Subjects and study design
This prospective physiologic study was conducted in the Respiratory Intensive Care Unit and the Respiratory Ward of the Division of Respiratory Diseases and Tuberculosis, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during September 2016–May 2017. This study was approved by the Siriraj Institutional Review Board (SIRB) (COA no. 455/2559[EC4]), and was registered in the Thai Clinical Trials Registry (TCTR) (reg. no. 20160902001). Written informed consent to participate was obtained from each subject or their relatives.
We enrolled patients who had a known diagnosis of COPD with post-bronchodilator forced expiratory volume at 1 s/forced vital capacity (FEV1/FVC) < 70% [1], who were 40–85 years old and who had presented an exacerbation that initially required NIV based on at least two of the following criteria [16]:
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Respiratory rate > 24 breaths/min.
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Use of respiratory accessory muscles or paradoxical motion of the abdomen.
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Acute respiratory acidosis (arterial pH ≤ 7.35 and/or PaCO2 ≥ 45 mmHg).
After the initial management and stabilization with NIV, patients were considered for the study. Patients were not enrolled in the study if they had any of the following exclusion criteria: arterial pH < 7.25, hemodynamic instability, persistent hypoxemia despite supplemental oxygen therapy, diminished consciousness or uncooperative, active hemoptysis, pneumothorax, and/or contraindication for esophageal balloon catheter insertion, such as recent upper airway/esophageal surgery or active upper gastrointestinal bleeding.
Device description
The HFNC device (Airvo-2™; Fisher & Paykel Healthcare, Auckland, New Zealand) consisted of a flow generator (up to 60 L/min), an air–oxygen blender that allows for adjustment of FiO2 from 21 to 100%, and an auto-fill MR 290 heated chamber. The gas mixture at 34–37 °C was delivered via a single-limb heated breathing tube to the patient via the Optiflow™ nasal cannula (Fisher & Paykel, Auckland, New Zealand). The dedicated NIV machine (BIPAP Vivo 40; Breas Medical AB, Mölnlycke, Sweden or Respironics V60; Philips Healthcare, Best, the Netherlands) was applied via an oronasal mask and was connected to an active humidification system (VH2000, VADI Medical Technology, Taoyuan, Taiwan). An appropriately sized oronasal mask was chosen to minimize leaks and to optimize patient comfort. The NIV settings, including inspiratory positive airway pressure, expiratory positive airway pressure, respiratory rate, and FiO2, were clinically adjusted by an attending physician and not modified during the study period.
Study protocol
Subjects meeting all of the eligibility criteria and none of the exclusion criteria were enrolled. An esophageal balloon catheter (Cooper Surgical, Inc., Trumbull, Connecticut, USA) was inserted through the nose and positioned in the lower one-third of the esophagus. The balloon was filled with 0.5 mL of air and connected to a pressure transducer (BIOPAC Systems, Goleta, California, USA). To confirm the position of the esophageal catheter, the presence of cardiac oscillations was checked and gentle pressure on the abdomen was applied to verify the absence of gastric pressure fluctuations. Esophageal pressure (Pes) was recorded using an MP150 Data Acquisition System and AcqKnowledge Data Acquisition and Analysis Software (both BIOPAC Systems, Goleta, California, USA).
At inclusion, subjects were ventilated with NIV using their clinical settings for 15 min, after which they were switched to HFNC starting at a flow rate of 10, with subsequent progressive increases to 20, 30, 40, and 50 L/min. The NIV step and all 5 HFNC steps were applied for 15 min each including a recording period of 5 min at the end (Fig. 1). During HFNC, the FiO2 was adjusted to achieve oxygen saturation measured by pulse oximetry (SpO2) of at least 92%, and then this adjustment was kept constant until the end of the study protocol. To enhance the maximum effect of HFNC, we encouraged patients to breathe with their mouth closed as often as possible. After completing the study, the type and settings of respiratory support were decided by the attending physician.
Data collection
Baseline demographic and clinical data, included age, gender, body mass index, co-morbidity, and most recent pulmonary function test were collected. Acute Physiologic and Chronic Health Evaluation (APACHE) II score and arterial blood gas were evaluated at the time of enrollment during NIV session. SpO2 and transcutaneous CO2 pressure (PtcCO2) were continuously recorded throughout the study using a SenTec Digital Monitoring System (SenTec, Therwil, Switzerland). Other physiologic variables, including respiratory rate, blood pressure, and heart rate, were recorded immediately after starting the protocol and at the end of each step.
From Pes, we used the recorded waveforms during the last 2 min of each step to calculate Pes swing and esophageal pressure–time product (PTPes). The average value of Pes swing (cmH2O), PTPes per minute (cmH2O × s × min−1), and PTPes per breath (cmH2O × s) as an index of inspiratory effort were calculated using a dedicated software program (Sistema Respiratorio, Barcelona, Spain). Since measurement of chest wall elastance in non-intubated patients is not possible, and determining the phase of inspiration without airflow signal is also very difficult, we modified the calculation of PTPes per breath by integrating the area under the Pes signal from the onset of negative deflection to the return of Pes to baseline. This technique was used and reported in a previous study [17]; we refer to it as a “simplified PTPes” (sPTPes). sPTPes per minute was obtained by multiplying sPTPes per breath by respiratory rate.
Outcomes
The primary outcome was inspiratory effort as evaluated by sPTPes per minute during NIV and during HFNC at different flow rates. Other physiologic variables included sPTPes per breath, Pes swing, respiratory rate, SpO2, PtcCO2, blood pressure, and heart rate.
Statistical analysis
There was no previous study evaluating patient inspiratory effort during HFNC in COPD patients with acute exacerbation. We performed a pilot exploratory study by enrolling 12 patients in this study. Normality of data distribution was assessed by the Shapiro–Wilk test. Normally distributed variables are expressed as mean ± standard deviation, and were analyzed by repeated measures analysis of variance (ANOVA) followed by a post hoc pairwise comparison with Bonferroni adjustment. Non-normally distributed variables are expressed as median and interquartile range, and were compared by Friedman’s two-way ANOVA by ranks with a Dunn’s test post hoc pairwise comparison with Bonferroni correction. Categorical variables are expressed as frequency and percentage. Data were analyzed using PASW Statistics version 18 (SPSS, Inc., Chicago, Illinois, USA). A two-sided p < 0.05 was considered as statistically significant.