BJA Advance Access originally published online on January 23, 2006
British Journal of Anaesthesia 2006 96(3):391-395; doi:10.1093/bja/ael008
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Large volume N2O uptake alone does not explain the second gas effect of N2O on sevoflurane during constant inspired ventilation
1 Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. 2 Department of Anesthesiology, Intensive Care and Pain Therapy, Onze Lieve Vrouwziekenhuis, Aalst, Belgium. 3 Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
* Corresponding author: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, H3576 Stanford, CA 94305-5640, USA. E-mail jcnwahendrickx{at}yahoo.com
Accepted for publication December 20, 2005.
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Abstract |
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Background. The second gas effect (SGE) is considered to be significant only during periods of large volume N2O uptake (VN2O); however, the SGE of small VN2O has not been studied. We hypothesized that the SGE of N2O on sevoflurane would become less pronounced when sevoflurane administration is started 60 min after the start of N2O administration when VN2O has decreased to
125 ml min–1, and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O2. Methods. Seventy-two physical status ASA I–II patients were randomly assigned to one of six groups (n=12 each). In the first four groups, sevoflurane (1.8% vaporizer setting) administration was started 0, 2, 5 and 60 min after starting 2 litre min–1 O2 and 4 litre min–1 N2O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min–1 O2. The ratios of the alveolar fraction of sevoflurane (FA) over the inspired fraction (FI), or FA/FI, were compared between the groups.
Results. Sevoflurane FA/FI was larger in the N2O groups than in the O2 groups, and it was identical in all four N2O groups.
Conclusions. We confirmed the existence of a SGE of N2O. Surprisingly, when using an FA of 65% N2O, the magnitude of the SGE was the same with large or small VN2O. The classical model and the graphical representation of the SGE alone should not be used to explain the magnitude of the SGE. We speculate that changes in ventilation/perfusion inhomogeneity in the lungs during general anaesthesia result in a SGE at levels of VN2O previously considered by most to be too small to exert a SGE.
Keywords: anaesthetics gases, nitrous oxide; anaesthetics volatile, sevoflurane; pharmacokinetics, uptake
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Introduction |
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Large volume N2O uptake (VN2O) during the early stages of N2O administration influences the increase of the alveolar fraction (FA) towards the inspired fraction (FI) of N2O itself (concentration effect) and that of a concomitantly administered potent inhaled anaesthetic (second gas effect, SGE). This results in a larger FA (larger
) and a more rapid rate of increase [larger d()/dt].1 2 Both the concentration effect and the SGE are traditionally explained by the concentrating effect and augmented inspired ventilation (increased tracheal inflow).3 While limitations of the classical diagram explaining the SGE on potent inhaled anaesthetics have been highlighted (e.g. the importance of the mode of ventilation) and some refinements have been suggested,4 5 there seems to be agreement that the SGE is significant only during periods of large VN2O. The magnitude and time course of the concentration and SGE relative to the uptake pattern of N2O has not been examined. We therefore hypothesized that (i) the SGE of N2O on sevoflurane would be most pronounced when sevoflurane administration would be started at the period of largest 
(2 min after circuit and alveolar wash-in); (ii) the SGE would become very small when sevoflurane administration would be started 60 min after the start of N2O administration when has decreased to 125 ml min–1;6 and (iii) the 
of sevoflurane started 60 min after the start of N2O administration would not differ from that during administration of sevoflurane in O2 because the effect of small would not exert a significant SGE according to the classical model of the SGE. |
Methods |
