This is an investigator-initiated, unblinded, single center, randomized controlled trial. This trial will be conducted in the emergency department, emergency intensive care unit, and respiratory intensive care unit of a large, urban, tertiary-care, teaching hospital. Written informed consent will be gained from all patients or their legal representatives.
Participants and eligibility criteria
We will enroll adult patients of any gender who are 18 years old or older with a diagnosis of mild-to-moderate AECOPD according to the most recent GOLD criteria. Mild-to-moderate AECOPD is currently defined as an acute hypercapnic respiratory failure with an arterial pH between 7.25 and 7.35 and a PaCO2 ≥55 mmHg4,17,18.
Exclusion criteria are: (1) those who have home care with NIV; (2) those who have received HFNC or NIV prior to this study enrollment; (3) those who have unstable clinical conditions, such as the need for vasopressors to maintain blood pressure, acute coronary syndrome, life-threatening arrhythmias, cardiac or respiratory arrest requiring cardiopulmonary resuscitation or tracheal intubation; (4) those who refuse informed consent; (5) those who are agitated or have altered mental status characterized by a Richmond Agitation Sedation Scale (RASS) ≥217; (6) those who are diagnosed with a failure in two or more than two organs; (7) those who have recent facial or neck trauma, congenital or pre-existing facial or neck deformities which may influence the proper application of HFNC or NIV; (8) pregnancy; (9) those who have been enrolled in other trials recently19.
In the intervention group, patients will receive HFNC when they are awake in daytime and early evening hours. When they are asleep or at night between 10pm and 6am, these patients will change to NIV. The HFNC group will be given a flow rate of 60 L/min and a temperature of 37° C17. If a patient is not tolerating these settings, flow rate and temperature will be titrated to the maximum tolerated level.
In the control group as well as during the NIV period of the intervention group, patients will receive NIV through full or nasal mask with any available ventilator in the hospital. The ventilator will be set to Pressure Support Ventilation (PSV) mode according to usual practice, including a maximal tolerated inspiratory pressure to obtain an expired tidal volume of 6-8 mL·kg-1 of ideal body weight and a PEEP between 3 and 5 cm H2O17.
The FiO2 will be set for both groups to maintain a peripheral oxygen saturation (SpO2) of 88-92%4. Besides the ventilatory support listed above, other standard therapies will be given based on current GOLD guidelines.
Criteria for discontinuing the trial
Each patient’s attending physician will make the decision to cease HFNC or NIV if the patient shows signs of worsening respiratory failure or if they show one or more of the following conditions: respiratory pauses with a loss of consciousness, bradycardia (heart rate <50 beats per minute (bpm)), hypotension with a blood pressure <90/60 mmHg, acute respiratory acidosis with an abnormal arterial blood gas (pH <7.35; PaCO2 >45 mm Hg)11, psychomotor agitation making nursing care impossible or requiring sedation2, respiratory or cardiopulmonary arrest. If such conditions happen to the patient, they may need to be intubated either to protect the airway or to manage tracheal secretions, and given mechanical ventilation as per usual practice. Finally, the trial will end if the patient or legal representative rescinds their informed consent.
The primary endpoint is the mean difference in PaCO2 from baseline to 24 hours after randomization. Secondary endpoints include: (1) the mean difference in PaCO2 from baseline to 6, 12, and 18 hours after randomization; (2) dyspnea score at 6, 12, 18 and 24 hours; (3) overall discomfort score related to the ventilatory strategy and proportion of patients showing poor tolerance to treatment at 24 hours (e.g. complaining about noise, pressure, temperature, gastric distension, vomiting, or claustrophobia); (4) the proportion of patients who change treatment strategies (switch to the other ventilatory strategy or to no support); (5) rate of treatment failure, defined as the proportion of patients who had PaCO2 worsening or reduction <10 mmHg from baseline, or worsening with no improvement of the dyspnea or respiratory rate >30 breaths per minute; (6) respiratory rate; (7) rate of endotracheal intubation within 24 hours (8) length of hospital stay; and (9) all-cause mortality.
