Use of a Nasal Cannula as a Preoxygenation Adjunct: A Randomized Crossover Study

Background Preoxygenation prior to induction of general anesthesia is intended to increase the oxygen reserve in the lungs. This technique delays the onset of hypoxemia during the placement of the tracheal tube. Objective To observe the benefits of oxygen through nasal cannula when used as an adjunct during preoxygenation. Methods We enrolled 30 healthy volunteers and conducted a sequence of six preoxygenation tests. These included 3-minute tidal volume breathing and 8 vital capacity breaths, with and without oxygen flowing through the nasal cannula as an adjunct. Subjects were kept at a supine position with a face mask on their faces. Their baseline vitals were measured and end-tidal O2 (ETO2) was recorded at the end of each test. The comfort of each technique was also assessed. Results When comparing the efficacy of the two preoxygenation methods, we found that the addition of oxygen through the nasal cannula improved the efficacy of preoxygenation with both the 3-minute tidal volume breathing method and the 8 vital capacity method (p < 0.001). The three-minute tidal volume breathing technique had higher end-tidal oxygen when compared to the eight vital capacity breaths. Conclusions The administration of oxygen through a nasal cannula during preoxygenation improves the efficacy of preoxygenation in healthy volunteers. Tidal volume breathing for three minutes achieves a higher end-tidal oxygen concentration compared to eight vital capacity breaths over one minute.


Introduction
Preoxygenation before induction and intubation is an accepted technique to delay the onset of hypoxemia during airway management.It helps to prolong the apnea time during tracheal intubation in patients undergoing general anesthesia with neuromuscular paralysis.Te efectiveness of preoxygenation is primarily based on two measurable factors, namely, efcacy and efciency.Te efcacy of preoxygenation is measured based on the increase in the fraction of alveolar O 2 (FAO 2 ), the reduction in alveolar nitrogen (FAN 2 ), and the increase in alveolar tension (PaO 2 ), while efciency is measured by the decrease in saturation (SaO 2 ) during apnea [1].Efective preoxygenation can be confrmed by an increase in end-tidal O 2 (ETO 2 ) more than 90% or an end-tidal nitrogen concentration of 5% [2].Techniques such as head-up position, use of positive airway pressure, and alternate breathing circuits have been tried to improve the efectiveness of preoxygenation [3][4][5][6].Apneic oxygen via nasal cannula (NC) has been advised as a part of difcult airway management to prolong apnea time and improve preoxygenation efciency [7].High fow oxygen through a NC has also been used for preoxygenation in the ICU and emergency departments.Te use of NC as an adjunct to mask preoxygenation can introduce leaks during preoxygenation with a facemask, possibly reducing the effcacy of preoxygenation [8,9].We hypothesized that the addition of oxygen via nasal cannula as an adjunct to the standard preoxygenation technique would improve its effcacy.Te primary objective of our study was to measure the ETO 2 at the end of preoxygenation using various fows through the nasal cannula.

Methodology
Tis prospective randomized crossover trail was conducted in 30 healthy volunteers, aged 20-50 years, in a tertiary care center.Pregnant women and people with facial trauma or dysmorphism, BMI > 30 kg/m 2 , and anticipated difcult airways were excluded from the trail.Male volunteers were asked to have a clean-shaven beard for the study.Written informed consent was obtained from the volunteers who were willing to participate in the trail.Te study was approved by the institutional ethics committee and registered with CTRI (no.CTRI/2020/04/024873).
Tus, each participant underwent six sequences of preoxygenation.
(1) 3 min TVB with NC 0 L/min (2) 3 min TVB with NC 5 L/min (3) 3 min TVB with NC 10 L/min (4) 8 VCB with NC 0 L/min (5) 8 VCB with NC 5 L/min (6) 8 VCB with NC 10 L/min All participants completed all 6 methods of preoxygenation in a random order, based on a Latin square method.Te sequence of preoxygenation was randomized by the author SP using an online balanced Latin square generator (https://damienmasson.com/tools/latin_square) to generate a 6 × 6 table.Te order in which these sequences would be performed was then randomized for 30 participants using an online randomizer.
Subjects were placed in a supine position with a pillow under the occiput.Baseline heart rate, blood pressure, and ETO 2 were documented.A closed anesthesia circuit (GE Carestation 650 with a 1.6-meter Limbo Circuit and 2 L bag) was fushed with 100% oxygen.Te nasal cannula was attached to the auxiliary oxygen port of the anesthetic machine and placed over the nostrils of the participants.Preoxygenation (10 L/min) with anesthesia circuit and NC oxygen was started according to the sequence selected.Participants were asked to breathe normally for 3 minutes of tidal volume breathing and take slow deep breaths every 7 to 8 seconds for the 8 vital capacity breaths.Te face mask was held by the investigators and adjusted to minimize leakage.Tis was confrmed by an adequate continuous waveform capnogram.Te distortion of the waveform capnogram indicated an inadequate seal, and the mask seal would be adjusted to optimize the waveform as much as possible.Flows through NC were stopped before the last three breaths for 3 min TVB and the last breath for VCB to prevent the dilution of ETO 2 .Te ETO 2 value at the end of the preoxygenation period was documented (E-sCAiO gas analyzer with a D-Fend Pro water trap, GE Healthcare).Each method of preoxygenation was followed by a washout period, with subject breathing room air, until the baseline ETO 2 value (±2%) was reached, as shown in supplementary material 1.
Te comfort of the participant was assessed after each preoxygenation sequence using the Likert scale [10].
(1) Very uncomfortable (2) Uncomfortable (3) Bearable (4) Comfortable (5) Very comfortable Based on the reference study [11], a clinically signifcant diference of 5% and pooled standard deviation was taken as 7% to give an efect size of 0.35.A change in ETO 2 of 5% was considered clinically signifcant cause it could increase the safe apnea time in an 80 kg male by 30 seconds.With a power of 0.8 and signifcance of 0.05, the calculated sample size for our study was 26.Tirty participants were enrolled to balance participants for fve sets of six sequences.
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) for Windows version 22.0 released in 2013.Armonk, NY: IBM Corp. Signifcance tests were performed with a univariate type III repeated-measures ANOVA with ETO 2 as the dependent variable and preoxygenation trials as the within subjects variable.A Bonferroni correction to the p values was used for the post hoc test.Te paired Student's t-test was used to compare the two preoxygenation techniques.

