A critical component of the safe delivery of emergency anesthesia is the avoidance of hypoxemia during the apneic phase of a rapid sequence intubation.1,2 Preoxygenation describes the process of having the patient breathe 100% oxygen for a brief period, washing out nitrogen (denitrogenation) and creating an oxygen reservoir in the functional residual capacity of the lungs to extend the duration of apnea before desaturation.3,4 Optimal preoxygenation, whether inside or outside the operating theatre may not always be possible due to facial trauma, edentulous, or uncooperative patients where a mask leak is unavoidable, or environmentally determined factors such as the unavailability of specialized anesthetic circuits, limited personnel, or an austere prehospital working environment.5–8
Recently, investigators have studied whether supplemental oxygen supplied via nasal cannula (NC) can enhance the completeness of preoxygenation achieved with equipment commonly used for critical care patients in and out of the operating room such as anesthetic circuits, nonrebreather masks and bag valve masks (BVM).5,9,10 These studies suggested that supplemental NC oxygen increased end-tidal oxygen (ETo2) values for BVM, anesthetic circuit, and nonrebreather masks when the NC flow rate of 10 liters per minute (lpm)9 or 5 lpm5 and the mask seal was imperfect. When the BVM mask seal was optimal however, 10 lpm did not improve ETo2.9 One possible explanation for these results is that the NC, when added to the BVM, produces a leak allowing entrainment of room air that is only overcome with NC flow rates of 5 to 10 lpm.
Because NC oxygen is also advocated for apneic oxygenation during laryngoscopy and thus likely to be placed on the patient before induction,2 the combination of NC oxygen and mask oxygenation is common. Clarifying whether the presence of NC impairs preoxygenation when used with a BVM and what NC oxygen flow is needed to compensate would facilitate clinical care. In principle, a wide range of NC oxygen flow are possible as rates up to 15 lpm are reasonably tolerated.11 Identifying the optimum NC oxygen flow rate that allows optimal preoxygenation may assist in preoxygenation in uncooperative patients.
To characterize the effect of supplemental NC oxygen flow on preoxygenation using a BVM, we performed a randomized crossover study on healthy volunteers. Our primary outcome was to compare the ETo2 after 3-minute preoxygenation between a well-sealed BVM and BVM + NC of different flow rates. Our secondary outcomes were the comparison of ETo2 for different flow rates at 1- and 2-minute preoxygenation.
We performed a randomized crossover study using healthy volunteers. Participants were recruited from all persons aged over 18 years attending clinical governance days at our institution. Exclusion criteria were pregnancy, known lung disease, suspected coronary or cerebrovascular disease, previous exposure to bleomycin or amiodarone, and beards, moustaches, dentures, or facial abnormalities that might affect mask seal. The study received ethics approval from the Sydney Local Health District Ethics Review Committee (HREC/15/RPAH/587) and has been registered as a clinical trial (ACTRN12617000337370). Written informed consent was obtained from all participants. This manuscript adheres to the EQUATOR guidelines.
All participants completed the preoxygenation trials lying supine with a pillow under the head for comfort. Each preoxygenation period consisted of 3 minutes of tidal volume breathing with the mask held in place by 1 of 2 investigators, Attending Physicians in Anesthesia (C.H.B.) and Emergency Medicine (D.M.; Figure 1). During these 3 minutes, we recorded ETo2 via a single expiratory breath into an in-circuit measuring device at 1, 2, and 3 minutes. A rest period of 2 to 3 minutes between trials allowed ETo2 values to return to baseline before commencing the next trial and was confirmed by measuring the ETo2 so it was within 2% of each participant’s baseline. The sequence of the trials was randomized in a balanced 5 treatment 5 period crossover design, so that another participant completing the trials in an opposite order would balance a participant completing the trials in 1 order. This sequence minimized any potential residual effect of the order of trials. To achieve this goal, a randomized table of 20 trial sequences was generated by 1 investigator (M.R.M.) using the statistical software R (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria)12 and these sequences were then reversed for the remaining 20 trials. The order in which these trials were performed was again randomized using R software. The investigators that conducted the trials were not blinded to the trial sequences. The 5 preoxygenation trials were BVM-only, BVM and NC with no oxygen flow (NC-0), BVM and NC at 5 lpm (NC-5), BVM and NC at 10 lpm (NC-10), and BVM and NC at 15 lpm (NC-15; Figure 2).
