Propofol in a dose of 2.5 mg/kg induces anesthesia in 95% of healthy unpremedicated patients (1). Because propofol does not have a strong analgesic effect, it is often administered in combination with opioids. The induction characteristics can be augmented, and the dose of propofol can be reduced with the addition of opiate analgesics, such as fentanyl (2–4).
Nitrous oxide (N2O) has been in use for more than 150 yr. It is a good analgesic; however, it is a weak anesthetic (5) and is used mainly as an adjuvant and a gaseous vehicle for the administration of more potent volatile anesthetics. Nitrous oxide reduces the minimum alveolar concentration requirement for volatile anesthetics (6,7), decreases the need for IV anesthetics (8), and 67% N2O decreases the 50% effective concentration (EC50) of propofol during maintenance by approximately 30% (9). Nitrous oxide has not been investigated as an inhaled additional drug for the induction of anesthesia, although the ease of placement of the laryngeal mask was enhanced by using a fixed induction dose of propofol 2.5 mg/kg (10). The objective of this study was to determine whether the induction dose of propofol could be reduced when N2O was concurrently administered.
This study was approved by our hospital ethics committee, and all patients gave informed consent. A total of 117 ASA physical status I and II patients, aged 18 to 55 yr, scheduled for elective gynecological, orthopedic, or general surgical procedures under general anesthesia were recruited. Exclusion criteria included pregnancy, morbid obesity, patients at risk of aspiration of gastric contents, and relative contraindications to the use of N2O during the induction of anesthesia, such as increased intracranial pressure and bowel obstruction. No premedication was prescribed.
Patients were randomly assigned into one of three groups and were encouraged to take deep breaths via a tight-fitting face mask. A circuit breathing system was used, and exhaled carbon dioxide was removed by the soda lime. Group FN received IV 1 μg/kg fentanyl and breathed a gas mixture of 4 L/min N2O + 2 L/min O2. Group PN received IV placebo (normal saline) and breathed a gas mixture of 4 L/min N2O + 2 L/min O2. Group FO received IV 1 μg/kg fentanyl and breathed 6 L/min O2. After receiving either fentanyl or placebo, patients inhaled the gas mixture for 1 min before 10 mg of lidocaine was given IV followed by an infusion of propofol at 20 mg/min delivered via a syringe pump. We observed that propofol, in titrated doses of 10 mg every 30 s, effectively reduced the total induction dose used and provided smooth induction of anesthesia in our population. The rate of 20 mg/min was chosen to maintain uniformity in all patients in the study.
A second investigator, blinded to the drugs given, determined when patients were anesthetized. Propofol infusion was stopped when there was loss of response to verbal command (i.e., to take deep breaths or open eyes). Onset of anesthesia was confirmed with disappearance of the eyelash reflex. The induction time was taken as time from the start of propofol infusion to loss of response and the induction dose as the amount of propofol administered in that time. Common monitors were used, and the data recorded.
Because the objective of this study was to determine dosage, we did not examine the incidence of side effects associated with a slow administration of propofol. Analysis of variance was used to compare parametric data and Kruskal-Wallis test for nonparametric data. Statistical significance was determined at P < 0.05.
There were no significant differences in age, weight, ASA physical status, and sex in the three study groups (Table 1). Inhalation of 66% N2O in O2 for 1 min before the IV induction of anesthesia reduced the induction dose of propofol and decreased the time taken for the induction (P < 0.001, Table 2).
Fentanyl 1 μg/kg IV administered 1 min before the start of propofol infusion in Group FN did not significantly decrease the dose of propofol subsequently required to induce anesthesia when compared with Group PN (Table 2). In all groups, Sao2 increased from baseline values after 1 min of inhalation of the gas mixture and maintained at a median of 100% throughout the induction period (Figure 1).