Results
Tirty healthy volunteers were enrolled in this study.Te CONSORT diagram describes the enrollment process (Figure 1).Te mean age was 27 years and the mean BMI was 23.7 ± 2.5 kg/m 2 (Table 1).When preoxygenated with 3 minute of TV breathing, the mean ETO 2 increased from 81.90 ± 2.41% to 91.07 ± 1.7% as the fow increased from 0 L/min to 10 L/min, while preoxygenation with 8 vital capacity breaths over one minute technique, the mean ETO 2 increased from 77.27 ± 2.26% to 87.87 ± 2.29% as the fow increased to 10 L/min (Tables 2 and 3).When comparing the efcacy of the two preoxygenation methods, we found that 3-minute TVB was better than the 8 VC method (Table 4, p < 0.001).Even with the use of a nasal cannula as an adjunct and 10 L/min of O 2 fow, the mean ETO 2 was higher with 3 min TV breathing (91.07%vs. 87.87%),which was clinically and statistically signifcant (p < 0.001).Te comfort level of the participants with various fows of O 2 through the nasal cannula was also documented.Flows of 10 L/min were uncomfortable or just bearable by most of the participants.Most subjects were comfortable with a 5 L/min fow through the nasal cannula (Figure 2).

Discussion
In our study, we compared the feasibility, efectiveness, and comfort of using nasal cannula as an adjunct to standard preoxygenation techniques in volunteers.We found that using nasal cannula as an adjunct improved the end-tidal oxygen concentration, irrespective of the preoxygenation technique used (3-minute tidal volume respiration and 8 vital capacity breaths over 1 minute).

