Acute respiratory failure is a common reason for admission to an intensive care unit (ICU) in Canada. Non-invasive positive pressure ventilation (NIV) is a life-saving intervention for selected patients with acute respiratory failure. Practice guidelines recommend using NIV in the management of acute exacerbations of chronic obstructive pulmonary disease (COPD), acute cardiogenic pulmonary edema, and mild to moderate acute respiratory failure in immunocompromised patients. Compared to endotracheal intubation and invasive mechanical ventilation (IMV) for the treatment of select cases of acute respiratory failure, NIV is safer, less invasive, preferred by most patients, and is associated with a reduced ICU length of stay (LOS), less pneumonia and mortality, and lower healthcare costs.
NIV failure can occur, necessitating endotracheal intubation and IMV. Patients who fail NIV have a greater mortality than those who do not fail. There are several risk factors associated with NIV failure.
Persistent patient intolerance despite optimization of the NIV settings occurs in up to 6% of patients. Causes of intolerance include discomfort related to the interface and the required high driving respiratory pressures. Thus, one third of patients being treated with NIV will become delirious and agitated, adding to the risk of NIV failure. NIV intolerance if not recognized and appropriately treated can leave physicians with no option but to proceed with IMV. About 44% of patients who have delirium, agitation, ventilator asynchrony and NIV intolerance will fail and require intubation and IMV.
The first line of treatment in patients who are uncomfortable, agitated, asynchronous, or intolerant is NIV optimization. In those that remain intolerant, sedation is a potential solution, however the evidence is sparse. Thus, despite NIV being a life-saving intervention, there are no recommended pharmacologic practices to reduce NIV failure due to agitation, delirium, and intolerance, leaving physicians with no option but to use IMV.
Why is inDEX needed now?
A survey of Chief Executive Officers in 174 Canadian hospitals predicts a 57% increase in the need for ICU beds with IMV capability by 2026, putting further strain on an already depleted system. In addition, with the third wave of Coronavirus-19 (COVID-19), predictive models suggest that ICU bed requirements will likely exceed capacity. NIV may be able to offset some of that strain. Advances in NIV technology to more efficient systems have increased the utility of NIV and it is often preferred to IMV secondary to fewer complications2. Compared with IMV, clinicians can initiate and use NIV in non-ICU settings like the emergency department, post anesthesia care unit (PACU), step-down care units and at smaller community hospitals that lack critical care support. Therefore, identifying interventions that improve NIV tolerance and reduce the need for IMV are critical.
The Potential Solution
Dexmedetomidine is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and when compared to γ-aminobutyric acid receptor agonists like benzodiazepines, reduces delirium. The 2018 SCCM Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) in critically ill adults issued a conditional recommendation to use propofol or dexmedetomidine over benzodiazepines for sedation during IMV. These guidelines also conditionally recommended the use of dexmedetomidine to treat delirium-agitation in mechanically ventilated adults when agitation was precluding spontaneous breathing trials and extubation.
Given the limited direct and indirect evidence, we hypothesize that dexmedetomidine is beneficial in patients undergoing NIV, by providing “awake” sedation without respiratory depression, preventing delirium, and possibly improving compliance with NIV. To further explore our hypothesis, we will conduct inDEX Retrospective Cohort Study, inDEX International Survey and inDEX Clinical Trial.
inDEX Retrospective Cohort Study
Prior to the conduct of international clinical trial on the use of dexmedetomidine in adults with acute respiratory failure that are being treated with NIV, current practice needs to be understood to inform the trail design. To our knowledge, there is no literature detailing current practice.
We hope to determine which sedatives are being used, what patient characteristics are associated with the use, incidence of NIV failure, and if sedatives are associated with reduced incidence of NIV failure.
inDEX International Survey
To further understand the current practice with using sedatives on agitated patients with NIV, we are distributing 18 questionnaire survey to critical care physicians across the world.
We hope to determine which sedatives are being used, what patient characteristics are associated with the use, and intensivist's attitude towards sedation during NIV.
inDEX Clinical Trial
We hypothesize that dexmedetomidine, when compared to placebo, will reduces NIV failure in hospitalized adults with acute respiratory failure and agitation or NIV intolerance.
Therefore, we are conducting pragmatic, international, multi-centred, stratified, randomized parallel-group, double-blind, placebo-controlled vanguard trial to access if dexmedetomidine compared to placebo results in a reduction of non-invasive ventilation failure.