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Onset Time for Sevoflurane/Nitrous Oxide Induction in Adults Is Prolonged with Increasing Age

Lewis, Michael C. MD; Gerenstein, Ricardo I. MD; Chidiac, Gilbert MD

doi: 10.1213/01.ane.0000205749.92049.91
Anesthetic Pharmacology: Research Report
Chinese Language Editions

Inhaled induction of anesthesia is occasionally used in adults. Using a modified vital capacity sevoflurane/nitrous oxide (N2O) inhaled induction, we evaluated the effect of increasing age on the onset time of anesthesia. Twenty patients, aged 26-65 yr, performed a vital capacity breath followed by regular tidal breathing from an anesthesia circuit primed with sevoflurane 8%/N2O/O2. The following values were recorded: time to loss of eyelash reflex (LOER); time to bispectral index ≤60 (BIS ≤60); expired fraction of sevoflurane at the time of induction, LOER and BIS ≤60. The mean times and 95% confidence intervals to LOER and BIS ≤60 were 54 s (37-70 s) and 175 s (143-207 s), respectively, and were significantly prolonged by aging (r = 0.65; P = 0.002). Times to LOER and BIS ≤60, predicted from the regression line, were 3.9 and 2 times longer in a 60-yr-old than in a 30-yr-old patient. The expired fraction of sevoflurane measured at time to LOER and BIS ≤60 decreases with increase in age. We conclude that inhaled induction with sevoflurane/N2O is dramatically prolonged with increased age.

IMPLICATIONS: This study demonstrates that aging significantly increases the time required to induce anesthesia using an inhaledtechnique. Because inhaled induction is gaining popularity in adults, the clinician should be aware of this effect.

Department of Anesthesiology, University of Miami, Miami, Florida; Division of Anesthesiology, Cleveland Clinic Florida, Weston Florida

Accepted for publication January 12, 2006.

Address correspondence and reprint requests to Michael C. Lewis, MD, Department of Anesthesiology, Miller School of Medicine at the University of Miami, P.O. Box 016370 (R-370) Miami FL 33101. Address e-mail to

Whereas the pharmacodynamic proprieties of inhaled induction with sevoflurane and nitrous oxide (N2O) are well described (1), the effect of aging on the speed of induction of inhaled anesthesia has not yet been investigated. Inhaled induction of anesthesia is a reasonable, but not frequently used, alternative to IV drugs in adult patients (2). The lack of pungency and the low solubility of sevoflurane permit its use for rapid inhalation induction technique (3–5).

An understanding of age-related pharmacokinetic effects of inhaled induction is important because of the ever-increasing number of elderly in the population (6). The aim of this study was to assess the effect of aging in adult patients on the onset time of anesthesia using a rapid inhaled induction technique with sevoflurane in N2O/O2.

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This study was approved by the IRB. After obtaining written informed consent we recruited 20 adults consecutive patients ASA physical status I-II, aged 26–65 yr, scheduled for elective surgeries. Patients were fasted for 8 h before the surgery. Individuals with a history of severe gastroesophageal reflux disease, hyperactive airway disease, uncontrolled hypertension, known ischemic heart disease, or with suspected difficult mask ventilation and/or intubation were excluded from the study.

The patients were not premedicated. In the operating room, standard monitors (electrocardiogram, noninvasive arterial blood pressure, pulse oximeter, capnograph, and temperature) were applied. A Bispectral Index (BIS) electrode (Aspect Medical Systems, Natick, MA) was applied to the patient's forehead and connected to a BIS 2000 monitor before the induction of anesthesia. A BIS smoothing rate of 15 s was selected. A stable signal was acquired before induction in every patient. A Datex Capnomac (Datex Instrumentarium®, Helsinki, Finland) was used to measure the expiratory fractional concentration of sevoflurane (Fe-S) in the anesthesia circuit. The anesthesia circuit was primed for 5 min with N2O (4 L/min)/O2 (2 L/min) and sevoflurane 8%, and this was not changed until the end of the study. The pressure release valve was left open to the scavenging system and the Y piece of the anesthesia circuit occluded with a gauze plug.

