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Anesth Analg 1999;89:774
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

A Demonstration of the Concentration and Second Gas Effects in Humans Anesthetized with Nitrous Oxide and Desflurane

Sharam Taheri, DDS, and Edmond I Eger, II, MD

Department of Anesthesia, University of California, San Francisco, California

Address correspondence to Edmond I Eger II, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to edmond_eger{at}quickmail.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In the present study, we explored both the existence of and the basis for the concentration and second gas effects. Groups of six normocapnic patients were given one of three gas mixtures via a nonrebreathing system: 65% nitrous oxide (N2O) plus 4% desflurane; 5% N2O plus 4% desflurane; or 65% N2O plus 0.5% desflurane plus 2% xenon (Xe). End-tidal carbon dioxide (CO2) was held constant by adjustments in ventilation. Confirming the existence of the concentration effect, the end-tidal (FA) concentration of N2O increased toward the inspired (FI) concentration more rapidly (i.e., FA/FI increased more rapidly) when the inspired concentration was 65% than when it was 5%. The FA/FI for desflurane also increased more rapidly when desflurane was given with 65% rather than 5% N2O, confirming the existence of the second gas effect. The small uptake of the second gas (desflurane) did not influence its own FA/FI or that of N2O; that is, the administration of 4%, rather than 0.5%, desflurane did not increase the rate of rise of FA/FI of either N2O or desflurane. One of the bases of the concentration and second gas effects, a concentrating of residual gases, was confirmed: administration of Xe with 65% N2O produced an FA/FI for Xe that exceeded 1.0. Patient sex did not seem to influence the rate of rise of FA/FI of either N2O or desflurane. Finally, we unexpectedly found that, despite an equal solubility in blood, the rise in FA/FI for N2O exceeded that for desflurane, perhaps because of differences in tissue solubilities and intertissue diffusion.

Implications: As predicted by the concentration and second gas effects, increasing the inspired concentration of nitrous oxide accelerated its rate of rise and the rate of rise of concurrently administered desflurane in humans.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Results from various computer and theoretical models (1–4) support the four-decade-old demonstration in dogs of the concentration (5) and second gas (6) effects. However, few studies have used humans to confirm the findings in dogs, few have used modern inhaled anesthetics as the second gas, and two reports have questioned the existence of the second gas effect (7).1 Two studies have shown that the concentrations of carbon dioxide (CO2) in cats (8) and oxygen (O2) in humans (9) may be increased by the administration of nitrous oxide (N2O). Results of two other studies in humans seem to confirm the existence of the second gas effect for halothane (10,11), and a third study in children confirmed the existence of the concentration effect (12).

Perhaps the limited data in humans for modern anesthetics and controversies regarding interpretation are reasons enough to reexamine the concentration and second gas effects. We were intrigued by another opportunity: the concentration and second gas effects are thought to result from the same two factors (13). The uptake of large volumes of N2O, the first gas during the induction of anesthesia, concentrates both the N2O and any gas delivered concurrently (the second gas) and increases the inspired ventilation relative to the expired ventilation, thereby increasing delivery of both the N2O and the second gas to the lungs. The inevitability of this increased delivery (i.e., of an increase in inspired ventilation) has been questioned by Korman and Mapleson (1), and Sun et al. (7) have questioned the applicability of both explanations.

The introduction of desflurane into clinical practice would seem to allow a test of the premise that the two factors described above (a concentrating of residual gases and an increase in input ventilation) apply to both the first and second gases and explain both the concentration and the second gas effects. Desflurane has a blood/gas partition coefficient indistinguishable from that of N2O (14,15). Thus, the rate of rise of the alveolar concentration during the induction of anesthesia should be the same for both desflurane and N2O during their concurrent administration, regardless of the inspired concentrations of each. We sought to confirm these predictions in humans in the following studies.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval from our committee on human research and informed consent, we studied three groups of ASA physical status I or II patients, six patients per group. Each patient was to undergo surgery. Before anesthesia for the surgery, we placed an IV cannula (through which we delivered lactated Ringer's solution) into each patient and applied standard clinical monitors. After preoxygenation for at least 3 min, we induced anesthesia with propofol (2 mg/kg) and fentanyl (1–3 µg/kg). Administration of rocuronium or vecuronium facilitated tracheal intubation with a 7.0-mm cuffed tube. Throughout the study, blood pressure was maintained at a mean value >65 mm Hg by adjusting the patient's position or by increasing the infusion of lactated Ringer's solution. Additional doses of fentanyl and/or propofol were given as indicated by the anesthesiologist managing the patient's care.