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The patients enrolled in this study were recruited in the Department of Anesthesiology, Intensive Care and Pain Therapy, Onze Lieve Vrouwziekenhuis, Aalst, Belgium. After obtaining IRB approval and informed consent, 72 ASA physical status I–II adult patients presenting for gynaecologic, urologic, or plastic surgery were enrolled. Patients undergoing laparoscopic surgery or morbidly obese patients (BMI>35) were excluded. Patients were randomly assigned to one of six groups (n=12 each) depending on management of O2 and N2O fresh gas flows (FGF) and the delivered sevoflurane concentration. The patients' age, height and weight were recorded. Premedication was titrated according to the patients' needs. After preoxygenation (O2 FGF 8 litre min–1) for 3 min, anaesthesia was induced with sufentanil (0.15 µg kg–1) and propofol (3 mg kg–1) and rocuronium was administered to facilitate tracheal intubation (0.7 mg kg–1). Controlled mechanical ventilation (CMV) was started (ADU anaesthesia machine, Datex-Ohmeda, Helsinki, Finland) with a fixed inspired tidal volume (500 ml) and ventilatory frequency (10 min–1) (constant inspired CMV). In the first four groups, sevoflurane (1.8% vaporizer setting) administration was started 0, 2, 5 and 60 min after starting 2 litre min–1 O2 and 4 litre min–1 N2O (groups N2O 0 min, N2O 2 min, N2O 5 min and N2O 60 min, respectively). To ensure adequate anaesthesia in the N2O 60 min group where sevoflurane was started 60 min after tracheal intubation, anaesthesia was supplemented with a propofol infusion until sevoflurane was administered. In the last two groups, sevoflurane administration was started after the start of CMV with a 1.8 or 3.6% vaporizer setting (1.8% sevoflurane in O2 and 3.6% sevoflurane in O2 groups, respectively) in 6 litre min–1 O2. The 3.6% sevoflurane in O2 group was added because differences in anaesthetic depth in the O2 groups could influence
. In all groups, when signs of light anaesthesia developed, an additional bolus of sufentanil (5–10 µg) was administered. Light anaesthesia was defined as tachycardia [heart rate (HR)>125% of HR before anaesthesia induction or HR>110 beats min–1] or hypertension [mean arterial pressure (MAP)>125% of MAP before anaesthesia induction or MAP>100 mm Hg]. Hypotension (MAP<75% of MAP before anaesthesia induction or MAP<60 mm Hg) and bradycardia (HR<50 beats min–1) were treated with ephedrine (5 mg) or atropine (0.5 mg), respectively. All data were collected using a single ADU anaesthesia workstation with a single vaporizing (Aladin®) cassette in the same operating room with the same agent analyser. The Datex-Ohmeda Compact Block was used, a patented part of the circle system containing inspiratory and expiratory valves, FGF connection and a small disposable canister containing soda lime. Because the volume of this circle system is only 3.4 litre, the wash-in time constant of the system (circle system+functional residual capacity of 2.0 litre) is <1 min when using a FGF of 6 litre min–1. By electronically compensating for compression volume and circuit compliance and by using FGF compensation, the actual inspired tidal volume matches the set tidal volume. Inspired and expired gases were sampled between the tracheal tube and heat and moisture exchanger and analysed by a multi-gas analyser (Datex-Engstrom Compact Airway Module M-CAiOV, Datex-Engstrom, Helsinki, Finland; accuracy for sevoflurane ±0.2%) that was calibrated each morning. Gases sampled by the agent analyser were not redirected to the anaesthesia circuit. Inspired and expired gas concentrations were automatically downloaded in a spreadsheet every 10 s.
was directly calculated from the data every 10 s, and the area under the curve (AUC) (from 0 to 15 min) was calculated to compare the groups (SigmaPlot 2002 for Windows Version 8.02, SPSS Inc., Chicago, IL). This methodology is similar to that described by Taheri and Eger,7 except that they used the area above the curve (1–) and ignored the first minute because they assumed that this mainly represents lung wash-in. Patient characteristics, MAP, HR and the AUCs of in the six groups were compared using ANOVA followed by Student Newman–Keuls test. P<0.05 was considered statistically significant. Data are presented as mean (SD) and the incidence of observations unless indicated otherwise.
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Results |
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Patient characteristics (Table 1) were identical in all groups. One patient in the 2 min N2O group was deleted because the hyperdynamic response after intranasal epinephrine injection led to an entirely different
over time curve. The 1.8% sevoflurane in O2 group needed more additional sufentanil boluses. MAP and HR (Table 2) were not different except for a lower HR at 0 min in the N2O 60 min group (P<0.05).
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The sevoflurane
patterns were similar in all the groups except between 0 and 4 min in the 1.8% sevoflurane in O2 group. The sevoflurane was larger in the N2O groups than in the O2 groups, and was identical in all four N2O groups and in both O2 groups (Table 1 and Figs 1 and 2). Figure 1 shows only the mean data for clarity, and Figure 2 shows the results of only the N2O 5 min, N2O 60 min, and 3.6% sevoflurane in O2 groups, with the 95% confidence intervals (=standard error of the meanx1.96).