Drugs currently used with propofol for the induction of anesthesia include thiopental (11), benzodiazepines (12,13), and opioids (2–4). Nitrous oxide has been a cornerstone of anesthetic practice since its first use in the 1840s. It has been used in total IV anesthesia and shown to decrease the need for IV anesthetics (8) and the EC50 of propofol (9). During the induction of anesthesia, the administration of N2O in O2 did not compromise oxygenation of patients (14), and inhalation of 70% N2O in O2 did not alter hemodynamic variables during propofol induction (15). Although placement of the laryngeal mask airway was found to be similarly easy with patients receiving fentanyl or breathing 50% N2O in O2 (10), the propofol-sparing effect with N2O has not been shown.
Slower infusion rates of propofol have been associated with a greater Sao2 at the end of the induction. However, when the infusion rate of propofol was reduced to 33.3 mg/min, breath holding occurred which caused the Sao2 to decrease (16). In this study of propofol at an infusion rate of 20 mg/min, none of the patients, including patients in Groups FN and PN who received 66% N2O in O2, desaturated at any point. The Sao2 was increased from a median baseline value of 98% to 100% (Figure 1). This shows that 66% N2O in O2 did not result in desaturation during a slow propofol induction and concurs with another study which showed that preoxygenation with mixtures of O2 and N2O did not compromise oxygenation of patients (14). The use of N2O during the induction should only be applied to patients undergoing elective surgery and when a difficult airway is not anticipated.
An attempt was made to measure inspired and end-tidal N2O in all patients. As we did not want to cause discomfort by achieving an airtight seal with the face mask in the awake patient, readings were either unobtainable or questionable in a majority of patients. After one minute of inhaling 66% N2O in O2, although some of the readings showed that the ratio of inspired:expired N2O was close to 1, the actual end-tidal value was between 45% and 55%.
The second investigator was blinded to the drugs and gas mixture administered to the patients. Although sedation might have appeared obvious in patients who received fentanyl or both fentanyl and N2O, the degree of sedation was rather variable, and all patients did receive some form of sedation (i.e., fentanyl, N2O, or both). The end point demonstrating onset of anesthesia was also clear cut. Patients were encouraged to take deep breaths, and when breathing grew shallow, irregular, or slowed down, they were reminded to take deep breaths. When there was no response, they were asked to open their eyes. If there was still no response, loss of the eyelash reflex confirmed onset of anesthesia.
When comparing different infusion rates of propofol ranging from 50 to 200 mg/min, with slower infusion rates, there was a reduction in the total dose of propofol used and an increase in the induction time (17,18). In young patients, premedicated with oral temazepam 20 mg one hour before surgery and 0.75 μg/kg fentanyl five minutes before the start of the induction of anesthesia, the slowest infusion rate that could induce anesthesia in <200 s was 50 mg/min (16). With a slower infusion rate of 33.3 mg/min, only 7 of 10 patients (or 70%) were anesthetized in <200 seconds. With an even slower infusion rate of 20 mg/min in unpremedicated patients, we found the induction time to be similarly prolonged. The induction of anesthesia within 200 seconds was achieved in only 14 of 39 patients (Group FO;Table 2). However, coadministration of 66% N2O in O2 shortened the induction time, enabling the number of patients anesthetized under 200 seconds to be increased to 35 patients (90%) each in Groups FN and PN. The upper limit of the 95% CI in patients receiving N2O was well under 200 s (Groups FN and PN, Table 2).
In young patients (i.e., 18 to 50 years of age), reducing the infusion rate of propofol for the induction not only increased the induction time significantly, but also did not appear to reduce the total dose of propofol used (16). At a propofol infusion rate of 33.3 mg/min, Peacock et al. (16) achieved a similar induction dose of 1.36 (0.28) mg/kg compared with 1.46 (0.12) mg/kg at 50 mg/min. In another study, patients (18 to 55 years of age) who were similarly premedicated, required 1.40 (0.33) mg/kg of propofol by using an infusion rate of 50 mg/min (18). With an infusion rate of 20 mg/min in a similar age group of patients, we achieved a similar induction dose of propofol (Group FO;Table 2). With regard to the induction dose, it appeared that there was little to be achieved in decreasing the propofol infusion <50 mg/min. However, inhalation of N2O resulted in a 44% reduction in the induction dose (Group FN;Table 2). Coadministration of N2O not only achieves more acceptable induction times with a slow propofol infusion, but also results in a further reduction in the total dose of propofol required when the infusion rate was reduced to 20 mg/min (Groups FN and PN;Table 2).
