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Clinical consensus recommendations regarding non-invasive respiratory support in the adult patient with acute respiratory failure secondary to SARS-CoV-2 infection☆

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. Currently, the World Health Organization (WHO) has defined the infection as a global pandemic and there is a health and social emergency for the management of this new infection. While most people with COVID-19 develop only mild or uncomplicated illness, approximately 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multiorgan failure. This consensus document has been prepared on evidence-informed guidelines developed by a multidisciplinary panel of health care providers from four Spanish scientific societies (Spanish Society of Intensive Care Medicine [SEMICYUC], Spanish Society of Pulmonologists [SEPAR], Spanish Society of Emergency [SEMES], Spanish Society of Anesthesiology, Reanimation, and Pain [SEDAR]) with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS, as well as sepsis and ARDS. The document provides clinical recommendations for the noninvasive respiratory support (noninvasive ventilation, high flow oxygen therapy with nasal cannula) in any patient with suspected or confirmed presentation of COVID-19 with acute respiratory failure. This consensus guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival and to allow for reliable comparison of investigational therapeutic interventions as part of randomized controlled trials.

This consensus document has been drafted in response to the current public health emergency and clinicians' demand for guidelines. As such, it focuses on specific situations encountered outside routine clinical practice in hospitals, and must be adapted to the particular circumstances of any given scenario.

General introduction
This consensus document has been drawn up by the scientific societies involved in treating acute respiratory failure in adult patients. It includes a more detailed description of the recommendations for the use of non-invasive respiratory support (NIRS) in the management of acute respiratory failure (ARF) secondary to infection by the new SARS-CoV-2 coronavirus that causes the disease called COVID-19 that is intended to supplement the regularly updated recommendations issued by the Ministry of Health, Consumer Affairs and Social Welfare (MH). 1,2 The World Health Organization (WHO) recently declared the disease caused by SARS-CoV-2 (COVID-19) 3 a public health emergency of international concern. The ongoing COVID-19 pandemic is devastating, despite the implementation of extensive control measures. In reality, there are significant regional differences in the availability and accessibility of healthcare resources among the more than 70 countries currently affected by the virus. These differences might partly explain the low mortality rates despite the high number of cases. Health authorities and governments worldwide have developed contingency plans to manage local outbreaks, 4 and these measures are essential for controlling the epidemic, protecting health workers on the front line, and mitigating the severity of patient outcomes.
Extrapolating these figures to the current situation in Spain compels us to anticipate events and demand that both national and regional health authorities draw up a contingency plan for managing healthcare resources and staff safety. This plan should include the procedures for using specific hospital areas, such as expert units capable of caring for ventilated patients (ICUs, intermediate respiratory care units [IRCU), emergency departments and wards equipped with the resources and staff needed to safely and efficiently deal with the epidemiological challenge of controlling and treating the COVID-19 outbreak in Spain. During the previous SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) epidemics, the infection rate among healthcare workers was 18.6% and 21% of cases during the MERS and SARS outbreaks, respectively. 7,8 For this reason, both working groups and scientific societies need to establish contingency plans for dealing with an increasingly critical situation and optimize both material and human resources to be prepared to meet unprecedented demands. Specifically, we believe that this contingency plan should include the following strategies: In conclusion, we cannot predict how many seriously ill COVID-19 patients we will receive, but we must learn from the experience of other countries and anticipate scenarios, distribute resources as rationally as possible, and do the best we can to be prepared and work together to overcome the epidemic.
The recommendations contained in this consensus document, prepared by the Spanish Society of Intensive and Critical Care and Coronary Units (SEMICYUC), the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), the Spanish Society of Emergency Medicine (SEMES) and the Spanish Society of Anaesthesiology (SEDAR) are based on studies in other viral pandemics (influenza, SARS, MERS) and on the latest studies published on COVID-19. The level of evidence currently available is therefore low, given the lack of methodological robustness and the very nature of the disease. This document will be updated as the state of the knowledge evolves and changes are made in the recommendations issued by national and international organizations and societies.