We connected an "artificial nose" (Humid-Vent® 1; Gibeck Respiration, AB, Väsby, Sweden) to the tracheal tube for airway humidification and connected the artificial nose to an 80-mL dead space. The dead space minimized/prevented contamination of end-tidal samples by inspired gas (see below for sampling site locations). The dead space connected the artificial nose to a Y-piece containing inspiratory and expiratory valves. The Y-piece was connected to an anesthetic circuit from which the standard inspiratory and expiratory valves had been removed. Fresh inflowing gas was delivered to the inspired side of the circuit either at the standard location (when only oxygen was delivered) or at a point immediately proximal to the inspiratory valve (proximal meaning between the valve and the anesthetic machine) at the Y-piece (when experimental gases were delivered). The flow rate of fresh inflowing gases exceeded minute ventilation (i.e., produced a nonrebreathing system that sustained a constant inspired concentration of test gases). Inspiratory gas samples were drawn from a port immediately proximal to the inspiratory valve at the Y-piece. End-tidal samples were drawn from a port between the artificial nose and the 80-mL dead space. Inspiratory and end-tidal gas samples were drawn into 50-mL glass syringes stored with the plungers upright (to ensure a small positive pressure in the syringes) until the gas samples were analyzed. Ventilation was controlled at a rate of approximately 10 breaths/min with a tidal volume adjusted to produce an end-tidal CO2 concentration of 33–37 mm Hg as measured by using an Ultima® infrared analyzer (Datex Corp., Helsinki, Finland). This procedure was used to make the expired ventilation the same for all three treatments.

The three groups were defined by the fresh gases the patients received immediately after intubation of the trachea and achievement of a stable delivery of ventilation. At time 0, the 100% O2 in fresh inflow gas was replaced for 20 min (the period of study) by one of the following three mixtures: Group 1: 65% N2O, 4% desflurane, balance O2; Group 2: 5% N2O, 4.0% desflurane, balance O2; and Group 3: 65% N2O, 0.5% desflurane, 2% xenon (Xe), balance O2. The gases were delivered from premixed cylinders calibrated against primary standards.

End-tidal samples were taken 0.5, 1, 1.5, 2, 3, 5, 7, 10, 15, and 20 min after initiating ventilation with the gas mixtures from the premixed cylinders. Using gas chromatography, the samples were analyzed for their concentrations of N2O, desflurane, and Xe. Inspired samples were taken at 5, 10, and 20 min for analysis.

For analysis of desflurane, we used a flame ionization detector gas chromatograph (Gow-Mac 580; Gow-Mac, Bethlehem, PA) equipped with a 4.5-m, 3-mm internal diameter column containing Porapak Q maintained at 50°C with a 20-mL/min carrier flow of nitrogen. The detector (at 111°C) received hydrogen at 20 mL/min and air at 200 mL/min. The chromatograph was calibrated before and at intervals during each test using secondary (cylinder) calibration standards. We prepared primary (volumetric) standards to calibrate each secondary standard.

For analysis of N2O and Xe, we used a thermal conductivity detector gas chromatograph (Gow-Mac 580) equipped with a 3-m, 3-mm internal diameter column containing Hayesep D 100/120 maintained at 81°C with a 10-mL/min carrier flow of helium. The detector was maintained at 110°C. The chromatograph was calibrated before and at intervals during each test using secondary (cylinder) calibration standards. We prepared primary (volumetric) standards to calibrate each secondary standard.

Desflurane was a gift from Ohmeda Pharmaceutical Products Divison (Liberty Corner, NJ). N2O was purchased from Puritan Bennett (San Carlos, CA), and Xe was purchased from Air Products and Chemicals, Inc. (Allentown, PA).

Data were summarized as the approach of the alveolar concentration (FA) to the inspired concentration (FI). That is, we determined the FA/FI ratio. Six values (one for each patient) for FA/FI were available for each time point, and we determined the FA/FI value (mean ± SD) for each time point. We obtained the value for the area under the curve for the difference 1 - FA/FI (i.e., the time-weighted average) for the period from 1 through 20 min by applying the trapezoid rule. We determined the significance of the differences among various groups for the time-weighted average for 1 - FA/FI by using an unpaired t-test, accepting P < 0.05 as significant (i.e., making no correction for repeated measures). We chose the period of 1–20 min because, by 1 min, most of the washin of the functional residual capacity would be complete (i.e., with normal ventilation, the time constant for the functional residual capacity is approximately 0.5 min). An unpaired t-test was used to assess whether the women had 1 - FA/FI values different from those for men for N2O or for desflurane when breathing 65% N2O for the period of 1–20 min. An unpaired t-test also was used to determine whether there were significant differences among the three groups for demographic or physiological variables. Again, we accepted P < 0.05 as indicative of significant differences.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Demographic, ventilatory, and cardiovascular data did not differ among volunteers in the three groups (Table 1). Vital signs did not differ among anesthetic groups at any time during anesthesia (Table 1).