An appropriate sized facemask was chosen. Patients were then instructed how to perform a vital capacity breath. After a maximal exhalation, the gauze plug was removed from the Y piece, which was rapidly connected to the facemask. Patients inhaled to vital capacity, held their breath for 10 s, and were then allowed to breathe normally (1).

An observer, blinded as to the purpose of the study, recorded the following:

  1. The Fe-S at the anesthesia circuit before the induction.
  2. Time to loss of eyelash reflex (LOER), obtained by gently brushing the eyelashes with cotton gauze every 5 s until this stimulus did not elicit a reflex. Fe-S was noted at this time.
  3. Time to reach a BIS value ≤60 (BIS ≤60). Fe-S was noted at this time.

The sample size was determined for an expected correlation coefficient ≥0.6, a Type I error of 5% and Type II error of 20%. Correlation between age versus LOER, age versus BIS ≤60, LOER versus BIS ≤60, Fe-S versus LOER, and Fe-S versus BIS ≤60 were determined by the least-squares regression analysis. Times to LOER and BIS ≤60 corresponding to 2 theoretical 30-yr-old and 60-yr-old patients were predicted using points on the regression line. The volume % of Fe-S is expressed as mean ± sd. Differences between Fe-S before the induction and at the times to LOER and BIS ≤60 were analyzed with analysis of variance and Student Newman-Keuls test. Times to LOER and BIS ≤60 are shown as mean and 95% confidence intervals (CI). Differences were considered significant when P < 0.05.

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All enrolled patients completed the study. A positive correlation was found between age and time to LOER as well as age versus time to BIS ≤60. The slope the regression line of “age versus LOER” was 2 (95% CI, 0.8–-3.1), its SE was 0.55; the intercept was -39 (95% CI, -95, 16); the SEE was 30 s; r = 0.65; P = 0.001 (Fig. 1). The slope of “age versus BIS ≤60” was 3.9 (95% CI, 1.6–6.2); its SE 1.09; its intercept was -6.9 (95% CI, -117, 103); the SEE was 59 s; r = 0.64; P = 0.002.

Figure 1

Figure 1

In our cohort, the average times required to reach LOER and BIS ≤60 were 54 s (95% CI, 37–70 s) and 175 s (95% CI, 143-207 s), respectively. Times to LOER and BIS ≤60 calculated from the regression line were respectively 3.9 (81 versus 21 s) and 2 (220 versus 110 s) times longer in a 60-yr-old than in a 30-yr-old hypothetical patient. A positive correlation between LOER and BIS ≤60 was found (r = 0.75; P = 0.0001) (Fig. 3.)

Figure 3

Figure 3

The Fe-S in the anesthesia circuit before the induction was 7.08 ± 0.4. Fe-S decreased to 5.2 ± 1.7 and 5.06 ± 1 at the time of LOER and BIS ≤60, respectively. Fe-S at times to LOER and BIS ≤60 decrease with age (r = 0.72, P = 0.0003 and r = 0.54; P = 0.02 respectively) (Figs. 4, 5).

Figure 4

Figure 4

Figure 5

Figure 5

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This study demonstrates that induction time of anesthesia with sevoflurane and N2O is longer in older as compared with younger adult patients (Figs. 1–2). Indeed, times to LOER and BIS ≤60 demonstrated an approximate threefold prolongation of the time required for inhaled induction produced by aging.

Figure 2

Figure 2

The speed of inhaled induction depends on many factors, including concentration of the anesthetic, minute ventilation, vital capacity, alveoli/blood gradient, cardiac output (CO), the presence of pulmonary or intracardiac shunts and patient cooperation. Increased functional residual capacity and decreased CO are well described with aging (7). The negative correlation found between age versus Fe-S at the time of reaching LOER and BIS ≤60 (Figs. 4–5) could represent dilution of sevoflurane in a larger functional residual capacity, slowing partial pressure increase in the lungs. Conversely, a lower CO would increase the speed of inhaled induction, decreasing the time to equilibrium. These changes may modify the rate of increase of Fi/Fe during inhaled induction in one direction or the other. Changes in the cardiovascular and respiratory systems are not great and cannot explain the significant delay in the induction time found in our study.