General recommendations for the management of acute respiratory failure secondary to COVID-19 Objectives
• To correctly identify patients with ARF who may require non-invasive respiratory support (NIRS). • To describe processes with high risk of NIRS failure.

Introduction
ARF is the most frequent cause of mortality in patients with influenza and viral infections in general. 9 With respect to COVID-19 (the infectious disease caused by SARS-CoV-2), 3.4% of infected patients in China presented with acute respiratory distress syndrome (ARDS), representing 40.3% of patients with severe disease. 5 It is therefore essential to implement a therapeutic strategy to treat ARDS secondary to COVID-19 infection.
Monitoring, preferably non-invasive, is a key element in the management ARF in patients with COVID-19. These patients need to be placed in individual rooms, ideally with negative pressure, and this calls for centralized monitoring (pulse oximetry, respiratory rate) and, preferably, video surveillance.

Therapeutic strategy for NIRS in COVID-19
The escalation therapeutic strategy proposed by Scala and Heunks for processes that cause ARF can also be used In SARS-CoV-2 infection. 10 Conventional oxygen therapy, consisting in the administration of oxygen at different concentrations, is the base of the therapeutic pyramid. The next step is high flow nasal oxygen (HFNO) therapy, in which a mixture of varying proportions of air and oxygen (FiO 2 ) are deliver at a high flow rate (up to 60 l/min) through a nasal cannula. The gas must be heated and 100% humidified. 11 HFNO, compared with conventional oxygen devices, maintains FiO 2 at a constant level, reduces dead space, generates positive pressure that redistributes intraalveolar fluid, and promotes alveolar recruitment. 12 The next step is non-invasive ventilation (NIV), which is administered under spontaneous breathing, so patients require very little sedation, or none at all. 13 The penultimate step is invasive mechanical ventilation (MV). In this case, volume control mode is usually used, and the patient must be intubated. 10 The last step is extracorporeal membrane oxygenation (ECMO). 14 The respiratory therapies currently used in NIRS are HFNO and NIV.
On the basis of the above, the general criteria for starting respiratory support in ARF secondary to COVID-19 are as follows 15 : Clinical criteria: • Moderate to severe dyspnoea with signs of respiratory effort and use of accessory muscles or paradoxical abdominal movement. • Tachypnoea over 30 bpm.
In patients meeting none of the above criteria, the initial treatment indicated is conventional oxygen therapy. In patients meeting one or more of the criteria, respiratory support, either invasive or non-invasive, is indicated. The use of NIRS for SARS and other viral pandemics is controversial, and in this context NIV failure rates are around 30%. 16 More recently, NIV was also used in patients with ARF secondary to swine flu, with failure rates ranging from 13% to 77%. 17---19 Despite the uncertainty of the evidence and the absence of randomized clinical trials, most observational studies suggest that NIV can be considered in carefully selected patients treated in a protected environment (ideally negative pressure rooms) in hospitals with experience in this technique. In the current epidemic in China, 5.1% of patients required NIV, 2.3% required MV and 0.5% ECMO. 5 Therefore, the choice of therapy will also depend on the patient's basic pathology, mainly respiratory, their location (negative pressure room, sealed individual room with air changes) and the potential need for aerosol-generating procedures. Overall, clinicians can encounter three clinical scenarios:

Recommendations for the prevention and control of infection in patients receiving NIRS Objective
To limit transmission of infection to both healthcare personnel and other patients.