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  		Table 1. Demographic and Experimental Values
 
The FA/FI of 65% N2O increased at the same rate in Group 1 as in Group 3 (Fig. 1, uppermost two curves). Similarly, the FA/FI of 0.5% and 4% desflurane given with 65% N2O increased at the same rates (Fig. 1, lowermost two curves). None of these points differed as assessed by using unpaired t-tests. Thus, the administration of widely different concentrations of desflurane affected neither its rate of rise nor that of concurrently administered N2O. Accordingly, in Figure 2, the data from Groups 1 and 3 for 65% N2O and for desflurane given with 65% N2O were combined.



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  		Figure 1. FA = alveolar (end-tidal) concentration, FI = inspired concentration. The FA/FI ratio of 65% N2O increased at the same rate in Group 1 as in Group 3 (uppermost two curves). Similarly, the FA/FI of 0.5% and 4% desflurane administered with 65% N2O increased at the same rates (lowermost two curves). Thus, the administration of widely different concentrations of desflurane affected neither the rate of rise of desflurane nor the rate of rise of concurrently administered N2O.

 


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  		Figure 2. FA = alveolar (end-tidal) concentration, FI = inspired concentration. The FA/FI of N2O increased to a significantly higher level at all time points, except the 0.5-min point, when delivered at a concentration of 65% (uppermost curve) than at a concentration of 5% (third curve from top). These results would be predicted by the concentration effect. Similarly, the FA/FI of desflurane increased to a significantly higher level when delivered with 65% N2O (second curve from the top) than when delivered with 5% N2O (lowermost curve). These results would be predicted by the second gas effect.

 
As shown by a comparison of the area under the curve for 1 - FA/FI for the period of 1–20 min, the FA/FI of N2O increased to a significantly higher level when delivered at a concentration of 65% (Table 2, Fig. 2, uppermost curve) than at a concentration of 5% (Fig. 2, third curve from top). Similarly, the FA/FI of desflurane increased to a significantly higher level when delivered with 65% N2O (Table 2; Fig. 2, second curve from the top) than with 5% N2O (Fig. 2, lowermost curve).


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  		Table 2. Effect of Anesthetics, Anesthetic Components, and Anesthetic Concentrations on the Area Under the Curve for the Approach of FA/FI to 1.0
 
When delivered in 65% N2O, the FA/FI of 2% Xe (Table 2, Fig. 3, uppermost curve) significantly exceeded a value of 1.0 (horizontal line in Fig. 3) and increased to a higher level than 3% Xe delivered in O2 only [Fig. 3, second curve from the top; data from previous study in volunteers (16)]. In turn, both Xe curves lay significantly above the curve for 5% N2O (Fig. 3, third curve from the top), which, in turn, lay significantly above the curve for 4% desflurane given with 5% N2O (Fig. 3, lowermost curve).



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  		Figure 3. FA = alveolar (end-tidal) concentration, FI = inspired concentration. When delivered in 65% N2O, the FA/FI of 2% Xe (uppermost curve) significantly exceeded a value of 1.0 (horizontal line at 1.0) and increased to a higher level than 3% Xe delivered in O2 only [second curve from the top; data from previous study in volunteers (16)]. This result would be predicted by the second gas effect and supports the argument that a concentrating of residual gases is at least partly responsible for the second gas effect. Consistent with Xe's lower solubility, both Xe curves lay significantly above the curve for 5% N2O (third curve from the top). In turn, the FA/FI for the less tissue-soluble N2O lay significantly above the curve for 4% desflurane administered with 5% N2O (lowermost curve).

 
Finally, we did not find that patient sex significantly influenced the approach of FA/FI to 1.0 for either N2O or desflurane (Table 3).


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  		Table 3. Effect of Patient Sex on the Area Under the Curve for the Approach of FA/FI to 1.0
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Results from the present study confirm previous findings for both the concentration (5) and second gas effects (6) (Table 2, Fig. 2) and do not support suggestions that the second gas effect does not exist (7).1

The administration of 65% N2O increased the FA/FI ratio for both N2O and concurrently administered desflurane relative to the administration of 5% N2O (Table 2). At 20 minutes of administration, the FA/FI ratios for 65% N2O and the associated desflurane were 7%–8% greater than those for 5% N2O and the associated desflurane. Although statistically significant, these differences are of marginal clinical significance because they are easily eliminated by small manipulations in anesthetic delivery.

