Novel coronavirus 2019 (2019-nCoV) infection has been declared a pandemic by the World Health Organization (WHO). We elaborated the epidemiology, preparedness of intensive care units, clinical course, intensive care needs and complication of patients with Coronavirus disease (COVID-19) in a previous article [1]. In this write-up, we will focus on the respiratory manifestations, progression and intensive care management of respiratory compli-cations of COVID-19. As we learn more about the 2019-nCoV (novel coronavirus) and the impact this has had on the patients and health care workers (HCW) globally, the focus has shifted to safety of the HCW so that the patients can be treated appropriately and kept safe. This is based on the lessons learned from previous epidemics and mitigating steps to reduce risks to HCW. Most of the following suggestions are based on expert opinionon providing safe care in these challenging times.

RESPIRATORY DISEASE DUE to 2019 nCoV INFECTION
Clinical Course

The most common presentation is short history of prodrome with myalgias, malaise, cough and low-grade fever. As per the case series from China, only 40-70% of the pediatric patients have fever as an initial presentation [2-4]. During the second week of illness, progression of the disease gradually leads to difficulty in breathing. Reports from China have suggested that it takes an average of 8 days for the development of dyspnea and 9 days for the onset of pneumonia/pneumonitis [5].

Investigations

CDC does not currently recommend chest radiography (CXR) or computed tomography (CT) to diagnose COVID-19 [6]. Viral testing remains the only specific method of diagnosis and has been discussed in detail in part-I [1]. Confirmation with the viral test is required, even if radiologic findings are suggestive of COVID-19 on CXR or CT scan [7].

Differential Diagnosis

The clinical presentation and findings on chest imaging in COVID-19 are not specific.The clinical presentation of COVID-19 overlaps with other infections like influenza, respiratory syncytial virus (RSV), adenovirus, human meta-pneumovirus, non COVID-19 coronavirus, atypical organisms (mycoplasma, chlamydia) and bacterial infections. It is not possible to differentiate COVID-19 from these infections clinically or through routine laboratory tests. In the context of pandemic and local transmission setting in, the travel history will become irrelevant. There are some radiological and hematological findings that may help indicate COVID-19, even though they are not very specific [1].

Classification of Severity

Severity of illness is based on the presenting symptoms and has been discussed previously [1]. Patients can shed RNA from 1-4 weeks after symptom resolution, but it is unknown if the presence of RNA equals presence of infectious virus. As per current guidelines, COVID-19 patients are “cleared” of isolation once they have 2 consecutive negative RNA tests collected >24 hours apart. This practice may not be clinically possible in our setting due to various constraints. Therefore, keeping them in isolation for longer duration is the key.

MANAGEMENT OF HYPOXEMIC RESPIRATORY FAILURE

One of the key considerations during management is mitigating risk to health care workers. Hypoxemia can be present due to impaired respiratory functions in COVID-19. Oxygen supplementation treatment can correct hypoxemia and relieve secondary organ damage caused by hypoxemia[8]. The management of children with Severe acute respiratory illness (SARI) in COVID is similar to any other viral pneumonia with ARDS but with strict precautions to reduce risk of transmission[9].

Protection From Aerosol

All aerosol generating procedures/events require donning of personal protective equipment which includes N95 mask, goggles or face shield, cap, full sleeve gown and shoe cover (Table I) [10]. Where possible, a nebulizer may be replaced with an MDI and spacer for administration of bronchodilators. NIV generates droplets >10 µm in size and most fall on local surfaces within 1-meter distance. Learning from droplet dispersion studies, HCWs who are providing NIV, chest physiotherapy or working within 1 meter of an infected patient should have a high level of respiratory protection [11-13].

Table I Aerosol Generating Events and Procedures in the Intensive Care Unit

		Aerosol generating events

		Procedures vulnerable to aerosol generation

		Inadequate seal during 

		Laryngoscopy

		NIV or HFNC

		Intubation

		Nebulization

		Front of neck access 

		Endotracheal suction

		Laryngoscopy

		CPR prior to intubation

		Bronchoscopy

		Extubation

		Coughing/sneezing

		NIV-non-invasive ventilation; HFNC – High flow nasal cannula.

