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

Department of Surgery, University of Melbourne, Melbourne, Australia 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 Collaboration between the Departments of Anesthesia and Surgery at Austin Hospital and the Department of Surgery at the University of Melbourne

Definition What is second gas effect? What do we know about it? Why is it important? Previous studies have demonstrated that when volatile agents are administered in combination with N2O-oxygen, the alveolar (and thus brain) concentrations increase more rapidly than when the volatile agent is administered with oxygen alone. This speedy delivery and onset of anesthetic gases is due to the second gas effect during induction. At the conclusion of anesthesia, the rapid elimination of N2O from the blood and tissues causes a pronounced, but transient dilution of all other alveolar gases. This is known as the Fink phenomenon, or diffusion hypoxia. With this knowledge in mind the authors sought to answer the following question…

Study concept Does the elimination of N2O affect the rate of decrease in end-tidal and arterial sevoflurane concentrations (…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) “Arguably, the diffusion or second gas effect during emergence is of more practical importance than the well-described second gas effect on anesthesia induction. An increase in alveolar and blood volatile agent partial pressure during induction can be achieved in the absence of nitrous oxide simply by “overpressure,” exploiting the concentration effect by increasing the inspired concentration. However, this result is not possible at the end of anesthesia because an inspired concentration of less than zero cannot be delivered.” (601)

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

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

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

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

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

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 Standard extubation criteria: spont respirations, clinically adequate Vt, SpO2 98% or greater

The dependent variables: Primary and Secondary Endpoints “Primary study endpoints”: Differences in the fraction of baseline partial pressures of sevoflurane in 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 Between the two groups

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

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] For final analysis, N=18. 21 patients were randomly assigned. One withdrawn from study due to health history and pulmonary complications intra-op. One outlier in each of the groups was excluded during two-tailed testing.

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

Limitations of study Small sample size (N=20, two outliers later excluded) Variations in characteristics of people who enrolled 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

Overall takeaway How can we use this in practice? A more rapid emergence? Per authors: “elimination of nitrous oxide at the end of inhalational anesthesia produces a clinically significant acceleration in the reduction of concentrations of the accompanying volatile agents, an emergence-phase form of the second gas effect. This effect may be an important contributor to the speed of emergence observed after inhalational anesthesia with nitrous oxide.” (601)