The present results support the notion that concentration and second gas effects result from the uptake of substantial volumes of gas, particularly N2O (17). Uptake of increased volumes of desflurane (i.e., as a result of using 4% vs 0.5% desflurane) did not alter the FA/FI ratio for either N2O or desflurane (Fig. 1). This would be expected because the absolute volumes of desflurane taken up must be small, and, although the proportionate increases in uptake might be large, the absolute increases would be small. For example, at any time of administration, we may estimate the approximate uptake of desflurane as (FI - FA) x VA, where VA is alveolar ventilation. We estimate VA as 3000 mL/min (assuming an O2 consumption of 2.5 mL · kg-1 · min-1 or 175 mL/min; a respiratory quotient of 0.8; an alveolar CO2 of 35 mm Hg [Table 1]; and a barometric pressure of 760 mm Hg). At five minutes of delivery, this gives a value of 3.4 mL for the patients given 0.5% desflurane and 27 mL for patients given 4% desflurane. The value for 5% N2O may be similarly calculated and equals 24 mL. However, the value for 65% N2O cannot be similarly calculated because the value for VA does not equally apply to the FI and FA values. This is because the volume inspired exceeds the expired volume by an amount equal to the uptake of N2O. For low concentrations (e.g., 5% N2O), this difference minimally affects the calculation, but at 65%, the difference is appreciable. If we assume that uptake increases in proportion to the greater end-tidal concentration of N2O and apply this factor to the above value calculated for 5% N2O, then the uptake of 65% N2O at five minutes equals 345 mL (i.e., 11.5% of the VA of 3000 mL/min).

The data for the FA/FI ratio for 2% Xe (Table 2, Fig. 3) provide further evidence for the uptake of substantial volumes of gas when 65% N2O is administered. The value for the Xe FA/FI ratio exceeded 1.0 for all collections after five minutes. This can only be explained by the uptake of more of the gases (particularly the N2O) associated with Xe than of the Xe itself. These results in humans confirm those obtained in dogs by Stoelting and Eger (13).

As would be predicted from their respective solubilities (14,18), at low inspired concentrations, the rate of rise of FA/FI of Xe exceeded that of N2O (Table 2, Fig. 3). However, despite an identity of the N2O and desflurane blood/gas partition coefficients (14,15), the rate of rise of N2O exceeded that of desflurane (Fig. 3). Two possibilities may explain this unexpected finding. First, although desflurane and N2O may be equally soluble in blood, desflurane is more soluble in tissues (19). Thus, uptake of desflurane by lung tissue and from blood perfusing tissues should be greater than such tissue uptake of N2O. Fat offers the greatest difference in tissue solubilities for desflurane versus N2O. The fat/gas partition coefficient for desflurane is 12, whereas that for N2O is 1.

The greater fat solubility of desflurane offers the second explanation. Beyond the greater desflurane uptake from blood distributed to fat, anesthetic absorption by fat (or tissues containing more fat) via intertissue diffusion (20, 21) may augment the difference between the FA/FI for desflurane and that for N2O. That is, movement of desflurane from gray to white matter, from heart to pericardial fat, from intestine to mesenteric and omental fat, from kidney to perirenal fat, from muscle or dermis to subcutaneous fat, probably exceeds the movement of N2O. This difference would augment and sustain a greater uptake of desflurane than of N2O and thus might explain the lower FA/FI found with desflurane.

Some factors do not explain the observed difference. First, although the uptake of N2O by the column in a gas chromatograph can increase the N2O peak height and the peak heights of concurrently injected gases (22), this effect should equally influence the readings for both the inspired and end-tidal gas values and thus should not affect the ratio. Second, although differences and changes in ventilation, cardiac output, and the distribution of blood flow can affect uptake and the FA/FI ratio (23), such differences or changes cannot affect the relationship of gases administered concurrently (as was the case with several of these experiments). We were also careful to sustain a constant end-tidal CO2 (Table 1), having found in preliminary studies (data not shown) that failure to do so resulted in "noise" that diminished or eliminated the statistical significance of the small differences seen in Table 2 and Figures 1–3.

Some investigators have suggested that uptake of inhaled anesthetics is constant after the first few minutes of anesthesia (24). Our data do not confirm this suggestion for the first 20 minutes of anesthesia. For example, except for the Xe values, the FA/FI values for all of the present study measurements at 20 minutes were significantly greater than the values at 10 minutes. This was particularly true for the desflurane values obtained with 5% N2O, in which the greater desflurane uptake increased the sensitivity of measurement (i.e., increased the ease with which a difference could be discerned) (Figs. 2 and 3).