Oxygen Therapy
 
Oxygen therapy is necessary for patients with oxygen saturation (SpO2) less than 90% and/or with signs of respiratory distress. It has been noted that many elderly patients with severe hypoxemia may not have obvious symptoms of respiratory distress [14]. It is pertinent that the evaluation of all children with respiratory symptoms should include pulse oximetry. Low flow oxygen devices are recommended as high flow devices have the potential for risk of spread through aerosol generation. Nasal cannula at flows of 2-4 L/min is a good choice for milder forms of SARI. A triple layer mask should be used to cover the mouth and nose of the patient over the nasal cannula, especially during transport, unless the child does not tolerate [15].

Heated Humidified High Flow Nasal Cannula (HHHFNC/HFNC)

HFNC therapy can be useful in special situations for hypoxia. A flow of 2-3 mL/kg with FiO2 targeted to SpO2 is used. However, it is necessary that when patient is on HFNC interface, HCW are wearing optimal airborne PPE and child is managed in negative pressure rooms,if available [16]. In infants, while HFNC is being given they can be placed in an oxygen hood to minimize dispersion. Surviving Sepsis Guidelines recommend HFNC in milder cases of adult SARI [17]. However, no such guidelines are there for children. HFNC should be tried for a maximum of 1-2 hours. Signs of improvement are decrease in heart rate and respiratory rate by 10-20%, decrease in FiO2 requirement to less than 50% and improvement in oxygen saturations.

Patients with worsening hypercapnia, acidemia, respiratory fatigue, hemodynamic instability or those with altered mental status should be considered for early invasive mechanical ventilation.

Non-invasive Ventilation

Over the last two decades, the use of non-invasive ventilation (NIV) is increasing in children with viral illness and the rates of intubation are reducing. At the same time there is paucity of literature regarding the use of NIV in respiratory pandemics.

In a Chinese observational study in adults of the SARS outbreak, it was shown that NIV was effective in preventing the use of endotracheal intubation in 70% of patients because of early initiation of NIV. In this study, none of the HCW acquired SARS from the patients. This was attributed to NIV being applied in a negative-pressure environment with strict PPE regime and close monitoring of the HCW involved [18]. In another study from Toronto during SARS, the use of NIV was discouraged after clinicians contracted the disease when a patient was intubated following NIV failure [19]. There-fore, some clinicians consider NIV is contra-indicated for acute respiratory failure due to airborne respiratory diseases unless it is used in a negative-pressure isolation room and strict precautions are taken [19].

After the two viral pandemics, most of the professional societies including the European Respiratory Society, European Society of Intensive Care Medicine, and American Association for Respiratory Care have recommended against NIV use to treat acute respiratory failure due to H1N1 influenza, particularly in severely ill patients. Thus, NIV is accepted as a high-risk procedure that should be used cautiously because of possible spread of infection [20-23].

Routine use of NIV is not recommended in COVID-19. It should be used only in selected patients with hypoxemic respiratory failure. Ideally, negative pressure single rooms are preferable for patients on NIV. However, in an outbreak of such a magnitude, some professional societies recommend keeping a distance of at least two meters between two beds. Due to the high percentage of failure with NIV and the rapid progression of the hypoxemic failure due to COVID-19, all patients receiving NIV need a clear plan for treatment failure.

Selection of interface is the key for success and protection of the HCWs. Preferred interfaces are helmet, total face mask and oro-nasal non-vented masks.Risks of NIV include delayed intubation, large tidal volumes and injurious trans-pulmonary pressures. Limited data suggest a high failure rate in patients with other similar viral infections such as MERS-CoV [24].

PaO2/FiO2is a sensitive and accurate indicator of oxygenation function on NIV and can be used to define the severity of ARDS once the patient has been on a PEEP of 5 cm for a minimum of 30 minutes. Invasive ventilation must be considered if PaO2/FiO2 ratio is below 300. In the absence of an ability to do an arterial blood gas, the SpO2/FiO2 can also be used to identify oxygenation failure as long as the FiO2 has been titrated to get saturations between 92%- 97%.

The most recent World Health Organization (WHO) interim guidance on management of the novel-CoV has also recommended the use of NIV for mild cases of ARDS without hemodynamic instability [8].

Conventional ventilators with NIV option having double lumen tubing is a safer option than NIV ventilator with single lumen tubing requiring exhalation port to washout the CO2. Antiviral/Antibacterial filters should be attached to the exhalation limb of the circuit to reduce environmental contamination. Alternatively, when these options are not available, home ventilators with built-in oxygen blender or transport ventilators can provide adequate mechanical ventilation.