Anesthesiology Research and Practice
Efective preoxygenation improves the safety of patients during airway manipulation by increasing the safe apneic time [12].Tis is especially evident in certain subset of patients such as pediatric, pregnant women, obesity, and full stomach and patients with a difcult airway.Te prevalence of unanticipated difcult airway is 0.9-1.9%[13].Te pediatric population is particularly susceptible to hypoxia during general anesthesia and sedation due to greater oxygen consumption and diminished functional residual capacity.It is reported that over 50% of critical events during the perioperative period in children are respiratory related [14].Various techniques have been studied to improve the efectiveness of preoxygenation; breathing at diferent respiratory capacities, breathing circuits, and diferent oxygen fow rates [1,[8][9][10][11][12][13][14][15].Te use of nasal cannula as an adjunct to preoxygenation has previously been studied on volunteers.Bradley et al. concluded that the addition of supplemental oxygen through a nasal cannula did not improve ETO 2 compared to preoxygenation with a bad mask valve device without leak [9].McQuade et al. [11] in their study found addition of nasal cannula with oxygen fow rate at 5 L/min delays optimal preoxygenation.Both studies attributed these fndings to a considerable leak introduced by the nasal cannula, which breaches the seal provided by the bag mask valve device.In our study, we ensured leak was minimal by adjusting the mask seal to minimize distortion in the continuous capnography waveforms.We were able to achieve similar ETO 2 values (82%) in our study to those achieved by the former authors (79% and 84%) with a tightftting bag mask valve device and no leak, possibly demonstrating that a good mask seal can be achieved even with a nasal cannula in place.A study by Russell et al. [8] that also employed a good mask seal concluded that the use of supplemental oxygen at 5 L/min through the nasal cannula improved the mean ETO 2 at the end of the 3-minute TV breathing method of preoxygenation.
We also evaluated the efcacy of nasal cannula adjunct during the 8 vital capacity (8VC) breathing technique of preoxygenation.We found that 3-minute TV breathing was better than 8 VC breaths over one minute as a preoxygenation technique, and the use of nasal cannula as an adjunct improved the ETO2 in both 3-minute TV and 8VC technique.Russell et al. found the addition of nasal cannula less efective while using the 8VC technique.Other studies also concluded that maximum ETO 2 was not reached at the end of one minute while taking 8 VC breaths [8].
A recent systematic review and network meta-analysis compared various techniques to identify the most efective technique [16].In their fndings, Carvalho et al. suggest use of high fow nasal oxygen (HFNO) along with head up position as the most efective preoxygenation technique prior to induction of general anesthesia to prolong safe apnea time.Tey also rank the use of pressure support with head up position as the number one technique which can  lead to the fastest rise in ETO 2 (data for rise in ETO 2 were unavailable for HFNO studies).Te better efcacy of preoxygenation while using a high fow nasal oxygen could be due to the increased total oxygen fow rates, which provide positive airway pressure that can cause alveolar recruitment and reduce ventilation perfusion mismatches.Other possible explanations could be increased CO 2 washout from the dead space by the high fow of oxygen, improving the FiO 2 delivered.It also presents a continuous source of oxygen during the apnea period (apneic oxygenation), improving safe apnea time.
Te use of nasal cannula as adjunct to the standard preoxygenation technique is an ingenious way to achieve the benefts of using a high fow nasal oxygen device in low resource settings.Te addition of oxygen via nasal cannula as an adjunct to standard mask preoxygenation increases the overall oxygen fow (10-20 l/min), while ensuring proper mask seal can create positive airway pressure.Tus, this combination can help achieve efective preoxygenation in scenarios where access to HFNO devices is limited.Te requirements to perform the preoxygenation techniques as in our study would be the standard anesthetic circuit, a nasal cannula, and an auxiliary oxygen source.
Te use of nasal cannula as an adjunct to preoxygenation has been associated with discomfort although tolerable.In our study, we found that discomfort with the nasal cannula increased with increasing fow rates.A fow of 5 L/min was found to provide a balance between tolerability and efective preoxygenation (Figure 2).Te fndings of our study lead us to advocate the use of nasal cannula as an adjunct during preoxygenation.
Tere has been an advent of newer ultra-short-acting anesthetic agents such as remizolam, which have proved to be particularly useful in several perioperative settings (e.g., cardiac pts undergoing cardiac or noncardiac surgery and the pediatric population) [17,18].Use of such agents could help tolerate very high fows and improve preoxygenation comfort, thereby safely achieving benefts of preoxygenation with minimal patient discomfort.
Preoxygenation with 5 L/min oxygen through the nasal cannula may be sufcient to overcome any possible leaks imposed by the presence of the nasal cannula when a reasonably tight ft of the mask can be ensured.Te nasal cannula can be left in place throughout airway management, providing an extra margin of safety.Other clinical scenarios where the nasal cannula could be useful are for emergency caesarean section.With limited induction and intubation time, the nasal cannula with 10 L/min oxygen fow and 8 VC breath may be able to provide adequate preoxygenation.Here, the discomfort of the higher fow is of comparatively shorter duration and hence patients might be more compliant.
Our trial is not free of limitations.Te trial was carried out on healthy volunteers, which limits its validity in a clinical setting.Te efectiveness of preoxygenation was not determined (only the efcacy was evaluated using ETO 2 ) and the use of ETO 2 as the end point of successful preoxygenation is inferior to the use of PaO 2 while assessing the efcacy of preoxygenation.ETO 2 was used as it is a noninvasive and commonly used technique of documenting end point of preoxygenation.Further studies in the clinical scenario and in special population (pregnancy, difcult airway) would strengthen the evidence for the use of nasal cannula as an adjunct for preoxygenation using standard face mask.
In conclusion, the administration of oxygen through a nasal cannula during preoxygenation improves the efcacy of preoxygenation in healthy volunteers.Tidal volume breathing for three minutes achieves a higher end-tidal oxygen concentration compared to eight vital capacity breaths for one minute.

Table 1 :
Characteristics of the participants.
#p value derived by repeated measures of ANOVA followed by Bonferroni's post hoc analysis.Source: authors.
#p value derived by repeated measures of ANOVA followed by Bonferroni's post hoc analysis.Source: authors.