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Large volume N2O uptake alone does not explain the second gas effect of N2O on sevoflurane during constant inspired ventilation†
British Journal of Anaesthesia 96 (3): 391–5 (2006)
doi:10.1093/bja/ael008
Advance Access publication January 23, 2006
Large volume N2O uptake alone does not explain the second gas effect of N2O on sevoflurane during constant inspired ventilationy J. F. A. Hendrickx1*, R. Carette2, H. J. M. Lemmens1 and A. M. De Wolf3 1
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. 2Department 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 [email protected]
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 min1 O2 and 4 litre min1 N2O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min1 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. Br J Anaesth 2006; 96: 391–5 Keywords: anaesthetics gases, nitrous oxide; anaesthetics volatile, sevoflurane; pharmacokinetics, uptake Accepted for publication: December 20, 2005
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 FA/FI) and a more rapid rate of increase [larger d(FA/FI)/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 y
The results of this study have been presented at the ASA annual meeting in Las Vegas, October 2004.
The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: [email protected]
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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 min1, and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O2.
Hendrickx et al.
sevoflurane administration would be started at the period of largest VN2O (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 VN2O has decreased to 125 ml min1;6 and (iii) the FA/FI 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 VN2O would not exert a significant SGE according to the classical model of the SGE.
Methods
Results 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 FA/FI 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). The sevoflurane FA/FI patterns were similar in all the groups except between 0 and 4 min in the 1.8% sevoflurane in O2 group. The sevoflurane FA/FI 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
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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 min1) for 3 min, anaesthesia was induced with sufentanil (0.15 mg kg1) and propofol (3 mg kg1) and rocuronium was administered to facilitate tracheal intubation (0.7 mg kg1). 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 min1) (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 min1 O2 and 4 litre min1 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 min1 O2. The 3.6% sevoflurane in O2 group was added because differences in anaesthetic depth in the O2 groups could influence FA/FI. In all groups, when signs of light anaesthesia developed, an additional bolus of sufentanil (5–10 mg) was administered. Light anaesthesia was defined as tachycardia [heart rate (HR)>125% of HR before anaesthesia induction or HR>110 beats min1] 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 min1) 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 min1. 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. FA/FI 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 (1FA/FI) and ignored the first minute because they assumed that this mainly represents lung wash-in. Patient characteristics, MAP, HR and the AUCs of FA/FI 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.
The second gas effect of N2O on sevoflurane
Table 1 Patient characteristics and AUC of sevoflurane FA/FI [data are presented as mean (SD) or mean (range) except for n and sex distribution]. *P<0.05 compared to each N2O group. yOne patient was deleted from analysis because the hyperdynamic response after intranasal epinephrine injection led to an entirely different FA/FI over time curve Group
n
Age (yr)
Ht (cm)
Wt (kg)
Sex (F/M)
AUC FA/FI
N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
12 11y 12 12 12 12
39 45 46 44 44 41
168 166 165 165 167 165
67 65 72 68 70 69
10/2 10/1 8/4 7/5 10/2 10/2
11.47 11.61 11.69 11.31 10.66 10.53
(23–61) (15–73) (26–69) (20–68) (23–60) (25–53)
(9) (7) (10) (11) (7) (9)
(14) (12) (10) (12) (13) (15)
(0.60) (0.73) (0.35) (0.54) (0.71)* (0.33)*
Table 2 MAP (mm Hg) and HR (beats min1). Data are presented as mean (SD). *P<0.05 compared with all other groups at 0 min. yOne patient was deleted from analysis because the hyperdynamic response after intranasal epinephrine injection led to an entirely different FA/FI over time curve n
Group
12 11y 12 12 12 12
HR
0 min
5 min
10 min
15 min
20 min
0 min
5 min
10 min
15 min
20 min
90 92 100 95 88 95
77 80 85 79 83 84
72 72 77 76 82 86
77 76 77 76 81 83
79 80 78 75 85 83
92 81 95 65 86 96
70 74 79 63 75 77
63 67 69 62 69 73
64 66 65 61 65 66
66 66 62 59 66 67
(14) (26) (19) (24) (20) (21)
(16) (13) (14) (11) (22) (17)
(13) (9) (9) (9) (19) (29)
(15) (8) (11) (10) (17) (21)
(13) (10) (11) (10) (30) (20)
(16) (12) (20) (7)* (23) (16)
(12) (13) (18) (9) (19) (12)
(11) (11) (17) (10) (17) (15)
(14) (11) (15) (10) (17) (9)
(12) (9) (17) (10) (18) (13)
0.90
0.85
Sevoflurane FA/FI
0.80
0.75
0.70
0.65 N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
0.60
0.55
0.50 1
2
3
4
5
6
7 8 Time (min)
9
10
11
12
13
14
15
Fig 1 Sevoflurane FA/FI in the six groups. Mean values are presented at 1 min intervals.