Korman and Mapleson (1) argue convincingly that the explanation for the concentration and second gas effects can be improved, in part, by minimizing the portion of the explanation that assumes an increase in inspired ventilation. They note that use of a constant volume ventilator diminishes or abolishes an increase in inspired ventilation, regardless of the uptake of the first gas. However, this argument assumes that the settings on the ventilator are not modified to maintain a constant end-tidal CO2, as in the present study. Maintenance of a constant end-tidal CO2 revives the original argument that an increase in inspired ventilation is an important part of the explanation for the concentration and second gas effects; as applied in the present study, it tended to make the expired ventilation the same for all three of our groups (13).

Finally, our results do not confirm the suggestion by Sun et al. (7) that "the `second gas effect' is not a valid concept." Sun et al. found that the administration of 80% N2O did not accelerate the rate of rise of either the FA/FI or the arterial partial pressure of enflurane during a five-minute delivery of 0.2% inspired enflurane. Their data are impressive in that the results for the FA/FI or the arterial values for enflurane with 80% N2O precisely overlie the values for enflurane administered in O2.

There are several differences between our study and that of Sun et al. (7). They (a) administered 80% rather than 65% N2O; (b) used enflurane as the second gas; (c) made measurements over 5 minutes rather than 20 min; and (d) did not adjust ventilation to maintain CO2 at exactly the same value in the high and low (zero) N2O groups. Did the administration of 80% N2O stimulate the circulatory system and augment cardiac output? That would have increased enflurane uptake and decreased the FA/FI ratio. However, such stimulation should have taken a few minutes to become manifest, but identity of their curves with and without N2O is present from the start of enflurane administration.

Sun et al. (7) present some arguments that do not seem to fit with the data from the present study. First, they note that part of the early difference between FA and FI may result from the need to fill the functional residual capacity, an action that might require one to two minutes and thus occupy a major portion of their five-minute study. Our results had no such limitation and showed the actions of the concentration and second gas effects well after filling the functional residual capacity (i.e., after one to two minutes of anesthetic delivery).

Second, Sun et al. (7) suggest that "the concentrating effect is very weak." Our finding that the administration of 65% N2O with Xe caused the FA/FI of Xe to exceed 1.0 (Table 2, Fig. 3) would argue otherwise.

Third, Sun et al. (7) suggest that an increase in inspired ventilation produced by uptake of N2O does not accelerate the rise of the second gas. Both we and they found that the uptake of N2O in the first several minutes of anesthesia may equal several hundred milliliters per minute. They cite an unpublished figure of 400 mL/min at three minutes of N2O administration, and, as noted earlier, we estimate a figure of 350 mL/min at five minutes. They suggest that the resulting "augmentation effect is nonexistent," but their argument seems incorrect if these values augment (e.g., increase by 11.5%) a normal alveolar ventilation of 3000 mL/min. Differences in ventilatory control between our study and that of Sun et al. may explain why this uptake produced different results in our study versus that of Sun et al. As noted above, Sun et al. kept the inspired ventilation, rather than PaCO2, constant. That is, their approach did not allow the uptake of N2O to influence (augment) the inspired ventilation, whereas ours did. This is precisely the concern expressed by Korman and Mapleson (1). This point is particularly relevant to the work of Sun et al. (7) because the augmentation of inspired ventilation (rather than a concentrating of residual gases) is a greater factor for more soluble compounds (25). Sun et al. (7) studied enflurane, a gas 4 times as soluble in blood as desflurane (15,26). Thus, their use of a constant inspired ventilation eliminated a major contribution to the second gas effect.

We conclude that both the concentration and second gas effects exist and apply to anesthesia in humans. We also conclude that they are, as previously suggested, explained by a concentrating of residual gases and an augmentation of inspired ventilation.


   Acknowledgments
 
Supported by NIH Grant 1P01GM47818-04.


   Footnotes
 
1 Lin C-Y, Wang J-S. Supramaximal second gas effect: a nonexistent phenomenon [abstract]. Anesth Analg 1993;77:870–1. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 5, 1999.




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Anesth. Analg., March 1, 2002; 94(3): 765 - 766.
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K.-i. Nishikawa, F. Kunimoto, Y. Isa, S. Miyoshi, K.-i. Takahashi, T. Morita, H. Arii, and F. Goto
Second gas effect of N2O on oxygen uptake
Can J Anesth, June 1, 2000; 47(6): 506 - 510.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press