Trial design and setting
This study was a randomized, open-label, crossover trial conducted in a mixed ICU at the JA Hiroshima General Hospital. The study protocol was approved by the ethics committee of the JA Hiroshima General Hospital. This study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki [13] and was registered at the UMIN Clinical Trials Registry on February 11, 2020 (UMIN 000039459), and reported in accordance with the CONSORT statement [14]. Written informed consent was obtained from all the patients or their relatives.
Participants
Patients receiving mechanical ventilation, who were considered at a high risk of post-extubation respiratory failure and planned for NIV after extubation, were screened. We included patients if the difference between PETCO2 and PaCO2 was ≤ 5 mmHg during the spontaneous breathing trial (SBT) and if an arterial line was placed. Patients with GCS ≤ 8, inability to protect the airway, hemodynamic instability, severe hypoxemia, agitation, NIV intolerance, chronic obstructive pulmonary disease, diagnosed pulmonary embolism or suspected, severe anemia (Hb < 7.0 g/dL), and arterial blood gas sample not collected were excluded. Moreover, patients whose cases were judged too difficult to include for analyses by a physician and those who refused consent were excluded.
Patients were considered at a high risk of post-extubation respiratory failure based on the criteria from a previous study (Additional file 1: Appendix S1) [15]. Briefly, as follows: age > 65 years; heart failure as the primary indication for mechanical ventilation; high severity score; obese; weaning process > 24 h (difficult or prolonged weaning, Additional file 1: Appendix S2) [16], 2 or more comorbidities (Additional file 1: Appendix S3), and mechanical ventilation for more than 7 days. All SBTs were performed at the lowest level of positive end-expiratory pressure (PEEP) and pressure support (PS) set at 5 cm H2O for 30–60 min. Considering these risks before extubation, the decision to perform NIV was made by the treating physicians.
Randomization
Enrolled patients were randomized in a 1:1 ratio to receive either the previous method or the novel method as the first measurement. Randomization was performed using a computer-generated randomization table (www.randomization.com). Allocation results were placed into numbered sealed opaque envelopes containing monitoring allocations. Once the patient provided written informed consent, the clinicians participating in the study opened the envelopes in order.
PETCO2 monitoring methods
We compared the following two methods of PETCO2 monitoring (the previous method and the novel method) in the included patients during NIV. After collecting the arterial blood gas sample, we switched to another method. The highest PETCO2 value within one minute of collection of the blood gas sample was recorded. For the primary outcome, we assessed the correlations and agreements between the PETCO2 and PaCO2 measurements performed by both methods.
Previous method: sidestream monitoring using nasal prong and oral scoop
The Smart Capnoline ® Plus (Oridion Medical 1987 Ltd., Jerusalem, Israel) is a nasal prong and oral scoop for use in non-intubated patients with the dual purpose of delivering oxygen and collecting exhalation from both the nose and mouth (Additional file 1: Appendix S4). The length of the cannula was approximately 255 cm, and the delay in CO2 measurement was approximately 240 ms. The patients were fitted with a face mask over the nasal prong.
Novel method: mainstream monitoring using the NPPV cap ONE mask ®
The cap-ONE mask set ® (Nihon Kohden Tokyo, Japan) is a unique interface for collecting exhaled air samples using an inner cup in a face mask and assessing them using the mainstream techniques. The inner cup in the face mask was placed under the patient’s nose and over the mouth to guide the patient’s exhaled flow into the CO2 measurement cell (Fig. 1). The CO2 measurement cell was connected to the inner cup of the NPPV cap-ONE mask ®. The mainstream capnometer was designed to be placed on the CO2 measurement cell outside the mask. The capnometer was calibrated before each application of NIV.
NIV for prevention of post-extubation respiratory failure
NIV was performed using the ventilator NKV 330 (Nihon Kohden Tokyo, Japan) and a face mask of the same size during both measurement periods. The NIV mode, setting, and duration were determined by treating physicians according to the following principles. It was recommended that the same mode and setting be maintained until the second measurement was completed, but they could be changed if necessary. NIV was continuously delivered immediately after extubation for a scheduled period to the next morning. NIV was interrupted once the patients were stable with oxygen administered via a mask or nasal cannula.
Data collection
The following patient characteristics were recorded at admission: reason for ICU admission, age, sex, severity of illness (Acute Physiology and Chronic Health Evaluation II [APACHE II] score [17], Sequential Organ Failure Assessment [SOFA] score) [18], updated Charlson comorbidity index (CCI) [19], and nasal gastric tube placement. The following information was also recorded: NIV parameters (for example, mode, settings, tidal volume, minute ventilation, leakage), respiratory rate, blood pressure, heart rate, and peripheral oxygen saturation during each monitoring method. We performed blood gas analysis 30–60 min after each monitoring method session.
Statistical analysis
We estimated the required sample size based on the correlation between PETCO2 and PaCO2 values measured in previous studies conducted in non-intubated patients [12, 20,21,22]. A sample size of 60 measurements was required to achieve 90% power for detecting an effect size of 0.41 with α set at 0.05.
Data are expressed as mean with standard deviation (SD), medians with interquartile ranges (IQR), or numbers with corresponding percentages, as appropriate. Continuous variables were compared using the paired t-test or Wilcoxon signed-rank test, according to the data distribution. Dichotomous variables were analyzed using the Chi-square test or Fisher’s exact test. The relationships between PaCO2 and PETCO2 were evaluated by computing the Pearson correlation coefficient, and the agreement between PaCO2 and PETCO2 was estimated using the Bland–Altman method, in which bias was the mean difference between PaCO2 and PETCO2, and the upper and lower LoA were the mean of the differences ± 1.96 SDs above and below the mean difference. Precision (the ability to reproduce the same measurement) was assessed based on the [bias—SD; bias + SD] interval, where SD is the SD of the distribution of the differences. Clinically unacceptable values were arbitrarily defined as values > 5 mmHg. In addition, we performed post hoc analyses to explore the source of the difference between PaCO2 and PETCO2. The correlations and agreement between the PETCO2 and PaCO2 measurements were evaluated in patients with small (≤ 40 L/min) and large (> 40 L/min) amounts of leakage. Furthermore, relationships between the difference and the following factors were evaluated using the Pearson correlation coefficient: the amount of leakage, tidal volume, respiratory rate, and minute ventilation. All statistical tests were two-sided, and a p-value < 0.05, indicating statistical significance. Statistical analyses were performed using Stata 15.1 (StataCorp LLC, College Station, TX, USA). The batplot command in Stata was used for the Bland–Altman analysis.