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GENERAL ARTICLES

The "Second Gas Effect" Is Not a Valid Concept

Xing-guo Sun, MD^*, Feng Su, MD, Yang-Qiang Shi, MSc, and Chingmuh Lee, MD^*

Departments of Anesthesiology, *Harbor-University of California Los Angeles Medical Center, Torrance, California; and Weifang Medical College, Weifang City, Shandong Province, Peoples Republic of China

Address correspondence and reprint requests to Xing-guo Sun, MD, Department of Anesthesiology, Harbor-UCLA Medical Center, Torrance, CA 90509-2910.

	Abstract

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To determine whether the "second gas effect" is valid, we determined the pharmacokinetics of 0.2% enflurane with or without 80% N₂O (n = 7 each) under controlled constant volume ventilation in 14 young healthy male patients before their operations. The alveolar (end-tidal) concentration (F_A) and inspired concentration (F_I) at the mouthpiece and the arterial blood concentration of enflurane were measured, and the ratio of F_A to F_I was calculated. The F_A/F_I of enflurane increased rapidly during the first few minutes of administration and then increased slowly. No significant difference was found in the F_A/F_I between the two groups at any time point (P > 0.05). The arterial blood concentrations of enflurane increased progressively and were not significantly different between the two groups at any time point (P > 0.05). The results indicate that, at high concentrations, N₂O neither facilitated the increase of F_A nor enhanced the uptake of a companion gas. The second gas effect is a nonexistent phenomenon in clinical practice because the concentrating effect is very weak and the augmentation effect is nonexistent under controlled ventilation.

Implications: We studied the effects of N₂O on the ratio of alveolar (end-tidal) concentration to inspired concentration of the second gas (enflurane) and on its blood concentration in humans. Nitrous oxide did not affect the alveolar or blood concentration of the second gas under controlled constant volume ventilation. The "second gas effect" is not a valid concept.

	Introduction

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The "second gas effect" is supposedly characterized by the facilitated increase of alveolar concentration (F_A) (or enhancement of uptake) of a companion gas due to a rapid and massive initial uptake of N₂O in the same lungs (1–4). Despite N₂O's relatively low blood solubility, the volume taken up early in anesthesia is large (1500 mL/min ) because N₂O is delivered in high concentrations (5).

Uptake of inhaled anesthetics is generally estimated from the square-root-of-time rule first proposed by Severinghaus (5,6) and expanded greatly by Lowe and Ernst (7) and Mapleson (8) in their classic descriptions. They expressed the rate of N₂O uptake over time as a power function of time: 1000 (mL) x t (min)^-1/2. This rule states that uptake at any point in time may be estimated as uptake during the first minute of anesthesia divided by the square root of time in minutes. However, this approximation made in the derivation of these t(min)^-1/2 functions do not separate the functional residual capacity (FRC) washin from the true body uptake. In considering the uptake of an inhaled anesthetic (at least, for the purpose of explaining the second gas effect), one should include only the amount of anesthetic crossing the alveolar membrane, not the amount moved across the mouthpiece. Only after separating the FRC washin could one calculate the true uptake through the alveolar membrane with measurements of the F_A and inspired concentrations (F_I) of N₂O and enflurane at the mouthpiece.

In clinical practice, some preliminary observations concerning inhaled anesthetics show that the second gas effect is either very weak (insignificant) or nonexistent (9–12). We performed the following study to elucidate the true change in the concentration of volatile inhaled anesthetics, with or without a high concentration of N₂O. In this study, the concentration of volatile inhaled anesthetic is purposefully set very low (F_I = 0.2% enflurane) because the circulatory depression effect may occur because of the higher concentration (for example, >1% enflurane).

	Methods

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With approval from our institutional committee on human research and informed consent from the subjects, our team studied 14 young healthy male patients scheduled for operations (ASA physical status I, age 20–30 yr, body weight 67 ± 4 kg, height 172 ± 6 cm). All data were collected before the operations.