Introduction
The use of NIRS carries a high risk of SARS-CoV-2 transmission. 37---40 The capacity of SARS-CoV-2 to infect healthcare workers has been confirmed, although it is still too early to compare it with MERS and SARS. 40 For this reason, the Ministry of Health, Consumer Affairs and Social Welfare has drawn up a series of recommendations for managing the disease, and the aim of this document is to disseminate measures for limiting transmission to healthcare personnel. 2,39 It is imperative for hospital staff to follow the general preventive measure when administering NIRS in patients with suspected or confirmed SARS-CoV-2 infection, and in order to do so, the authorities must ensure sufficient supplies of protective material for safe NIRS. • Long-sleeve fluid resistant isolation gowns. (b) The feasibility of performing aerosol-generating procedures will depend on the patient's location within the hospital. Most of the evidence available on NIRS devices as invasive procedures and the risk of transmitting respiratory pathogens to healthcare staff concerns orotracheal intubation, patients with artificial airways, and non-invasive ventilation, although the results come from small, low-quality studies and are therefore difficult to interpret (Table 1). In mild cases, therefore, the patient should be placed in a negative pressure room. If this is not available, the patient should be place in a single-occupancy room with bathroom. The door of the room must be closed at all times. 39 Serious cases with severe hypoxaemia should be admitted to special units. (c) For intrahospital transfer, both the patient and the staff member transferring the patient must wear surgical masks. During transfer, the patient's bed must be covered with a clean disposable sheet that is then removed and disposed of as hazardous medical waste (group 3, biological agents). 39

Conventional oxygen therapy
The Ministry of Health, Consumer Affairs and Social Welfare recommends administering oxygen through masks with an exhalation filter, but these masks are not universally available in our setting. In the absence of such masks, a surgical mask can be safely placed over the nasal prongs or oxygen mask to limit the spread of the virus. There are no studies comparing the efficacy of exhalation filter masks and surgical masks in reducing the spread of SARS-CoV-2, 39 but oxygen therapy is considered a low-risk aerosol-generating procedure. 39,40 High flow nasal oxygen therapy The aforementioned general recommendations should be followed, observing a minimum distance of 2 m between patients and healthcare personnel without adequate protection. 42 Although the extent of particle dispersion in this type of therapy remains unclear, and the benefit of placing a surgical mask over the nasal prongs has not been studied, it is an option in an extreme situation.  Results of studies selected for the systematic review that measure the risk of transmission of SARS to healthcare workers exposed vs. not expose to the procedures listed. 48,49

Non-invasive mechanical ventilation
A minimum distance of 2 m should be maintained between patients and healthcare personnel without adequate protection.
In general, according to the available evidence, the use of NIRS is not contraindicated in patients with COVID-19, but the respiratory therapy used will not only depend on the severity of the respiratory failure but also on the availability of a room that complies with the isolation and safety recommendations of the World Health Organization (WHO). The most serious cases that will probably require rapid intubation should be placed in the ICU in order to avoid intubation delays that would affect the patient's evolution (Fig. 1).

Ventilator settings:
• Although there are uncertainties surrounding particle dispersion in COVID-19, in the SARS epidemic some  Figure 1 Treatment sequence to identify early failure and proceed to elective orotracheal intubation.
articles showed particle dispersion to a radius of no more that 4 feet (1.25 m) when using a single-limb circuit with a leak port. 8,43,44 • Double limb circuits are preferable, since they prevent air leaks from both the inspiratory and expiratory breathing circuits. High efficiency antibacterial expiratory filters should be used to avoid reverse contamination from the patient to the ventilator. 39 • If double limb systems are unavailable and single limb ventilators are unavoidable, attach a highefficiency, low resistance antimicrobial filter to the leak port of the single limb to minimize dispersion of exhaled gas that may contaminate ambient air. It also appears feasible to connect a T valve to the circuit in order to place the filter and leak port distal to the valve, although this will increase dead space. • If an antimicrobial filter cannot be connected to the leak port, a similar filter must be placed between the patient/ventilator interface (no leak ports) and the circuit. In this case, the ventilator settings may need to be adjusted to increase pressure support to compensate for the increased resistance. • Instead of double limb or single limb systems with leak port, a single-limb systems with an active valve can be used, placing an antimicrobial filter at the outlet of the active valve. • We do not recommend using heat and moisture exchangers (HME). 45

