High‐flow nasal cannula versus face mask for preoxygenation in obese patients: A randomised controlled trial

Preoxygenation efficacy with high‐flow nasal cannula (HFNC) in obese patients is not clearly established. The primary aim of this study was to compare heated, humidified, high‐flow nasal cannula with face mask for preoxygenation in this population.


| INTRODUC TI ON
Critical desaturation during induction of general anaesthesia may occur rapidly in obese patients. [1][2][3] This is mainly due to reduction in the functional residual capacity (FRC), higher oxygen consumption and increased incidence of difficult airway management compared to normal weight subjects.. [4][5][6][7][8][9] Preoxygenation with face mask and high fractions of inspired oxygen (FiO 2 ) creates an alveolar oxygen reservoir that increases apnoea tolerance during airway management. 10,11 A head up tilt and application of positive end expiratory pressure (PEEP) expand the FRC further prolonging time to desaturation in obese subjects. [12][13][14][15] In some patients, a perfect mask seal is not possible and/or PEEP is not well tolerated, impairing the efficacy of preoxygenation 16,17 A high-flow nasal cannula (HFNC) system that supplies heated, humidified high-flow oxygen through the nose may be an alternative in these patients. HFNC increases airway pressures and endexpiratory lung volume directly related to the flow and inversely related to mouth opening, which may be beneficial in obese patients. [18][19][20][21][22] Unfortunately, studies of preoxygenation with HFNC are relatively scarce in the obese population and the evidence regarding the efficacy of preoxygenation is conflicting. [23][24][25][26][27] The primary aim of this study was to compare HFNC with a tightly fitted, ventilator-connected, standard anaesthesia face mask with PEEP applied for preoxygenation during anaesthesia induction for bariatric surgery.

| Study design, setting and ethics
This was a single-centre, open-labelled, randomised, controlled trial performed in compliance with the Declaration of Helsinki.
The study was conducted at a satellite outpatient surgery unit at Uppsala university hospital, a tertiary referral centre in Sweden between 23 October 2018 and 11 February 2020. The protocol was registered at the ISRCTN registry (#ISRCTN37375068) 19 October 2018 (isrctn.com). Ethical approval for this study (2018-007) was provided by the Regional Ethical Committee of Uppsala, Sweden, on 4 April 2018. Written informed consent was obtained from all subjects.

| Participants
Patients aged 18-60 years with a BMI ≥ 35 kg m −2 presenting for elective laparoscopic bariatric surgery were eligible for inclusion.
Exclusion criteria were non-BMI-related ASA class >2, chronic obstructive pulmonary disease or asthma causing restrictions in daily activities, heart failure with New York Heart Association functional classification >2, restrictive lung disease associated with a reduction of total lung capacity >20%, allergy to any of the anaesthetic agents used in the study or being unable to understand oral and/or written study information.

| Randomisation and masking
Randomisation was performed with an allocation ratio of 1:1 and a block size of two using sealed opaque sequentially numbered envelopes. There was no masking.

| Interventions during preoxygenation
An arterial cannula was placed under local anaesthesia and ultrasound guidance. Subjects were randomly assigned to receive 5 min of preoxygenation with a FiO 2 of 1.0 using a tightly fitted standard anaesthesia face mask connected to the ventilator (Maquet FLOW-i®, Maquet) with a PEEP of 7 cm H 2 O (PEEP group) and a flow rate of 8 L min −1 or HFNC (POINT® high-flow system, Armstrong Medical) with a flow rate of 70 L min −1 (HF group) approximately corresponding to a PEEP of 7 cm H 2 0 during closed mouth breathing. 28 A good mask seal in the PEEP group was determined by clinical assessment of leaks, by observing a normal square waveform capnography trace, and by appropriate inspiratory O 2 and expiratory CO 2 values. All subjects were instructed to breathe normally and subjects in the HF group were further instructed to breathe with their mouths closed.

| Interventions after anaesthesia induction
After induction of general anaesthesia, subjects in the PEEP group were bag-mask ventilated with a FiO 2 of 1.0 until commencement of laryngoscopy during which the face mask was removed. Bag-mask ventilation was performed manually by the attending physician and was not protocolised. In the HF group, a jaw thrust was immediately applied after loss of consciousness