Two peripheral 16-gauge IV catheters were inserted, and lactated Ringer's solution was administered. One 20-gauge arterial catheter was inserted into the left radial artery for blood sampling. Anesthesia was induced with thiopental 5–8 mg/kg and fentanyl 4–5 µg/kg IV. After breathing oxygen via a mask, succinylcholine 1.5 mg/kg or atracurium 25 mg was administered IV. The trachea was intubated, and a nylon catheter was inserted into the distal end of the endotracheal tube for the end-tidal sampling. Anesthesia was maintained by a continuous infusion of 1% procaine and 0.08% succinylcholine (or 0.01% atracurium) mixture (first hour, 0.8 mL · kg^-1 · min^-1; second hour, 0.5 mL · kg^-1 · min^-1; third hour, 0.35 mL · kg^-1 · min^-1) and fentanyl 0.1–0.2 mg IV at an interval of 60 min or as indicated by blood pressure and heart rate. Ventilation (inspiratory tidal volume 8–10 mL/kg, fresh gas flow 10 L/min; frequency 10 breath/min and ratio of inspired time to expired time 1:1.5–2) was controlled via a nonrebreathing system (Frumin nonrebreathing valve; Invengineering Inc., Belmar, NJ) to produce normocapnea (end-tidal carbon dioxide 5.5%–6.5%) with patients in the supine position and was then maintained constant during the research period. The inspired and end-tidal concentrations of N₂O, enflurane, oxygen, and carbon dioxide were measured continuously by using an infrared anesthetic gas analyzer (Capnomac Ultima^TM; Datex, Helsinki, Finland) and recorded. Standard monitoring was used. Body temperature was monitored and maintained at 36.5–37°C.

Fourteen patients were randomly divided into two groups of seven patients each. In Group 1, the patients were given 0.2% enflurane in oxygen (0.2% ENF/O₂) for 5 min. In Group 2, the patients were given 0.2% enflurane with 80% N₂O in oxygen (0.2% ENF/N₂O/O₂) for 5 min. The anesthesia circuits were pre–washed-in for approximately 5 min before being connected to the patients. All types of stimulation, such as urinary catheterization and postural change, were avoided before and during this study. After study, the inhaled anesthetics were administered according to the clinical needs. End-tidal gas was sampled from an endport of the tracheal tube. Inspired gas was collected from a port on the nonrebreathing valve just proximal to the valve assembly.

During the study, the end-tidal and inspired samples were collected at 0.5, 1, 2, 3, 4, and 5 min. All gas samples were obtained in 20-mL glass syringes sealed with nylon three-way stopcocks. An initial sample was drawn into the syringe and then discarded. This was repeated twice. The fourth sample was used for analysis. The syringes were stored upright until the gas contents were analyzed. At 1, 2, 3, 4, and 5 min, arterial blood samples were drawn from an indwelling catheter into 20-mL glass syringes (previously calibrated and heparinized) capped with three-way stopcocks. Each blood sample drawn amounted to 11–12 mL. All bubbles and free gases were ejected before the blood samples were stored for analysis. All gas and blood samples were analyzed for enflurane concentration by gas chromatography using previously published methods (12–15).

The data were analyzed for differences using both Student's t-test and analysis of variance. For all measurements, P < 0.05 was accepted as significant. F_A/F_I and arterial blood concentration of enflurane were plotted against time using the Fit spline or LOWESS curve/point-to-point function of the graphic program GraphPad Prism 2 (GraphPad; San Diego, CA). All data are expressed as means ± SD.

	Results

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There were no statistically significant differences in the clinical, spirometric, and hemodynamic data between the two groups.

The F_A/F_I of enflurane increased rapidly during the first few minutes (0.5, 1, 2, and 3 min) of administration (P < 0.01 for each compared with the previous time point), then increased slowly (P > 0.05 for each compared with the previous time point) (Fig. 1, Table 1). The F_A/F_I was not significantly different between the two groups (P > 0.05) at any time measured. The arterial blood concentration of enflurane increased progressively (P < 0.01) (Fig. 2, Table 1). The arterial blood concentrations were not significantly different between the two groups at any time point (P > 0.05).

View larger version (18K): [in this window] [in a new window]   Figure 1. The ratio of alveolar (end-tidal) concentration (FA) and inspired concentration (FI) of enflurane (ENF) increased rapidly at the beginning of the administration, then slowly. There was no difference between the two groups.

View larger version (17K): [in this window] [in a new window]   Figure 2. The arterial blood concentration of enflurane (ENF) increased progressively. There was no difference between the two groups.

	Discussion

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Because it is impossible to place the measurement probe at the alveoli, the uptake and elimination of an anesthetic is measured at the mouthpiece. Because the space of FRC between the alveolar membrane and the mouthpiece is rather large, one must consider the FRC washin by ventilation gas (with F_I) during the beginning period of the inhaled anesthetic administration (at least, for the purpose of explaining the second gas effect). As previously suggested (16), one could calculate a theoretical FRC washin curve. The difference between the theoretical FRC washin curve and the measured F_A/F_I curve is the uptake. Accordingly, the characteristic of the uptake curve is that it increases rapidly at the beginning, reaches a peak at the third minute, then slowly decreases. However, the rate of uptake is not constant, nor does it obey the square-root-of-time rule. Even the peak uptake rate (at the third minute) of high concentrations of N₂O is only approximately 400 mL/min (unpublished data). The uptake rate of N₂O at the first minute of administration could be >1000 mL/min only if the FRC washin is not taken into account (not subtracted) (unpublished data). The rapid increase of the F_A/F_I of anesthetics at the beginning of administration is mainly caused by the FRC washin.