Tissue solubility of volatile anesthetics increases with age (8). Lerman et al. (9) reported that blood-gas partition coefficient of isoflurane of 1.19 in newborns increases to 1.28 in children and to 1.46 in middle-aged adults. Increased tissue solubility results in a slower increase of the anesthetic partial pressure in the alveoli and the brain. Together with the described dilution effect in the lungs, this could be responsible for the smaller Fe-S observed in the older patients.

The literature does not identify any influence of aging in the speed of inhaled induction with sevoflurane in adult patients nor time to reach a BIS ≤60 as a benchmark for level of hypnosis. Strum et al. (10) reported that aging delays the anesthetic elimination of inhaled anesthetics, but their study had no power to demonstrate a pharmacokinetic effect attributable to aging during induction. Our results for averaged time to LOER correspond with the results of other studies (2,11). The effects of inhaled induction on levels of BIS have been described elsewhere (12,13).

Inhaled induction in adult patients has not been very popular, possibly because of the apparent prolonged time required to achieve an adequate level of anesthesia when compared with traditional standard IV induction. This was true of the older, highly soluble volatile anesthetics (14). However, conditions have changed (4,5,15). Sevoflurane is a fast-acting, low-solubility volatile anesthetic with minimum risk of airway irritability. Several studies comparing inhaled versus IV induction of anesthesia demonstrated similar speed of induction, hemodynamic profile, and patient acceptance (2,10). Inhalation induction with sevoflurane was suggested as a useful technique for anesthesia settings as dissimilar as ambulatory or cardiovascular surgery (3,16–17).

BIS ≤60 is widely used as an end-point of hypnosis during general anesthesia (18–21). We selected this value to find out how age affects the time required for a deeper level of pharmacologic-induced hypnosis. Although LOER and BIS ≤60 show good agreement (Fig. 3), it is apparent that both measurements signal different levels of hypnosis. Indeed, time required to reach a BIS ≤60 was 3 times longer than time to LOER. The latter has been used previously as an end-point to measure the time of loss of consciousness produced by induction of general anesthesia (10,15). However, this level of hypnosis may not be enough to safely proceed with the endotracheal intubation. It has been suggested that the stimulus of tracheal intubation during light anesthesia could increase the chances of recall (22). Several studies reported that 120-300 s are required for appropriate placement of a laryngeal mask after a vital capacity induction with sevoflurane (23).

In our study 2 patients had longer than the average time to LOER and BIS ≤60. They were 60 and 65 yr old and their times to LOER and BIS ≤60 were 145 s and 170 s and 235 s and 360 s, respectively, versus a group mean of 54 s and 175 s. The prolongation in the onset time was detected in both patients with 2 different tests (LOER and BIS ≤60), which minimizes the possibility of bias in the recording of the data or an instrumentation misreading. A review of these patients' medical records failed to show any possible clinical explanation for this prolongation. We presume that this shift from the mean represents the normal variability found in any biological measure.

One limitation of our study was the inability to measure the actual end-tidal concentration of sevoflurane. The study began with the patient awake and ended at the time of loss of consciousness. At that point, an endotracheal tube or a laryngeal mask had not yet been placed to obtain an accurate measurement of the end-tidal of sevoflurane. Although a change in Fe-S may parallel end-tidal sevoflurane, the anesthesia mask used before the tracheal intubation introduces a mixing chamber that dilutes the concentration of sevoflurane before the gas sample is taken at the anesthesia circuit (11).

In conclusion, this study demonstrated that aging significantly prolongs the onset time of inhaled anesthesia. Although inhaled induction could be well suited for a smooth and fast induction in a young patient, the clinician should be aware of this effect of age-related delay in older patients if and when inhaled anesthesia is selected.

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