Editorial Comment
High-flow nasal cannula (HFNC) is gaining increased attention and may provide safe preoxygenation, especially in obese patients. This randomised clinical trial compared HFNC with best practice of face mask preoxygenation in 40 patients with BMI ≥ 35. Although all patients reached an EtO 2 ≥ 0.85 after 5 min, and there were no desaturations during intubation, the average EtO 2 was marginally higher in patients preoxygenated with face mask with 7 cm H 2 O of PEEP. This manuscript provides valuable safety information concerning use of HFNC before tracheal intubation in obese patients. and HFNC was maintained at 70 L min −1 during apnoea and laryngoscopy until intubation. Laryngoscopy was initiated 90 s following the administration of muscle relaxant. If desaturation, defined as a peripheral capillary oxygen saturation (SpO 2 ) ≤95%, occurred during laryngoscopy, rescue bag-mask ventilation was allowed in both groups.

| Common anaesthesia management
Standard perioperative monitoring including electrocardiogram, pulse oximetry, non-invasive blood pressure (NIBP) and train-offour monitoring was applied in the operating room. Subjects were placed in the ramped sniffing position using standardised pillows with the operating table at zero degrees angle. The attending anaesthetists were given thorough briefings of the study protocol before the patient arrived in theatre. General anaesthesia was induced according to local guidelines using fentanyl (≈2 µg kg −1 adjusted body weight, ABW) and a target-controlled infusion (TCI) of propofol titrated to clinical effect (initial effect site target concentration 5-7 µg ml −1 ABW). Rocuronium (≈0.6 mg kg −1 lean body weight) was used to facilitate endotracheal intubation. The exact dosing of anaesthetic drugs was determined at the discretion of the attending anaesthesiologist.

| Outcomes
The primary outcomes of this study were EtO 2 after 2.5 and 5.0 min of preoxygenation. Secondary outcomes were the proportion of subjects with an EtO 2 ≥0.85 and ≥0.90, partial pressure of arterial oxygen (PaO 2 ), partial pressure of arterial carbon dioxide (PaCO 2 ), SpO 2 , end tidal carbon dioxide (EtCO 2 ), NIBP and heart rate at 2.5 and 5.0 min of preoxygenation and the level of discomfort during preoxygenation.
Apnoea time following induction of general anaesthesia was registered and defined as time from discontinuation of bag-mask ventilation or time from last spontaneous breath as assessed visually to endotracheal intubation confirmed by waveform capnography in the PEEP group and HF group respectively. EtO 2 , EtCO 2 , PaO 2 , PaCO 2 , NIBP and heart rate were measured immediately following intubation. End-tidal gas fractions were recorded during the first breath delivered manually by the anaesthetist following intubation and arterial blood gas sampling was performed at the inflation of the endotracheal tube cuff. The lowest SpO 2 during apnoea was noted.

| Measurements
EtO 2 and EtCO 2 were measured with the subject continuously breathing through the face mask in the PEEP group or by two intermittent exhalations at 2.5 and 5.0 min, respectively, in the y-piece in the HF group and analysed by the ventilator (Maquet FLOW-i®, Maquet). To ensure reliable measurements, subjects in the HF group practised exhalation through the y-piece on room air at least 5 min before preoxygenation started. We considered the technique satisfactory when normal capnograms could be observed and similar EtO 2 values obtained during two consecutive exhalations. Arterial blood gas results were analysed using a point-of-care blood gas analyser (Abbot i-STAT® 1, Abbott Laboratories). SpO 2 , NIBP and heart rate were analysed using a standard multi-parameter monitor display (Dräger Infinity Delta® monitor, Dräger Medical System Inc.).
Following adequate recovery from anaesthesia and at least 1 h in the post anaesthesia care unit, the level of discomfort during preoxygenation was assessed using a four-step ordinal scale defining increasing levels of discomfort as none, mild, moderate or severe. Aborting the procedure was considered equivalent to severe discomfort.