60 min, and 3.6% sevoflurane in O2 groups, with the 95% confidence intervals (=standard error of the mean·1.96).
Discussion We found that N2O clearly exerts a SGE on sevoflurane: FA/FI 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 VN2O 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
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N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
MAP
Hendrickx et al.
0.90 N2O 5 min N2O 60 min 0.85
3.6% sevoflurane in O2
Sevoflurane FA/FI
0.80
0.75
0.70
0.65
0.60
0.55
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time (min) Fig 2 Sevoflurane FA/FI in the N2O 5 min, N2O 60 min, and 3.6% sevoflurane in O2 groups. Mean values and 95% confidence interval are presented at 1 min intervals.
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 VN2O will therefore cause a decrease in expired ventilation and consequently an increase in FaCO2 . 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 VN2O 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%, VN2O is 450 ml min1 according to the Severinghaus formula (VN2O at an FA of 65% is 1000/Ht ml min1, 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 FA/FI 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 VN2O 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 FA/FI of sevoflurane was similar during small and large VN2O as indicated by the similar FA/FI 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 FA/FI in the 60 min N2O group was larger than that in the O2 groups, indicating that small VN2O (125 ml min1) still has a clearly measurable SGE. The demonstration of a SGE when VN2O is small (100 ml min1) 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 VN2O) and the O2 groups, indicating that even small VN2O 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 reanalysing Nunn’s data, Peyton found PaO2 in spontaneously
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0.50
The second gas effect of N2O on sevoflurane
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 VN2O levels previously considered by most to be too small to exert a second gas effect.
References
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1 Eger EI II. Anesthetic Uptake and Action. Baltimore/London: Williams & Wilkins, 1974 2 Eger EI II. A mathematical model of uptake and distribution. In: Papper EM, Kitz RJ, eds. Uptake and Distribution of Anesthetic Agents. New York: McGraw-Hill, 1963 3 Stoelting RK, Eger EI II. An additional explanation for the second gas effect: a concentrating effect. Anesthesiology 1969; 30: 273–7 4 Korman B, Mapleson WW. Concentration and second gas effects: can the accepted explanation be improved? Br J Anaesth 1997; 78: 618–25 5 Eger EI II. Uptake and distribution. In: Miller RD, ed. Anesthesia. 5th edn. New York: Churchill Livingstone, 2000; 74–95 6 Severinghaus JW. The rate of uptake of nitrous oxide in man. J Clin Invest 1954; 33: 1183–9 7 Taheri S, Eger EI II. A demonstration of the concentration and second gas effects in humans anesthetized with nitrous oxide and desflurane. Anesth Analg 1999; 89: 774–80 8 Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthesia mixtures: the second gas effect. Anesthesiology 1964; 25: 364–71 9 Bengtson JP, Bengtsson A, Stenqvist O. Nitrous oxide uptake during spontaneous and controlled ventilation. Anaesthesia 1994; 49: 25–8 10 Nunn JF. Factors influencing the arterial oxygen tension during anaesthesia with artificial ventilation. Br J Anaesth 1964; 36: 327–41 11 Peyton PJ, Robinson GJ, Thompson B. Effect of ventilation– perfusion inhomogeneity and N2O on oxygenation: physiological modeling of gas exchange. J Appl Physiol 2001; 91: 17–25 12 Nunn JF, Bergman NA, Coleman AJ. Factors influencing the arterial oxygen tension during anaesthesia with artificial ventilation. Br J Anaesth 1965; 37: 898–914 13 Bojrab L, Stoelting RK. Extent and duration of the nitrous oxide second-gas effect on oxygen. Anesthesiology 1974; 40: 201–3 14 Nishikawa K, Kunimoto F, Isa Y et al. Second gas effect of N2O on oxygen uptake. Can J Anaesth 2000; 47: 506–10 15 Xie GM, Lauber R, Zbinden AM. Nitrous oxide decreases solubility of isoflurane and halothane in blood. Anesth Analg 1993; 77: 761–5 16 Shaw AD, Chamberlain SK, Spased-Byrne SM, Lockwood GG. Nitrous oxide and carbon dioxide have no effect on the blood-gas solubilities of sevoflurane and isoflurane. Anesth Analg 1998; 87: 1412–15
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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 VN2O’ (100 ml min1) increase PaO2 (10). This effect is opposite to absorption atelectasis, where alveolar collapse in lung units with very low V/Q results in a decrease in PaO2 . The reduction in PaO2 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 VN2O 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 PaO2 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 VN2O was considered to be too small to exert any SGE. While peak VN2O with 5% N2O (77 ml min1) 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 VN2O cause different changes in V/Q inhomogeneity, and that the SGE becomes minimal below a certain alveolar N2O concentration. Could N2O increase FA/FI 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
doi:10.1093/bja/ael008
Advance Access publication January 23, 2006
Large volume N2O uptake alone does not explain the second gas effect of N2O on sevoflurane during constant inspired ventilationy J. F. A. Hendrickx1*, R. Carette2, H. J. M. Lemmens1 and A. M. De Wolf3 1
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. 2Department 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 [email protected]
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 min1 O2 and 4 litre min1 N2O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min1 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. Br J Anaesth 2006; 96: 391–5 Keywords: anaesthetics gases, nitrous oxide; anaesthetics volatile, sevoflurane; pharmacokinetics, uptake Accepted for publication: December 20, 2005
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 FA/FI) and a more rapid rate of increase [larger d(FA/FI)/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 y
The results of this study have been presented at the ASA annual meeting in Las Vegas, October 2004.
