In patients hospitalized with COVID-19, an increase in oxygen needs causes the doctor to decide how and when to escalate treatment. A key goal of treatment is to avoid, when possible, the need for invasive mechanical ventilation. However, up to 20% of hospitalized patients in the UK require admission to intensive care units, and around 40% of those requiring invasive mechanical ventilation for COVID-19 pneumonitis do not survive.
To date, the only treatments that have been shown to reduce the need for invasive mechanical ventilation are dexamethasone and interleukin-6 blockade.
Non-invasive respiratory support strategies , such as continuous positive airway pressure (CPAP) or high-flow nasal oxygen (HFNO), are attractive treatment options that could avoid the need for invasive mechanical ventilation and its inherent risks.
In the context of COVID-19, concerns have been raised that these strategies may cause harm to patients through delays in tracheal intubation or exacerbation of lung injury, to healthcare workers through nosocomial infections, and to health care workers. health care systems through high oxygen level. demand for devices.
This uncertain balance of harms and benefits has resulted in marked variation in international practice. A survey of 1,132 participants in 85 countries used a case vignette of a previously healthy patient with severe hypoxemia. The choice of initial oxygen strategy included HFNO (47%), CPAP or non-invasive ventilation (26%), and immediate tracheal intubation (7%), with the remainder of respondents choosing to optimize conventional oxygen therapy.
Variability in practice was associated with country, hospital rurality, intensive care unit bed availability, and individual physician characteristics. There is a paucity of high-quality evidence for non-invasive respiratory support strategies in COVID-19.
A multicenter randomized controlled trial (RCT) reported no difference in ventilator-free days in 109 patients with COVID-19 and moderate to severe hypoxemia who were treated with non-invasive helmet ventilation or high-flow nasal oxygen, although a limitation of This study was the absence of a control group that received standard oxygen therapy treatment.
Other direct evidence remains limited to retrospective case series and cohort studies with inconsistent findings and the inherent risk of bias associated with observational study design.
For example, a retrospective study reported failure rates of 66% in COVID-19 patients receiving CPAP and high mortality (55%) in those requiring invasive mechanical ventilation after CPAP failure. Evidence for HFNO, CPAP, and non-invasive ventilation as effective treatments for acute hypoxemic respiratory failure is drawn from non-COVID-19 patient populations.
For example, a systematic review and network meta-analysis concluded that noninvasive ventilation delivered by the helmet-mask interface reduced the risk of all-cause mortality and tracheal intubation, and that HFNO reduced the need for tracheal intubation.
However, the patient populations in the included studies were those with community-acquired pneumonia. COVID-19 is a new disease and generalization of data from other causes of acute hypoxemic respiratory failure is inherently problematic.
In patients with viral influenza and other coronaviruses, high noninvasive ventilation failure rates of over 70% have been reported, so CPAP or HFNO may serve only to delay, rather than prevent, tracheal intubation.
One concern regarding the use of non-invasive ventilation in patients with more compliant lungs is the possibility that large tidal volume breathing could lead to patient self-induced lung injury , which has a similar pathogenesis to ventilator-induced lung injury. . However, the converse argument is that liberal use of tracheal intubation and mechanical ventilation in COVID-19 is likely to increase ventilator-associated complications and mortality.
The risk of nosocomial transmission of COVID-19 to healthcare workers providing non-invasive respiratory support strategies centers on the potential generation of aerosols. Early evidence from mechanistic assessments of aerosol and droplet spread suggested that the risks of noninvasive strategies are comparable to standard oxygen therapy. Aerosol generation can be influenced by the device, settings and interface, but also by patient characteristics such as viral load or cough profile.
However, the absence of substantive evidence does not indicate an absence of risk.
More research is needed to understand the risk to both healthcare workers and other patients.
International guidelines on the treatment of acute hypoxemic respiratory failure and the use of non-invasive respiratory strategies in the context of COVID-19 are prolific. In the UK, clinicians can be informed by recommendations from NHS England and the respiratory anesthesia and intensive care communities, as well as global organisations.
Across all guidelines, there is marked variability in the transparency of development, the evidence synthesis process, and the recommended approach. For example, in November 2020, NHS England recommended CPAP as the preferred form of non-invasive respiratory support in COVID-19 and advised against the use of HFNO on the basis of perceived lack of efficacy, oxygen use and potential. transmission of infection to healthcare workers, although NICE is reviewing this guidance.