| Sample size calculation
We assumed that mean EtO 2 would be 0.90 in the face mask group after 2.5 min preoxygenation with standard deviation of 3% partly based on previous studies of preoxygenation in non-obese subjects. 17 With a type I error of 5% and a power of 80%, a sample size of 16 subjects in each group was calculated to detect a mean EtO 2 difference of 3%. To compensate for dropouts, we planned for inclusion of a total of 40 subjects.

| Statistical analysis
All data were analysed using Microsoft Excel and R (version 4.0.2) with the R package"Rcmdr" (R Commander. R package version 2.7-0). Assumption of normality was tested using quantilequantile plots and/or Shapiro-Wilk test. Continuous data were presented as mean and standard deviations (±SD) or median and ranges (min-max). Categorical data were presented as number and percentages. The two primary outcomes were analysed with unpaired t-test. We did not correct for multiple statistical analysis of the primary outcome. Secondary outcomes were analysed with unpaired t-test or Mann-Whitney's test for normally and nonnormally distributed variables as appropriate. Chi-square test or Fisher exact test was used to compare categorical variables.
Ordinal regression was used to calculate odds ratio for discomfort during preoxygenation. Effect size was estimated with 95% confidence intervals (95% CI) for mean differences. Correlation was analysed using the Pearson correlation coefficient. We did not correct secondary or post-hoc analysis for multiple statistical analysis and these results should therefore be considered exploratory. Imputation was not done for missing data. All tests were two-sided and p-values less than 0.05 were considered statistically significant.

| RE SULTS
Forty subjects were included in the study. Subjects in the HF group were a mean of 5.7 years older. More patients were ongoing or previous smokers in the HF group. Baseline characteristics (Table 1) and baseline measurements (Table 2) were otherwise similar between groups. In the PEEP group, two subjects withdrew consent and arterial access could not be achieved in two additional subjects. Eighteen subjects in the PEEP group were thus available for analysis of endtidal gas fractions and hemodynamic variables during preoxygenation and 16 subjects were available for analysis of arterial blood gas results. In the HF group, all 20 patients were included in the final analysis ( Figure 1). There was one unexpected difficult intubation in the PEEP group and two in the HF group, all three requiring three intubation attempts (Table 1).

| Primary outcome
EtO 2 increased rapidly in both groups from baseline during preoxygenation ( Figure 2). Mean EtO 2 was similar at 2.5 min of preoxygenation. At 5.0 min, mean EtO 2 was higher in the PEEP group compared with the HF group (Table 2).

| Secondary outcomes
There were no differences in the proportions of subjects with EtO 2 > 0.85 at 2.5 or 5.0 min. A higher proportion of patients in the PEEP group reached EtO 2 > 0.90 at 5.0 min, but the difference was not statistically significant. All subjects in both groups reached an EtO 2 ≥ 0.85 at 5 min of preoxygenation (Table 2). There were no differences between groups in mean PaO 2 when comparing values at 2.5 and 5.0 min of preoxygenation, respectively. There were no differences in EtCO 2 , PaCO 2 , SpO 2 , NIBP or heart rate respectively, at any of the predefined time points (Table 2).
By study design, apnoea time differed between the PEEP group and the HF group. PaO 2 was higher at intubation in the PEEP group compared with the HF group, but the difference was not statistically significant.
A majority of subjects in both groups reported no or mild discomfort ( Figure 3). Only one subject reported severe discomfort (PEEP group). None of the interventions were aborted.

| Adverse events
There were no adverse events related to the use of face mask or HFNC. There were two cases of difficult intubation in the HF group, both requiring 3 laryngoscopy attempts. One subject had a BMI of  the trachea in 45 s during which the SpO 2 fell once more to 92%.
All difficult intubations were unexpected, and all three patients had been thoroughly assessed pre-operatively including mouth opening, Mallampati score, cervical spine mobility and thyromental distance.