The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: [email protected]
Downloaded from http://bja.oxfordjournals.org/ by guest on March 25, 2015
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 min1, and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O2.
Hendrickx et al.
sevoflurane administration would be started at the period of largest VN2O (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 VN2O has decreased to 125 ml min1;6 and (iii) the FA/FI 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 VN2O would not exert a significant SGE according to the classical model of the SGE.
Methods
Results 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 FA/FI 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). The sevoflurane FA/FI patterns were similar in all the groups except between 0 and 4 min in the 1.8% sevoflurane in O2 group. The sevoflurane FA/FI 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
392
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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 min1) for 3 min, anaesthesia was induced with sufentanil (0.15 mg kg1) and propofol (3 mg kg1) and rocuronium was administered to facilitate tracheal intubation (0.7 mg kg1). 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 min1) (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 min1 O2 and 4 litre min1 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 min1 O2. The 3.6% sevoflurane in O2 group was added because differences in anaesthetic depth in the O2 groups could influence FA/FI. In all groups, when signs of light anaesthesia developed, an additional bolus of sufentanil (5–10 mg) was administered. Light anaesthesia was defined as tachycardia [heart rate (HR)>125% of HR before anaesthesia induction or HR>110 beats min1] 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 min1) 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 min1. 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. FA/FI 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 (1FA/FI) and ignored the first minute because they assumed that this mainly represents lung wash-in. Patient characteristics, MAP, HR and the AUCs of FA/FI 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.
The second gas effect of N2O on sevoflurane
Table 1 Patient characteristics and AUC of sevoflurane FA/FI [data are presented as mean (SD) or mean (range) except for n and sex distribution]. *P<0.05 compared to each N2O group. yOne patient was deleted from analysis because the hyperdynamic response after intranasal epinephrine injection led to an entirely different FA/FI over time curve Group
n
Age (yr)
Ht (cm)
Wt (kg)
Sex (F/M)
AUC FA/FI
N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
12 11y 12 12 12 12
39 45 46 44 44 41
168 166 165 165 167 165
67 65 72 68 70 69
10/2 10/1 8/4 7/5 10/2 10/2
11.47 11.61 11.69 11.31 10.66 10.53
(23–61) (15–73) (26–69) (20–68) (23–60) (25–53)
(9) (7) (10) (11) (7) (9)
(14) (12) (10) (12) (13) (15)
(0.60) (0.73) (0.35) (0.54) (0.71)* (0.33)*
Table 2 MAP (mm Hg) and HR (beats min1). Data are presented as mean (SD). *P<0.05 compared with all other groups at 0 min. yOne patient was deleted from analysis because the hyperdynamic response after intranasal epinephrine injection led to an entirely different FA/FI over time curve n
Group
12 11y 12 12 12 12
HR
0 min
5 min
10 min
15 min
20 min
0 min
5 min
10 min
15 min
20 min
90 92 100 95 88 95
77 80 85 79 83 84
72 72 77 76 82 86
77 76 77 76 81 83
79 80 78 75 85 83
92 81 95 65 86 96
70 74 79 63 75 77
63 67 69 62 69 73
64 66 65 61 65 66
66 66 62 59 66 67
(14) (26) (19) (24) (20) (21)
(16) (13) (14) (11) (22) (17)
(13) (9) (9) (9) (19) (29)
(15) (8) (11) (10) (17) (21)
(13) (10) (11) (10) (30) (20)
(16) (12) (20) (7)* (23) (16)
(12) (13) (18) (9) (19) (12)
(11) (11) (17) (10) (17) (15)
(14) (11) (15) (10) (17) (9)
(12) (9) (17) (10) (18) (13)
0.90
0.85
Sevoflurane FA/FI
0.80
0.75
0.70
0.65 N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
0.60
0.55
0.50 1
2
3
4
5
6
7 8 Time (min)
9
10
11
12
13
14
15
Fig 1 Sevoflurane FA/FI in the six groups. Mean values are presented at 1 min intervals.
60 min, and 3.6% sevoflurane in O2 groups, with the 95% confidence intervals (=standard error of the mean·1.96).