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Discussion |
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We found that N2O clearly exerts a SGE on sevoflurane:
of sevoflurane was larger in the N2O groups than in the O2 groups. At first sight, these observations are compatible with the classical model of the SGE. According to this model, large amounts of result in a concentrating effect and augmented inspired ventilation. These mechanisms have been didactically presented by a graphical ‘box’ approach, which also allows the calculation of the expected SGE.4 5 8 In our study, only the concentrating effect could have contributed to a SGE because CMV was used without any attempt at keeping the end-expired carbon dioxide constant (‘constant inspired ventilation’).8 Augmented inspired ventilation can only occur during spontaneous ventilation (‘constant outflow’), because during CMV no additional gases can be drawn into the lungs during inspiration, and will therefore cause a decrease in expired ventilation and consequently an increase in 
. We now could calculate the expected magnitude of the SGE in, for example, the 5 min N2O group using the classical graphical representation.3 In this group is very large at the moment sevoflurane is started and therefore would be expected to result in a large SGE. At the time the sevoflurane vaporizer is set at 1.8%, is 450 ml min–1 according to the Severinghaus formula ( at an FA of 65% is 1000/
t ml min–1, with t=anaesthesia duration).6 9 With a TV of 500 ml and a ventilatory frequency of 10, there is 45 ml uptake of N2O per breath. If FRC is 2000 ml, the FRC would be expected to be reduced by 2.25%, hence the concentrating effect is calculated to increase FAsevo by 2.25%. However, with the same FI, we found that the of sevoflurane was 10 and 12% larger than in the 1.8% sevoflurane in O2 and 3.6% sevoflurane in O2 groups 5 min after the start of sevoflurane, respectively. Note that this calculation even ignores the decrease in that occurs between 5 and 10 min after the start of N2O administration, and therefore may be a high estimate of the concentrating effect. So even after 10 min of N2O administration, the SGE is more pronounced than the classical model would suggest. This means that the graphical representation of the SGE fails to predict the magnitude of the SGE. Similarly, the use of more elaborate versions of the graphical representation of the SGE fail to accurately predict the magnitude of the SGE.4 On the contrary, Korman and Mapleson4 suggest that the SGE is more pronounced with the constant inspired ventilation scenario, quite the opposite of what is currently accepted.7
We also found that the magnitude of the SGE of N2O on the of sevoflurane was similar during small and large as indicated by the similar of sevoflurane in all the N2O groups (where sevoflurane was administered 0, 2, 5 and 60 min after the start of N2O administration). In addition, the in the 60 min N2O group was larger than that in the O2 groups, indicating that small (125 ml min–1) still has a clearly measurable SGE. The demonstration of a SGE when is small (100 ml min–1) is a new finding. It is obvious that the classical model of the SGE fails to explain these two observations. We cannot exclude that with the use of spontaneous respiration (allowing augmented inspired ventilation) and a more precise determination method of the concentration of the gases using gas chromatography a difference could be demonstrated between the early and late N2O groups. Nevertheless, we showed a difference between the late N2O group (small ) and the O2 groups, indicating that even small has a significant SGE.
If the classical model cannot explain our observations, are there alternative explanations? Nunn10 documented a SGE of N2O on O2, but according to Peyton this went unnoticed by Nunn himself ‘because of the assumption that, at the expected rates of VN2O, this would be trivial'. When re-analysing Nunn's data, Peyton found 
in spontaneously breathing patients to be larger when using 30% O2 with 70% N2O than with 70% N2.10–12 Using a physiological model of gas exchange, Peyton calculated that in the presence of ventilation/perfusion (V/Q) inhomogeneity typically present during general anaesthesia, so-called ‘steady-state levels of ’ (100 ml min–1) increase (10). This effect is opposite to absorption atelectasis, where alveolar collapse in lung units with very low V/Q results in a decrease in . The reduction in 
caused by absorption atelectasis is attenuated by nitrogen but worsened by N2O and the use of 100% O2. However, in Peyton's model, the concentrating effects of small on alveolar PO2 in moderately low V/Q compartments consistently outweighed the effect of increased shunting as a result of absorption atelectasis. We propose that this SGE mechanism as explained by Peyton could equally apply to other gases present in the alveoli, like sevoflurane. Indeed, Peyton's calculations support our findings that small VN2O still exerts an important SGE. There are no clinical data in the literature to compare our results with; nobody has studied the SGE of N2O after 60 min of N2O administration. The SGE on 
has been documented to last for at least 30 min after the start of N2O administration.13 14 Data comparing the SGE of different concentrations of N2O are limited and are difficult to interpret. Taheri and Eger7 observed a much smaller SGE of 5% N2O on desflurane than of 65%, but did not include an O2 only control group, presumably because the SGE of small was considered to be too small to exert any SGE. While peak with 5% N2O (77 ml min–1) is still of the order of magnitude that according to Peyton could change V/Q inhomogeneity, and therefore could cause a SGE, the SGE in Taheri's 5% and 65% N2O groups did differ. It is possible that different combinations of alveolar N2O concentrations and cause different changes in V/Q inhomogeneity, and that the SGE becomes minimal below a certain alveolar N2O concentration.
Could N2O increase by lowering the blood solubility of sevoflurane? Even though a plausible explanation, studies examining the effect of N2O on blood solubility of potent inhaled anaesthetics are conflicting. N2O has been reported to increase blood solubility of isoflurane by 5%.15 However, a more recent study found no effect of N2O on the blood solubility of neither isoflurane nor sevoflurane.16
In conclusion, our observations suggest that during constant inspired ventilation the classical model of the SGE alone, including the graphical representation, cannot be used to explain all aspects of the SGE nor quantify its effects. The main value of the graphical representation of the SGE is to illustrate its concept and to make it intuitively acceptable. We speculate that changes in lung ventilation/perfusion inhomogeneity caused by general anaesthesia result in a concentrating and thus a SGE of N2O on sevoflurane, and this at levels previously considered by most to be too small to exert a second gas effect.
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The results of this study have been presented at the ASA annual meeting in Las Vegas, October 2004. 
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References |
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