of 28-day mortality or beneficial effects on hospital stay duration. In the lopinavir-ritonavir arm of the trial, patients were randomised to receive lopinavir-ritonavir (n=1,596) or usual care (n=3,376).^{Footnote 97} There was no significant difference in the primary endpoint of 28-day mortality, the risk of progression to mechanical ventilation or length of hospital stay. Based on these results, the use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients should not be considered outside of a clinical trial setting.

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