Nitrous Oxide and the Second Gas Effect on Emergence from Anesthesia

1. Nitrous Oxide and the Second Gas Effect on Emergence from Anesthesia Molly Orr, BS, BSN, CCRN, SRNA Oakland University-Beaumont Graduate Program of Nurse Anesthesia

2. Peyton, P. J., Chao, I., Weinberg, L., Robinson, G. J. B., & Thompson, B. R. (2011). Nitrous oxide and the second gas effect on emergence from anesthesia. Anesthesiology, 114(3), 596-602. Departments of Anesthesia and Surgery, Austin Hospital, Melbourne, Australia Department of Surgery, University of Melbourne, Melbourne, Australia

3. Definition • What is second gas effect? • What do we know about it? • Why is it important?

4. Study concept • Does the elimination of N2O affect the rate of decrease in end-tidal and arterial sevofluraneconcentrations (…and thus speed emergence)? • The null hypothesis: The rapid diffusion of N2O at the end of inhalational anesthesia has no effect on the rate of reduction in end-tidal and arterial concentrations of volatile anesthetic (i.e. sevoflurane)

5. Study design • Randomized controlled study • Patients randomly assigned to experimental or control group via sealed envelope (N=20) • Control group (n=10): Gas mixture of sevo in air-oxygen • Experimental (nitrous oxide) group (n=10): Gas mixture of sevo in a 2:1 mixture of nitrous oxide-oxygen

6. Inclusion criteria • Adults (> 18 yo) capable of giving informed consent • General surgery at least 1 hour duration • Requires arterial line for hemodynamic monitoring • Arterial line samples used for gas analysis

7. Exclusion criteria • History of severe lung disease (PFT criteria) • Symptomatic ischemic heart disease • Super obesity (BMI>45) • Pregnancy • H/O severe PONV • Critically ill/immunologically compromised • Vit B12 or folate deficiency • Presence of gas-filled, space occupying lesion

8. Methods used • Premed: 1-2 mg midazolam IV • Standard monitoring + arterial line + BIS • Preoxygenated • Induction: 1.5-2.5 mg/kg propofol IV, opioids (1-2 mcg/kg fentanyl and/or morphine 0.05-0.1 mg/kg), nondepolarizing neuromuscular blocker • Endotracheal intubation, controlled ventilation 12-15 breaths/min, EtCO2 maintained 28-33 mmHg • Maintenance: Inhalational anesthetic mixture (with air-oxygen or with nitrous-oxygen) initiated and sevo concentration adjusted to maintain BIS 40-60 (N2O does not affect BIS!) • Normothermia with forced air warming device

9. Methods cont’d At conclusion of surgery: • Baseline 10 mL arterial blood sample + 1 mL sample for respiratory blood gas analysis • End-tidal gas concentrations over 20 sec recorded simultaneously with gas analyzer • Baseline hemodynamic, ventilation data, SpO2, temp and BIS numbers recorded • After baseline obtained, neuromuscular blockade reversed with 2.5 mg neostigmine and 0.4 mg glycopyrrolate, fresh gas mixture changed to 100% O2 at 9 L/min

10. Methods cont’d • Arterial blood gas samples drawn, end-tidal gas analysis, and other vital data collected at 2 min and 5 min • Patient then loudly commanded to open his or her eyes, command repeated every 30 sec until response; time from command until eye opening was noted • Extubation after standard criteria met; time to extubation noted • Final arterial blood gas sample obtained in PACU at 30 min

11. The dependent variables: Primary and Secondary Endpoints • “Primary study endpoints”: • Differences in the fraction of baseline partial pressures of sevofluranein arterial blood at 2 min and 5 min • End-tidal sevo partial pressures at 2 min and 5 min • End-tidal and arterial concentrations of CO2 were also determined at 2 min and 5 min • “Secondary study endpoints”: • BIS number comparisons between the two groups at 2, 5, and 10 min • Time to eye opening • Time to extubation

12. Statistical Analysis • Estimated 20 patients required for analysis • Two-tailed t test for unpaired data (with Bonferroni correction for multiple measurements in each patient) • Two-way ANOVA to determine whether any measured differences changed significantly over time • Best-fit curves for primary endpoints were generated using least squares method • Two-tailed t test used for secondary endpoints (after Kolmogorov-Smirnov normality testing) • P value of 0.05 or less considered statistically significant

13. Results/Conclusion • During the first 5 min after conclusion of anesthesia, the arterial partial pressure of sevo was 39% higher in the control group than in the nitrous oxide group (P<0.04), but was not found to be statistically significant at 2 min and 30 min • End-tidal differences in sevo were not significant between the two groups at 2 min and 5 min • PaCO2 decline at 2 min was significant in N2O group vs. the control group (d/t diffusion hypoxia), but no sig diff remained at 5 min • No significant diff in BIS at 2 and 5 min between two groups • Times to eye opening and extubation were significantly shorter in nitrous oxide group (8 min and 10 min, respectively) compared to control group (11 min and 13 min). [P<0.04]

14. Strengths of study • Independent variables were consistent between the two groups (e.g. age, sex, weight, operative time, baseline vent parameters, baseline VS, baseline temps and BIS numbers) • Anesthetic technique was standardized between two groups (apart from administration of nitrous oxide) • Measurements conducted in identical manner between two groups

15. Limitations of study • Small sample size (N=20, two outliers later excluded) • Variations in characteristics of people whoenrolled in study (e.g. age, end organ function, smoker vs. non-smoker, V/Q mismatching, etc.) • Confounding variables as identified by authors, such as trend toward lower HR and BP in nitrous oxide group, which correlates to 10-20% lower cardiac output and may affect alveolar anesthetic concentrations • Use of nitrous with volatile anesthetic reduces volatile anesthetic dose; has “MAC sparing” effect • No statistical significance was found in end-tidal sevo (i.e. alveolar) concentrations between the two groups

16. Overall takeaway • How can we use this in practice? • A more rapid emergence?