The BVM used was a disposable self-inflating resuscitator with a 2-L reservoir bag (Mayo Healthcare, Mascot, NSW, Australia)13 and expiratory cap connected to a heat moisture exchange filter and catheter mount at a flow rate of 15 L/min (Figure 2). Single use adult straight-prong NC (Mayo Healthcare, Mascot, NSW, Australia) were used for all participants with the flow rate varied for each trial.
The ETo2 was measured with a Datex Capnomac Ultima side-stream gas analyzer (Datex-Engstrom, Helsinki, Finland). This device was serviced before commencing the first trial and had an accuracy of ±1%. The measurements were performed by having the participants exhale a controlled forced expiratory breath into the tight fitting mask over 4 seconds to achieve an alveolar plateau on the monitor.
Analysis was performed using the statistical software R (version 3.1.2, R Foundation for Statistical Computing).12 ETo2 was analyzed using type-III 2-way repeated measures analysis of variance (ANOVA), with preoxygenation trial and time of ETo2 sampling as the within-subjects variables and ETo2 as the dependent variable. Both the main effects of each variable and interaction between trial and time were tested. Sphericity was examined with Mauchly’s test, and if these were violated, Greenhouse-Geisser correction to P values was used. Our primary and secondary outcomes were whether a main effect of NC flow rate existed, and also an interaction effect between NC flow rate and time. Planned post hoc tests were pairwise comparisons of NC flow rate versus time if a significant effect was found for the interaction, or fixed effects for NC flow rate if only a main effect was found. This analysis was performed using the R package post hoc interaction analysis,14 with Bonferroni correction to P values to account for multiple comparisons (these are applied within the statistical test). Confidence intervals (CIs) for the ANOVA effect sizes were then calculated with the method described by Hollands and Jarmasz15 which takes into account the degrees of freedom and number of levels of variables to account for multiple comparisons. A 2-sided P value <.05 was considered significant, and was used for all tests.
A sample size calculation was performed using G*Power 316 (Version 126.96.36.199, University of Dusseldorf) for repeated measures ANOVA before beginning the study. The effect size we chose was initially 0.35 (converted from Cohen’s d from a mean difference of 5% and a standard deviation of 7%); however, we settled on using a more conservative medium effect size (f = 0.25)17 across 5 trials and 3 measurements and this determined 30 participants were required. We chose a 5% difference in ETo2as clinically relevant as it would equate to 30 seconds of additional safe apnea time ([5% × 2400 mL]/250 mL/min oxygen consumption) in an 80 kg male and is consistent with previous research.3,9 We aimed to recruit 40 participants to allow for dropout.
Overall 40 participants completed the trial. One ETo2 measurement was missing leaving 39 with complete data for analysis (29 males and 10 females). The mean age of participants was 41 (standard deviation = 9), with a mean body mass index of 26 (standard deviation = 3).
We found that both the nasal prong flow rate (P < .001), and time primarily affected the efficacy of preoxygenation (P < .001). In addition, we found an interaction between nasal prong flow rate and time (P < .001). Table 1 and Figure 3 present ETo2 results for all NC flow rates tested at each time period. For our primary outcome, pairwise comparisons revealed no difference in ETo2 between NC-15, NC-10, or BVM-only groups at 3 minutes (Figure 3, column 3). The ETo2 for NC-0 at 3 minutes was lower than all other flow rates, while NC-5 was greater than NC-0 (9%, 95% CI, 8%–12%; P = .001) but lower than BVM-only (−11%, 95% CI, −8% to −14%; P< .001), NC-10 (−9%, 95% CI, −8% to −12%; P < .001) and NC-15 (−12%, 95% CI, −9% to −15%; P < .001).
For the secondary outcomes (difference in ETo2 at 1 and 2 minutes), pairwise comparisons showed NC-0 and NC-5 recorded the lowest ETo2 at all times (Figure 3 and Table 2). There was no difference in ETo2 between NC-10 and NC-15 at all measurements (Table 2). There was a difference in ETo2 between NC-15 and BVM-only at 1 minute (7%; 95% CI, 5%–9%; P = .009).
In this volunteer study, we found that increasing rates of NC oxygen flow during preoxygenation leads to sequentially higher ETo2, but that even 15 lpm NC oxygen flow did not improve ETo2 compared to a tightly fitted BVM facemask at 3 minutes.