Bubble CPAP

In situations where both non-invasive and invasive mechanical ventilation are not available, bubble nasal CPAP (commercial or indigenous) may be used for newborns and children with severe hypoxemia as these are readily available alternative in resource-limited settings.To minimize environmental contamination the infant could be placed in an oxygen hood to reduce droplets.

These patients should be on continuous monitoring and cared for by experienced personnel capable of performing endotracheal intubation in case the patient acutely deteriorates or does not improve after a short trial (about 2 hours).

Patients with known contraindications for NIV like moderate/severe ARDS with PaO2/FiO2 ratio below 200, hemodynamic instability, multi-organ failure, or abnormal mental status should receive invasive ventilation from the very beginning.

Intubation

During the previous SARS epidemics in China and Singapore, infection rates were higher in doctors and nurses carrying out endotracheal intubation [relative risk (95% CI)-13.3 (2.99–54.04)] [20]. In an observational study of influenza-A and influenza-B in exhaled breath, viral RNA was seen in one-third of infected patients and 99% of particles had a diameter of <5 µm when sampled during tidal breathing [25]. Studies have demonstrated that particles <10 µm in diameter are more likely to cause infection in the lower respiratory tract [9,10]. Corona-virus virions (or ‘particles’) are spherical particles with diameters of approximately 125 nm (0.125 µm) [26].

Tracheal intubation should be performed as early as possible for patients with aPaO2/FiO2 ratio <300, worsening trend of the SpO2/FiO2 ratio <200, worsening respiratory distress, high concentration (>60%) of oxygen on HFNC or multiple organ dysfunction.

Table II Intubation Trolley and Tray and Modifications for Use in COVID-19 Patients

		Equipment (size appropriate)

		Specific for COVID-19 patients

		Laryngoscope with blade

		Video laryngoscope is preferred to increase the distance between the health worker and patient

		Endotracheal tube

		Micro-cuffed and cuffed tubes to minimize aerosol as well as leak in acute respiratory distress syndrome (ARDS)

		Suction catheter

		Closed suction to minimize contact with secretion, aerosol release & de-recruitment

		Hydrophobic viral filter

		Used between the ambu bag and mask as well as in the ventilator circuitat the expiratory end 

		Oxygen & ventilation delivery 

		For pre-oxygenation, use non-rebreathing mask or a flow inflating device (Jackson Rees) Ensure devices adequate mask seal Avoid bagging if using self-inflating bag

		Drugs – Sedo-analgesia & neuromuscular blockade

		Use liberal sedation &neuromuscular blockade to avoid coughing and ultra-rapid sequence intubation 

		Adjuncts

		Stylet, Bougie and second-generation laryngeal mask airway (LMA) devices readily available if initial plan fails0

Fig. 1 (a) The assembly of bag, viral filter and mask along with plastic sheet to minimize aerosol; (b) Preparing the sheet with an opening for the mask.

Preparation : Prepare the plan, ready the equipment and set-up the ventilator prior to intubation (Table II). At least three personnel are needednamely, airway operator, airway assist and a nurse for medication. The most experienced person should intubate to ensure minimum number of attempts to decrease aerosol generation. Wherever possible, usedisposable equipment. Video laryngoscopy is ideal to protect the intubating HCW from operating too close to the airway (Fig.2). If equipment or expertise isnot available, take measures to reduce droplets during the procedure using a plastic sheet (Fig. 1).

Fig. 2 (a) Video-laryngoscope assisted intubation; (b) shows a sheet covering the face and chest during intubation.

Pre-medication: Use benzodiazepine (midazolam 0.1-0.2 mg/kg) with opioid (fentanyl 2-3 µg/kg) combination for sedation and analgesia. Short acting neuromuscular blockers like rocuronium is preferred (if unavailable, use a higher dose of vecuronium or atracurium as per availability).

Pre-oxygenation: After a quick assessment for anatomically difficult airway, pre-oxygenation is carried out with non-rebreathing mask (NRM) or tight-fitting face mask attached to a self-inflating ambu-bag with 100% oxygen for 5 minutes. A hydrophobic viral filter between the mask and ambu-bag is recommended and some units cover the head, neck and chest with transparent plastic apron/sheet to prevent aerosol contamination (Fig.1). Avoid bag and mask ventilation (BMV) to limit aerosol and if needed, use low tidal volume with lesser breaths.