Discussion We found that N2O clearly exerts a SGE on sevoflurane: FA/FI 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 VN2O 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
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N2O 0 min N2O 2 min N2O 5 min N2O 60 min 1.8% sevoflurane in O2 3.6% sevoflurane in O2
MAP
Hendrickx et al.
0.90 N2O 5 min N2O 60 min 0.85
3.6% sevoflurane in O2
Sevoflurane FA/FI
0.80
0.75
0.70
0.65
0.60
0.55
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time (min) Fig 2 Sevoflurane FA/FI in the N2O 5 min, N2O 60 min, and 3.6% sevoflurane in O2 groups. Mean values and 95% confidence interval are presented at 1 min intervals.
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 VN2O will therefore cause a decrease in expired ventilation and consequently an increase in FaCO2 . 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 VN2O 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%, VN2O is 450 ml min1 according to the Severinghaus formula (VN2O at an FA of 65% is 1000/Ht ml min1, 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 FA/FI 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 VN2O 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 FA/FI of sevoflurane was similar during small and large VN2O as indicated by the similar FA/FI 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 FA/FI in the 60 min N2O group was larger than that in the O2 groups, indicating that small VN2O (125 ml min1) still has a clearly measurable SGE. The demonstration of a SGE when VN2O is small (100 ml min1) 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 VN2O) and the O2 groups, indicating that even small VN2O 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 reanalysing Nunn’s data, Peyton found PaO2 in spontaneously
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0.50
The second gas effect of N2O on sevoflurane
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 VN2O levels previously considered by most to be too small to exert a second gas effect.
References
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1 Eger EI II. Anesthetic Uptake and Action. Baltimore/London: Williams & Wilkins, 1974 2 Eger EI II. A mathematical model of uptake and distribution. In: Papper EM, Kitz RJ, eds. Uptake and Distribution of Anesthetic Agents. New York: McGraw-Hill, 1963 3 Stoelting RK, Eger EI II. An additional explanation for the second gas effect: a concentrating effect. Anesthesiology 1969; 30: 273–7 4 Korman B, Mapleson WW. Concentration and second gas effects: can the accepted explanation be improved? Br J Anaesth 1997; 78: 618–25 5 Eger EI II. Uptake and distribution. In: Miller RD, ed. Anesthesia. 5th edn. New York: Churchill Livingstone, 2000; 74–95 6 Severinghaus JW. The rate of uptake of nitrous oxide in man. J Clin Invest 1954; 33: 1183–9 7 Taheri S, Eger EI II. A demonstration of the concentration and second gas effects in humans anesthetized with nitrous oxide and desflurane. Anesth Analg 1999; 89: 774–80 8 Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthesia mixtures: the second gas effect. Anesthesiology 1964; 25: 364–71 9 Bengtson JP, Bengtsson A, Stenqvist O. Nitrous oxide uptake during spontaneous and controlled ventilation. Anaesthesia 1994; 49: 25–8 10 Nunn JF. Factors influencing the arterial oxygen tension during anaesthesia with artificial ventilation. Br J Anaesth 1964; 36: 327–41 11 Peyton PJ, Robinson GJ, Thompson B. Effect of ventilation– perfusion inhomogeneity and N2O on oxygenation: physiological modeling of gas exchange. J Appl Physiol 2001; 91: 17–25 12 Nunn JF, Bergman NA, Coleman AJ. Factors influencing the arterial oxygen tension during anaesthesia with artificial ventilation. Br J Anaesth 1965; 37: 898–914 13 Bojrab L, Stoelting RK. Extent and duration of the nitrous oxide second-gas effect on oxygen. Anesthesiology 1974; 40: 201–3 14 Nishikawa K, Kunimoto F, Isa Y et al. Second gas effect of N2O on oxygen uptake. Can J Anaesth 2000; 47: 506–10 15 Xie GM, Lauber R, Zbinden AM. Nitrous oxide decreases solubility of isoflurane and halothane in blood. Anesth Analg 1993; 77: 761–5 16 Shaw AD, Chamberlain SK, Spased-Byrne SM, Lockwood GG. Nitrous oxide and carbon dioxide have no effect on the blood-gas solubilities of sevoflurane and isoflurane. Anesth Analg 1998; 87: 1412–15
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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 VN2O’ (100 ml min1) increase PaO2 (10). This effect is opposite to absorption atelectasis, where alveolar collapse in lung units with very low V/Q results in a decrease in PaO2 . The reduction in PaO2 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 VN2O 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 PaO2 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 VN2O was considered to be too small to exert any SGE. While peak VN2O with 5% N2O (77 ml min1) 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 VN2O cause different changes in V/Q inhomogeneity, and that the SGE becomes minimal below a certain alveolar N2O concentration. Could N2O increase FA/FI 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