Our results are consistent with existing literature. When compared to preoxygenation with BVM-only, NC-0 and NC-5 were less effective, a finding similar to Groombridge et al.10 One possible explanation for this observation is that the concurrent presence of NC introduces a leak to the intended tight fit of a BVM facemask. This leak allows entrainment of room air, thereby diluting the fraction of inspired oxygen (Fio2). Taken together, current evidence thus suggests that concurrent NC with no flow or a flow rate of 5 lpm may impair the efficacy of preoxygenation with a BVM.
The ETo2 achieved with BVM and NC-10 is equivalent to BVM without NC-10. This finding is consistent with our previous study,9 was observed across all time points in our study, and suggests that 10 lpm may be sufficient to overcome the mask leak introduced by NC but not enough to increase Fio2 overall. In addition, while NC-15 did increase ETo2 after 1 minute of preoxygenation, the magnitude of this difference decreased at the 2- and 3-minute time points, and NC-15, NC-10, and BVM-only were statistically and clinically equivalent at the 3-minute time point.
Our findings and those of others have clinical relevance. If NC is used concurrently with BVM, either for preoxygenation or apneic diffusion oxygenation, setting the oxygen flow rate through those cannula at <10 lpm may result in slower and less complete denitrogenation. In addition, our data suggest that if an inadvertent leak were introduced, then the NC equal or greater to 10 lpm may offset the diminished Fio2 that occurs with the entrainment of room air.9 Also, if NC are to be used for apneic oxygenation, by placing the NC on the patient before the preoxygenation phase, they need not be removed during the time critical apneic period. Our data also raise the possibility that NC at 15 lpm may be able to achieve the same level of preoxygenation in 1 minute as BVM-only can at 3 minutes.
Our study has limitations. We used healthy volunteers, which may limit the generalizability of our findings. For example, the effects we report may not be reproducible in obese patients or those with respiratory failure. In such populations, our study is thus only hypothesis generating. In addition, the equipment tested was the standard used by our service and results achieved with different equipment may not be the same. In particular, the gooseneck introduces a deadspace of up to 40 mL. Our in-line ETo2 sampling method differs from the single-exhalation technique used in previous studies9,10 and may theoretically lead to higher absolute ETo2 readings due to continuous oxygen flow contaminating the sampling line. To mitigate these effects, we sought to record the ETo2 at the end of the alveolar plateau, so that a typical tidal volume breath of 500 mL should washout the deadspace of the circuit during measurement. In addition, this technique is consistent with previous anesthetic literature18–20 and allowed us to make serial measurements each minute. The ETo2 levels measured in our study is similar to previous studies9,10 suggesting this method is reliable. Finally, our study looks at the period of preoxygenation created by the participants’ spontaneous respiratory efforts before the onset of apnea. Oxygenation after apnea but before laryngoscopy by way of ventilating the patient either manually21 or mechanically22 remains an option in all patients but this remains controversial and not part of a classical rapid sequence induction.
In conclusion, we found that NC at 0 and 5 lpm prevent optimal preoxygenation with a BVM. In addition, we found no decrement in preoxygenation efficacy when NC-10 was used concurrently with BVM. Our findings indicate that oxygen flow >10 lpm should not impair the preoxygenation process. Further study is needed to better understand the clinical consequences of our findings.
The authors would like to thank the staff of the Greater Sydney Area Helicopter Emergency Medical Service as well as attendees of the clinical governance days for volunteering their time. Assistance was graciously given by Dr Karel Habig, Dr Brian Burns, and Sandra Ware of NSW Ambulance Aeromedical Service.
Name: David McQuade, MBChB.
Contribution: This author helped design the study, write the protocol, liaise with the ethics committee, recruit and perform the measurements on the participants, and contribute to the introduction and discussion and review the manuscript as a whole.
Name: Matthew R. Miller, MBChB.
Contribution: This author helped design the study, write the protocol, perform the statistical analysis, write the methods and results section, and contribute to the introduction and discussion and review the manuscript as a whole.
Name: Clare Hayes-Bradley, MBBS.
Contribution: This author helped design the study, liaise with the ethics committee, recruit and perform the measurements on the participants, and
contribute to the introduction and discussion and review the manuscript as a whole.
This manuscript was handled by: Avery Tung, MD, FCCM.
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