In contrast, the Surviving Sepsis Campaign guidelines support the use of HFNO, although they recognize that the strength of this recommendation is weak and based on low-certainty evidence.
The WHO guideline adopts a balanced recommendation, including the use of all non-invasive respiratory support strategies, justified by the inadequate evidence base for any individual approach.
Others, including the Intensive Care Society of Australia and New Zealand, have moved away from a previous position of favoring one strategy over another, and now base their recommendations on life guidelines that suggest that decisions regarding non-invasive respiratory support should be based on risk assessment of the individual patient and the healthcare environment, with emphasis on reducing the risk of transmission of infections to healthcare workers.
RCTs are urgently needed to evaluate the effectiveness of non-invasive respiratory support strategies in patients with COVID-19. Currently, clinical practice is governed by personal preferences and influences, previous experience and local availability of methods in the context of oxygen delivery.
But in this context of uncertain evidence about the safety, effectiveness, and optimal approach to the management of acute hypoxemic respiratory failure, it is essential that clinicians demonstrate balance and randomize patients to clinical trials available in their healthcare jurisdictions. .
For example, there have been several reports of pneumomediastinum and pneumothorax in patients with COVID-19 receiving standard oxygen therapy or non-invasive respiratory support.
These reports are cause for concern, although they are confounded by many unmeasured factors due to their observational nature. Because non-invasive respiratory support is used as part of usual care in many settings without evidence of no harm , such reports further support the need for RCTs of non-invasive respiratory support in patients with COVID-19 compared to standard care.
Clinical trials of noninvasive respiratory support should exclude patients with a contraindication to noninvasive support and ensure that data on harms, such as the incidence of pneumomediastinum and pneumothorax, are reported.
By far the largest trial in this area is the UK RECOVERY-Respiratory Support Trial funded and prioritized by the National Institute for Health Research as an urgent public health study. This multicenter adaptive RCT evaluates the effectiveness of HFNO or CPAP versus standard oxygen therapy in hospitalized patients with COVID-19 and acute hypoxemic respiratory failure, with a primary outcome of tracheal intubation or mortality within 30 days of randomization. As of April 12, 2021, more than 1,200 patients have been randomized, with trial enrollment occurring across two UK guidance pathways.
During a pandemic, when the demand for intensive care resources exceeds available capacity, the use of non-invasive respiratory support on an individual patient in the absence of established evidence could be considered the only possible treatment , particularly if there is no option to participate in a clinical trial.
However, when there are no critical care capacity issues and there are options to participate in a clinical trial, clinicians should keep in mind that provision of this treatment outside the rigorous infrastructure of RCTs represents randomized empirical care. If one of these interventions is shown to be beneficial, this approach will have delayed answering the urgent clinical question at hand.
If an intervention does not show any favorable effects (or worse, harm), doctors will need to justify their continued use of that unproven treatment as part of usual care rather than within the framework of a trial, as well as their decision to withhold patients the opportunity to participate. in research prioritized at the national level.
Understanding the most effective non-invasive respiratory support strategy in COVID-19 requires investigation of the relative benefits and harms to both the patient and the broader healthcare system, which can only be addressed through randomization to clinical trials.
Declarations of interest : All authors are responsible for the conduct and execution of the RECOVERY-Respiratory Support trial, funded by the National Institute for Health Research (NIHR) and referred to in this commentary. BC reports Fisher & Paykel educational fees, and its institution receives NIHR funding for a trial in critically ill patients with acute respiratory failure; she is director of research at the Intensive Care Society. GDP reports NIHR grants. DFM reports personal consulting fees for GlaxoSmithKline, Boehringer Ingelheim, Bayer, Novartis, and Eli Lilly, and for serving on an ethics and data monitoring committee for a trial conducted by Vir Biotechnology. The DFM institution has received grants from several sponsors for studies in patients with acute respiratory distress syndrome and COVID-19; In addition, he has a patent (US8962032) granted to his institution for a treatment of inflammatory diseases. DFM is Director of Research at the Intensive Care Society and Program Director of the NIHR Mechanisms and Efficacy Evaluation programme.