The traditional explanation of the second gas effect has two components: the concentrating effect of the uptake of N₂O on the second gas and the associated augmentation of ventilation (17,18). If FRC = 2500 mL, tidal volume (VT) = 500 mL, respiratory rate = 10 bpm, and peak uptake rate of N₂O = 400–500 mL/min, the uptake volume is only approximately 40–50 mL/breath, which is <2% FRC. The concentrating effect of N₂O uptake is <2%. At the same time, each breath could exchange approximately 20% of FRC. This means that the concentrating effect is weak and that the VT plays a more important role than that of the concentrating effect. The absorption that produces the concentrating effect presumably continues during expiration; therefore, expired minute volume should transiently decrease, at least during the period of rapid uptake of N₂O. However, no evidence of this was found (1), and "under desirable conditions (PaCO₂ of 40 torr or less), increases in PaCO₂ following N₂O administration are small" (19). Under controlled ventilation, the lung could not draw in any gas from the anesthesia circuit (no augmentation effect). Because the second gas effect was predicated on an increase in inspiratory ventilation secondary to absorption of gas into blood, it should be possible to show a transient increase in inspiratory ventilation and an excess of this over expiratory ventilation during the period of rapid uptake (1). Unfortunately, not only our results, but also those of Epstein et al. (1), indicate that inspiratory ventilations were very stable and were similar to the expiratory ventilations. Previous work (4) also contradicts the idea of the augmentation effect (1). All of these indicate that the concentrating effect is very weak and that the augmentation effect is nonexistent.

According to the mass/balance principle, uptake is equal to the transport by blood: uptake = (C_a - C_v) x Q, where Q is the cardiac output, C_a is the arterial blood concentration, and C_v is the venous blood concentration. In this study, the circulatory function is maintained stable; thus, the Q is a constant. During the first few minutes of administration, most of the transferred anesthetic (high oil solubility) can be absorbed by blood-rich tissues, and the C_v is very low (unpublished data). If C_v is zero during the first few minutes of administration, C_a is the only factor that can respond to the change of uptake. Because C_a is very low at the beginning of administration, then increases rapidly during the initial period, the uptake at the beginning is very low, but increases rapidly at first. Further, C_a was not significantly different between the two groups at any time; therefore, the high concentration of N₂O could not enhance the uptake of a companion gas.

In previous works (1,4), the F_A/F_I of potent inhaled anesthetics is greater with high concentration N₂O than without. However, as mentioned above, the uptake is the difference between the theoretical FRC washin curve and the measured F_A/F_I curve. Therefore, the higher the F_A/F_I, the lower (not higher) the uptake. This is supported by previous investigations (18,20), which indicate that a larger blood-gas partition coefficient (i.e., blood solubility) will produce a greater uptake and, hence, a lower F_A/F_I (18) and that the concentration effect can be mimicked by a decrease in blood solubility (i.e., the higher F_I, the higher F_A/F_I and the lower blood solubility) (20). There are many factors, particularly ventilation (21) and cardiac out-put (22), that may affect the value of F_A/F_I. The inhaled anesthetics are direct and potent myocardial depressants; they decrease cardiac output in a dose-related manner (23–26). The most common interaction of N₂O with a volatile inhaled anesthetic is a predictable reduction in the requirement of the volatile inhaled anesthetic (2). A minimum alveolar anesthetic concentration (MAC) sevoflurane or isoflurane of 1.5 compared with an equipotent mixture of sevoflurane or isoflurane plus N₂O (0.85 MAC sevoflurane or isoflurane plus 0.65 MAC N₂O) showed similar decreases of the cardiac index (27). Previous investigators (1,4) administrated a higher concentration of volatile inhaled anesthetic (0.5% halothane, 0.65 MAC) with or without high concentrations of N₂O (80% or 65% N₂O, 0.8 or 0.65 MAC). When the same concentration of a volatile inhaled anesthetic is accompanied by high concentrations of N₂O, the level of anesthesia would be deeper than that with only a volatile inhaled anesthetic (1.45 or 1.3 MAC compared with 0.65 MAC), and the depression of circulation function would also be more severe. Accordingly, the uptake of the second gas should be decreased, not enhanced. This may be an explanation of the previous works (1,4).

In summary, this study indicates that high concentration of N₂O per se neither facilitates the increase of F_A and C_a nor enhances the uptake of a companion gas. It is clear that the concentrating effect is very weak, and the augmentation effect is nonexistent under controlled constant volume ventilation. Therefore, we conclude that the second gas effect is not a valid concept for clinical inhaled anesthesia.

	Acknowledgments

 
Our thanks to Brain K. Tsang, MD, and Laszlo Gyermek, MD, for their help.

	References

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