Intubation: Cuffed endotracheal tubes (ETT) must be used in all ages and cuff needs to be inflated immediately following intubation. Disposable ventilator circuit with a viral filter attached at the expiratory limb (between circuit and machine) is used. Heat moisture exchanger (HME) is preferred for humidification. Ventilator should be in ‘stand-by’ mode and only to be turned on after connected to the patient. Prior to connecting to ventilator, the ETT can be clamped or attached to a viral filter. Closed suction (inline suction catheters) is preferred to prevent aerosol generation. If not available, open suction may be performed with aerosol precautions and after adminis-tering a dose of short acting neuromuscular blocking agent.

Invasive Mechanical Ventilation

Lung protective mechanical ventilation (MV) is recommended strategy for management of acute hypoxemic respiratory failure. SSC guidelines in adults recommend low tidal volume strategy (4-8mL/kg), limiting plateau pressures to <30 cmH2O and using higher PEEP (>10 mm Hg) [17]. Permissive hypercapnia is well tolerated and may reduce volu-trauma. Viral filters should be utilized, and circuits should be maintained for as long as allowable (as opposed to routine changes) (Table III).

Table III Strategies in the Management of Acute Respiratory Distress Syndrome in COVID-19

		Management similar to any ARDS

		Specific with respect to COVID

		Lung protective ventilation

		Early invasive ventilation – avoid HFNC and NIV   

		  Tidal volume 4-6 mL/kg   

		Avoid steroids – may prolong viral shedding

		  Limit Plateau pressure <28 cm H2O   

		Use liberal neuromuscular blockadeto prevent coughing

		  PEEP start with 7-10 and titrate to 15 cm H2O   

		Proning involves risk of exposure to HCW and best avoided

		  Limit FiO2<60% with permissive hypoxemia

		Avoid nebulization 

		Avoid fluid overload (FO) - target FO <5%

		Sedo-analgesia titrated to sedation scores

		Early enteral nutrition – initiate within 24 hours and achieve full feeds by 48 hours
 

		Transfusion trigger hemoglobin<7 g/dL if stable hemodynamics and oxygenation

		Target hemoglobin 10g/dL in refractory hypoxemia or unstable shock 

		NIV – non-invasive ventilation; HFNC – high flow nasal cannula; HCW-healthcare worker; PEEP – peak end-expiratory pressure.
	

Prone Ventilation

Prone ventilation is a recommended strategy in adults with PaO2/FiO2 <150 to improve lung mechanics and oxygenation.Patient is usually kept prone for12-16 hours. Prone ventilation can be ceased once PaO2/FiO2is > 150 for more than 4 hours in the supine position. However, in children and resource-limited setting, due to limited availability of HCWs and PPEs, it may not be possible to prone the child and may unnecessarily increase the risk of infection to the healthcare workers.

Fluid Management

To reduce pulmonary exudation and improve oxyge-nation, the fluid balance should be strictly controlled while ensuring adequate end-organ perfusion. Fluid restriction to 70-80% maintenance is necessary to prevent fluid overload.

Strategies to Prevent Ventilator-Associated Pneumonia (VAP)

VAP bundled strategies should be strictly implemented as per recommendations [27].

Weaning and Extubation

Once the patient’s PaO2/FiO2 is more than 300 the neuromuscular blockade and sedatives must be weaned and discontinued. Extubation should be performed if the patient is considered ready for extubating to nasal O2 as post-extubation NIV is avoided where possible.Aerosol precautions are essential during extubation. Few units practice extubating using a plastic bag over the face with a tight seal after inflating with oxygen (Fig. 4) or some units use a transparent large plastic sheet over the face and chest to capture droplets from coughing and suctioning. Post-extubation, the need for HFNC or NIV can be assessed while reducing monitoring.

Fig. 3 Use of expiratory filter in single limb NIV tubing (use a non-vented mask).

Fig. 4 Covering the face with a plastic bag or a sheet, to prevent aerosol spread during extubation.

Various professional bodies have given their recommendations for respiratory support in pediatrics and adult [8,15,17,28] and these are summarized in Table IV.

Table IV Summary of Respiratory Support Guidelines for COVID-19 Patients

		WHO 

		SCCM 

		PICS 

		ANZICS 

		[7]

		[16]

		UK [27]

		[14]

		HFNO with precautions

		+/–

		+

		+

		+

		NIV with precautions

		+/–

		+/–

		+

		–

		Invasive ventilation

		+

		+

		+

		+

		WHO – World health organization, SCCM – Surviving sepsis campaign, PICS UK – Pediatric intensive care society UK, ANZICS – Australian and New Zealand Intensive Care Society.