To the Editor,

We read with great interest the article by Obeidat et al.,1 who retrospectively analyzed 148,284 patients and found that use of nitrous oxide (N2O) at any time during anesthesia was dose-dependently associated with a shorter postanesthesia care unit (PACU) length-of-stay (LOS). High-dose N2O significantly decreased patients’ PACU LOS by 9.1 min (95% confidence interval, -10.5 to -7.7), and the effect was most pronounced (38.9 min) after complex surgery with intraoperative antiemetic therapy.1 We think this is an important finding—that simple use of N2O could make a significant clinical difference.

Groups were created by dividing N2O concentration with total duration of anesthesia. The high-dose N2O concentration in this study was 39% [interquartile range (IQR), 30–47] and the low-dose concentration was 2.8% [IQR, 0.4–6.0].1 These numbers, especially the low-dose concentrations of N2O, do not make much sense to anesthesia providers who usually utilize 50–70% N2O and rarely 25–30%. Indeed, in our study,2 which was the first to specifically show the dose-response of N2O on postoperative nausea and vomiting (PONV) after inhalational anesthesia, we used 50% and 70% of inhaled N2O but not lower doses, since they are rarely used in operating rooms.

The duration of N2O administration was not provided by Obeidat et al.1 who suggested that administration of high-dose N2O for only a brief period at the end of surgery resulted in an overall lower median dose. Therefore, the authors1 could not recommend how to administer N2O. But timing, duration, and concentration of N2O administration is of crucial importance. When N2O is administered throughout the anesthetic, it increases PONV in a dose-dependent fashion,2 but if 70% N2O is administered for only 30 min, it does not increase the risk of PONV even without PONV prophylaxis, as we found in the ISONATE study3 when 70% N2O was administered at a mean (standard deviation [SD]) of 27.1 (10.1) min at the end of isoflurane anesthesia.

The analgesic effects of N2O could help reduce pain in the PACU. Unfortunately, tolerance of N2O analgesia develops quickly. Rupreht et al.4 showed in volunteers that received three hours of 60–80% N2O that significant antinociception developed within two minutes of exposure to N2O. The maximal analgesic effect was observed between 20 and 30 min of exposure but the analgesic effect gradually decreased and was absent in all volunteers within 150 min.4 This effect was clearly shown in our two studies with N2O.2,3 When we used 0%, 50%, and 70% N2O during anesthesia with a duration > 70 min, there was no difference in mean (SD) 100-mm visual analogue scale (VAS) pain scores in first two hours postoperatively (21.6 [13.0] vs 25.4 [12.9] vs 23.9 [15.1] mm; P = 0.30) nor in postoperative meperidine consumption (6.5 [22.0] vs 7.1 [16.4] vs 10.1 [19.6] mg; P = 0.27).2 In contrast, when 70% N2O was used for about 30 min at the end of two hours of anesthesia, VAS pain scores were significantly lower in patients who received N2O (38.2 [14.6] vs 47.4 [15.2] mm; P = 0.008).3 Moreover, 18% of N2O patients (n = 7/40) were never administered any postoperative opioids but all patients without N2O (n = 42) received opioids postoperatively (P = 0.005).3 This suggests that N2O’s analgesic effects might not be dose-dependent and could last even after N2O administration is stopped.

Using 70% N2O for 30 min at the end of surgery maximizes benefit of the analgesic effect of perioperative N2O while eliminating its PONV side effects even without PONV prophylaxis. Combination of these two beneficial effects of the ISONATE technique3 should help reduce LOS in the PACU. A prospective randomized controlled study looking specifically at PACU LOS in longer and more complex surgeries would give the definitive answer.