A propofol infusion was used in the study to accurately determine the minimum dose required to induce anesthesia. In clinical practice, this calculated dose of propofol can be administered with N2O as a slow bolus and still achieve the induction of anesthesia within a reasonable time. Although we did not study the acceptability of breathing gas mixtures of O2 and N2O during the induction period, none of the patients complained postoperatively of any unpleasantness or the prolonged induction time. In conclusion, we showed that the coadministration of N2O during the induction of anesthesia reduces the induction dose of propofol.
1. Cummings GC, Dixon J, Kay NH, et al. Dose requirements of ICI 35,868 (propofol, ‘diprivan’) in a new formulation for induction of anaesthesia. Anaesthesia 1984; 39:1168–71.
2. Ben-Shlomo I, Finger J, Bar-Av E, et al. Propofol and fentanyl act additively for induction of anaesthesia. Anaesthesia 1993; 48:111–3.
3. Lindholm P, Helbo-Hansen HS, Jensen B, et al. Effects of fentanyl or alfentanil as supplement to propofol anaesthesia for termination of pregnancy. Acta Anaesthesiol Scand 1994; 38:545–9.
4. Jakobsson J, Davidson S, Andreen M, Westgreen M. Opioid supplementation to propofol anaesthesia for outpatient abortion: a comparison between alfentanil, fentanyl and placebo. Acta Anaesthesiol Scand 1991; 35:767–70.
5. Eger EI II, Gaskey NJ. A review of the present status of nitrous oxide. AANA J 1986; 54:29–36.
6. Katoh T, Ikeda T. The minimum alveolar concentration (MAC) of sevoflurane in humans. Anesthesiol 1987; 66:301–3.
7. Saidman LJ, Eger EI. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiol 1964; 52:302–6.
8. Heath KJ, Sadler P, Winn JH, McFadzean WA. Nitrous oxide reduces the cost of intravenous anaesthesia. Eur J Anaesthesiol 1996; 13:369–72.
9. Davidson JAH, Macleod AD, Howie JC, et al. Effective concentration 50 for propofol with and without 67% nitrous oxide. Acta Anaesthesiol Scand 1993; 37:458–64.
10. Johnson GW, St John Gray H. Nitrous oxide inhalation as an adjunct to intravenous induction of general anaesthesia with propofol for day surgery. Eur J Anaesthesiol 1997; 14:295–9.
11. Naguib M, Sari-Kouzel A. Thiopentone-propofol hypnotic synergism in patients. Br J Anaesth 1991; 67:4–6.
12. McClune S, McKay AC, Wright PMC, et al. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992; 69:240–5.
13. Short TG, Chui PT. Propofol and midazolam act synergistically in combination. Br J Anaesth 1991; 67:539–45.
14. Khoo ST, Woo M, Kumar A. Preoxygenation techniques: the value of nitrous oxide. Acta Anaesthesiol Scand 1993; 37:23–5.
15. Carlier S, Van Aken H, Vandermeersch E, et al. Does nitrous oxide affect the hemodynamic effects of anesthesia induction with propofol? Anesth Analg 1989; 68:728–33.
16. Peacock JE, Spiers SPW, McLauchlan GA, et al. Infusion of propofol to identify smallest effective doses for induction of anaesthesia in young and elderly patients. Br J Anaesth 1992; 69:363–7.
17. Peacock JE, Lewis RP, Reilly CS, Nimmo WS. Effect of different rates of infusion of propofol for induction of anaesthesia in elderly patients. Br J Anaesth 1990; 65:346–52.
18. Stokes DN, Hutton P. Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics. Anesth Analg 1991; 72:578–83.