Choice of interface:
The interface is the device that facilitates both the physical and functional relationship between two independent elements: the ventilator and the patient. It is an indispensable element in NIV, and delivers positive pressure to the patient without the need for an artificial airway. The recommendations for NIV interfaces in SARS-CoV-2 infection are as follows 40,41,46,47 : • An interface without a leak port should be used, and accessory ports, if any, should not be used.
• The use of helmets should be prioritized if available and staff are trained in the placement and use of this device. • In general terms, the first alternative to the helmet is the full face mask and, failing that, the oronasal mask. • Face mask should be monitored for leaks, particularly oronasal interfaces. Any leaks should be corrected, primarily to avoid injuries to the patient's skin, but also to ensure the integrity of the closed circuit and prevent exhalation of contaminated air. Protective patches, which can increase leakage, should be avoided, and hyper oxygenated oil should be applied as required. • Nasal masks are not recommended as they generate more aerosols, and because SARS-CoV-2 infection usually involves acute hypoxaemic failure. 3. Choice of elbow 46 : • We recommend using elbows without an anti-asphyxia valve. These elbows are usually colour-coded blue, and require strict monitoring to guard against possible ventilator malfunction. However, the risk/benefit balance (asphyxia vs. dispersion) favours these elbows, and there is little risk of accidental disconnection that remains undetected or is not corrected in time, since these patients are located in highly complex rooms under the continuous care of specialized healthcare personnel. Nevertheless, the nurse-patient ratio must remain above the minimum safe level. • We advise against the use of anti-rebreathing elbows (which have anti-asphyxia valves) due to the risk of greater dispersion of exhaled air.

Inhaled therapy 1,39
The current pandemic of COVID-19 cases requires infection control precautions to be maximized. Nebulizers generate aerosol particles of between 1 and 5 m that can carry bacteria and viruses to the lung. The risk of transmitting infection through droplet nuclei and aerosols may increase when using nebulizers due to their potential to generate a high volume of respiratory aerosols that can be propelled further than the distance achieved by natural dispersion. Furthermore, larger particles can stimulate coughing in patients and passers-by, thereby increasing the risk of disease spread. Nebulizer therapy in patients with COVID-19 infection has the potential to transmit potentially viable COVID-19 to susceptible subjects. Some hospitals have recently replaced nebulizers with metered-dose inhalers (MDI) with spacers or valved-holding chambers (VHC). Inhaled therapy should preferably be administered with an MDI with a VHC; however, it is important to note that patients with acute respiratory failure will have difficulties using these devices.
Nebulizer therapy should only be used in the following situations: In order to reduce the risk of in-hospital transmission of infectious respiratory diseases in the context of the current COVID-19 pandemic, we encourage all healthcare professionals to seriously consider avoiding the use of open nebulizers in spontaneously breathing patients if the aforementioned inhalers are not available. Patient and staff safety must be our top priority.
If inhaled therapy is indicated, we recommend using vibrating mesh nebulizers with a mouthpiece or face mask. The risk of dispersion can be reduced by placing a surgical mask over the device. Bear in mind that a higher drug dose may be needed if a mouthpiece with an anti-dispersion valve is used (particularly in the case of beta 2 -adrenergic agonist bronchodilators), so the prescription should be adjusted accordingly.
Jet systems have a greater capacity for particle dispersion than other nebulizers, and should therefore be avoided. If unavoidable, the nebulizer must be covered with a surgical mask.
When using inhaled therapy in combination with NIRS, we recommend the following: • Generally speaking, inhaled therapy should be administered via a pressurized cartridges with an adapter or spacer chamber. If used in combination with NIV, the nebulizer should be connected to the inspiratory limb of the ventilator and the aerosol drug should be delivered during inspiration.
• If aerosol therapy is used, the first choice should be a circuit with a vibrating mesh nebulizer elbow. Failing this, a vibrating mesh nebulizer can be connected to the NIV circuit using a T valve. Being a ''closed system'' there is no risk of dispersion, provided the mask is closely monitored for unintentional leaks. • Jet nebulizers with a T tube generate greater turbulence, larger particles, and therefore a higher risk of particle dispersion. • In patients receiving HFNO, pressurized metered dose inhalers with spacer, a mouthpiece with a vibrating mesh nebulizer or a mesh nebulizer connected to the dry limb of the water reservoir should be used. • Generally speaking, pressure support in NIV and temperature in HFNO should be reduced, respectively, when combined with aerosol therapy.