Future high-priority research questions

PICO Question 1: LTH-NIV in chronic stable hypercapnic COPDStrategies for initiating NIV. It is obvious that ventilator setting and acclimatisation to NIV are crucial for effectiveness, including better adherence. NIV may be initiated in the hospital or at home. In-hospital initiation can be easily performed in some centres; however, it is more expensive and complex.
The benefits of NIV in subgroups of patients with COPD. The variability of both adherence and treatment response may vary according to different clinical phenotypes. Indeed, it seems that the response is better in those patients with PaCO2 >50 mmHg and PaCO2 reduction to normal following NIV. A phenogrouping strategy of hypercapnic COPD subgroups is needed for better defined the populations to be prioritised in further studies.
The impact of comorbid conditions in this population e.g. the effect of obesity, OSA-overlap, cardiovascular diseases, and clinical frailty upon clinical outcome.
Assessment of other underestimated factors, such as lack of social support and patient-ventilator asynchrony, which may impact the effectiveness of LTH-NIV.
Cost effectiveness studies reporting the health economic value of LTH-NIV in chronic stable COPD.
PICO Question 2: LTH-NIV in COPD following an episode of acute hypercapnic respiratory failureDeveloping more accurate criteria for identifying patients who are likely to benefit from LTH-NIV, such as severity of illness (hypothesis that treatment of higher PaCO2 at initiation will drive greater clinical benefits), trajectory of hypercapnia recovery after exacerbation (as some patients return to eucapnia more rapidly than others) and treatment response (e.g. early reduction in PaCO2 level after starting LTH-NIV, with the hypothesis that greater reduction in PaCO2 will drive greater clinical benefit).
Physiological and biological mechanisms of action of LTH-NIV: physiological mechanisms determining reduction in PaCO2; the biological effects of PaCO2 reduction in chronic hypercapnia upon the immune system, pulmonary vasculature and skeletal muscle; biological mechanisms determining reduction in exacerbation; and physiological mechanisms determining enhanced sleep quality.
The effects of NIV upon mental health and cognition upon patients, including effects upon HRQL and, cognitive function after an acute hypercapnic respiratory failure, the relationship between HRQL and cognitive function upon adherence and acceptability of LTH-NIV.
Health service delivery research to promote the delivery of LTH-NIV after an acute hypercapnic respiratory failure to the right patient at the right time and prevent the “overuse” or “underuse” of the treatment.
Assessment of novel home treatments, e.g. high flow humidified nasal oxygen, that are capable of reducing PaCO2 in stable hypercapnic COPD patients.
PICO Question 3: LTH-NIV to normalise or reduce PaCO2The impact of NIV ventilator strategy targeted to maximise PaCO2 reduction compared to conventional ventilator modes on long-term clinical outcomes (i.e. hyperinflation, exacerbations, cardiovascular complications, hospitalisations, survival, costs, patient adherence).
PICO Question 4: Fixed pressure versus new adaptive/auto-titrating modes in LTH-NIVThe role of adaptive/auto-titrating modes to improve the long-term outcome of COPD, acute exacerbation versus chronic stable hypercapnic COPD and optimisation of overnight ventilation, especially in specific subgroups in which ventilatory requirements may vary substantially overnight.
The assessment of auto-EPAP modes (in addition to adaptive/auto-titrating modes) in the sub-group of patients with COPD–OSA overlap syndrome.
The clinical efficacy and cost effectiveness of auto-titrating modes in the inpatient versus outpatient settings avoiding the need for hospitalisation to initiate NIV, thereby increasing access to NIV.

PICO: target population-intervention-comparator-outcome; LTH-NIV: long-term home non-invasive ventilation; NIV: non-invasive ventilation; PaCO2: partial pressure of carbon dioxide in arterial blood; HRQL: health-related quality of life; OSA: obstructive sleep apnoea; EPAP: expiratory positive airway pressure.