Sample size calculation
Based on previous studies20, we set the non-inferiority cutoff at 10mmHg. So after the High flow nasal cannula therapy with sequential noninvasive ventilation, in intervention group, PaCO2 may not elevated more than 10mmHg after 24h.To assess non-inferiority using an α = 0.50, power = 0.80, and 1-sided testing, 66 subjects were needed totally.
Assignment of interventions, allocation and concealment mechanisms
Patients will be randomized into either an intervention group and a control group through a 1:1 ratio using a computer-generated randomization sequence via an independent investigator, who will not be involved in the trial. Allocation concealment will be maintained using sequentially numbered sealed opaque envelopes. Each envelope contains the patient’s allocation to either control or intervention group, with a unique study patient code. The baseline is defined as the time of randomization.
Assignment of interventions: blinding
Because of the design of this trial using HCNC or NIV, neither the investigators nor the patients can be blinded to the treatment allocation.
We will recruit participants from the emergency department, emergency intensive care unit and respiratory intensive care unit of a large, urban, tertiary-care, teaching hospital. Investigators will explain the purpose, methods, possible risks, benefits and rights to patients who are eligible to participant in this trial. If the participant agrees to be enrolled and meets the eligibility criteria, the investigator will ask the patient or their guardian to sign the study’s informed consent form.
Participant retention and withdrawal
Once the participants are enrolled, the research team has the responsibility to achieve a low rate of loss to intervention. Before the start of the intervention, investigators will take the time to educate, detail the duration of the intervention and possible adverse effects. All patients will be informed that they have the right to withdraw from the study at any time during the intervention and the Data Monitoring Committee (DMC) will discuss and analyze the reasons for dropouts with data collectors, which will be documented in a standardized form.
Data collection and measurement
We will collect patient personal and baseline clinical characteristics as delineated above (e.g., age, gender, RASS, etc.). Furthermore, we will collect vital signs, systolic and diastolic pressure, heart rate, peripheral oxygen saturation, the presence of dyspnea based on the Borg dyspnea scale(score from 0 to 10 after 6 minutes’ walk, 0 means no dyspnea, 10 means the maximum), the arterial blood gas at inclusion, starting time and settings for HFNC/NIV at 6, 12, 18, and 24 hours. During the study intervention, patients will have continuous SpO2, electrocardiogram, respiratory rate, and noninvasive blood pressure monitoring. All relevant variables and endpoints will be evaluated at 6, 12, 18, and 24 hours after randomization. In particular, we will record the NIV and HFNC settings as well as the proportion of patients who change treatment modality during the study period (i.e., switch to the other ventilatory strategy or to no ventilatory support). The discomfort score related to different ventilatory strategies will also be assessed at the established time points, and the proportion of patients showing poor tolerance to the treatment but who do not interrupt or withdrawal due to noise, temperature of flow, gastric distension, vomiting, or claustrophobia will be recorded. We will also record the rate of treatment failure due to a worsening PaCO2, a less than 10 mmHg reduction in PaCO2 from baseline, a worsening or lack of improvement in dyspnea, or a respiratory rate >30 breaths per minute. Hospital length of stay and any-cause in-hospital mortality will all be collected.
We will use descriptive statistical methods to measure patient characteristics and baseline clinical features. For primary and secondary outcomes, continuous variables will be presented as means ± standard deviations or median interquartile ranges (IQR). Categorical variables will be expressed as counts with percentages. We will use Student’s T-tests or Mann–Whitney U-tests to evaluate the differences between treatments in continuous variables according to normal distribution. Categorical variables will be compared using Chi-squared or Fisher’s exact tests. All data collected will be analyzed by an independent statistical expert using SPSS (SPSS 22.0). A p-value <0.05 will be considered statistically significant.