| DISCUSS ION
The main finding of this study was that preoxygenation using a standard anaesthesia face mask with PEEP provided higher EtO 2 TA B L E 2 Results. PEEP group, n = 18. HF group n = 20. End-tidal gas fractions, arterial blood gas results, pulse oximetry and hemodynamic variables at baseline, during preoxygenation and immediately after intubation Data are presented as mean ± standard deviation if not stated otherwise. Duration of apnoea is presented in the intubation column.
values compared with HFNC after 5 min of preoxygenation. This difference may be due to a lower alveolar ventilation in the HF group secondary to dead space CO 2 washout. 29 However, this explanation is in part contradicted by the fact that subjects in the HF group investigators found that preoxygenation with HFNC resulted in inadequate preoxygenation, and a significant variability in EtO 2 after 3 min of preoxygenation. 26 However, they conducted the study with a flow of 50 L min −1 and the subjects were instructed to take deep breaths, which may have led to high inspiratory flows and entrainment of room air explaining the observed difference. In another study of normal weight subjects, a flow rate of 70 L min −1 and tidal volume breathing were used. 25 They found a greater variability in EtO 2 values after 2.5 min and fewer subjects reaching an EtO 2 of 0.90 compared with our results, which is more difficult to explain.
The difference could perhaps be due to different breathing patterns, but this was not recorded in either study. Similar to a third study, 24 we report high PaO 2 levels in both groups during preoxygenation.
Long apnoea times were observed in the HF group and although two unexpected difficult laryngoscopies with apnoea times that BMIs. This is similar to patients undergoing rapid sequence induction in the intensive care unit, where HFNC seems to prevent critical desaturation if the cause of intubation is non-hypoxemic in contrast to hypoxemic causes of intubation. 36,37 Both patients intubated for hypoxemic respiratory failure and patients with morbid obesity may thus need more PEEP than HFNC can provide, which is further supported by a study comparing non-invasive ventilation (NIV) to HFNC in a more diverse obese population than ours. 27 Although not studied in the obese, a combination of preoxygenation with NIV followed by apnoeic oxygenation with HFNC during laryngoscopy may be the most efficient method. 38 Our study has several limitations. First, due to the nature of the intervention, subjects and anaesthetists were not blinded to the allocated intervention, increasing the risk of bias. Second, the small sample size reduces statistical power and the single-centre design and the homogenous study population limit generalisability.
However, most anaesthetists were registrars conversely increasing generalisability. Third, measurement of EtO 2 may be prone to errors, especially in the HF group. We tried to minimise technical errors by practising the technique before starting preoxygenation in the HF group and included PaO 2 as a supportive secondary outcome less likely to be biased. Fourth, controls in this study received preoxygenation with PEEP, which may not be generalisable to centres F I G U R E 2 Mean ± SD EtO 2 at baseline and after 2.5 and 5.0 min of preoxygenation with high-flow nasal cannula (HF group) or a standard anaesthesia face mask with positive end expiratory pressure (PEEP group). Asterisk (*) indicates p < .05

| CON CLUS IONS
In obese patients with no or mild systemic disease presenting for elective bariatric surgery, preoxygenation using a standard anaesthesia face mask with PEEP was superior to preoxygenation with HFNC. However, HFNC provided adequate preoxygenation quality in all patients and although further research is warranted, HFNC may be considered in selected patients in whom face mask preoxygenation is not feasible.

CO N FLI C T S O F I NTE R E S T
JR and PF declare that they have no conflict of interest. DF has received travel funding to participate in a scientific symposium on HFNC sponsored by Armstrong Medical Ltd.

AUTH O R S ' CO NTR I B UTI O N S
JR: Patient recruitment, data collection, data analysis, data interpretation, writing the first draft of the manuscript and critical revision of the manuscript. DF and PF: Study design, patient recruitment, data collection, data analysis and interpretation and critical revision the manuscript.

E TH I C S A PPROVA L , TR I A L R EG I S TR ATI O N A N D CO N S E NT TO PA RTI CI PATE
The protocol was approved by the Regional Ethical Committee of

CO N S E NT FO R PU B LI C ATI O N
Not applicable.

P R E S E N TAT I O N
Preliminary data from this study were in part presented as an abstract at the World Airway Management Meeting in Amsterdam, November 2019.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.