Complications caused by nitrous oxide in dental sedation.

The first clinical application of nitrous oxide (N2O) was in 1844, by an American dentist named Horace Wells who used it to control pain during tooth extraction. Since then, N2O has shared a 170-year history with modern dental anesthesia. N2O, an odorless and colorless gas, is very appealing as a sedative owing to its anxiolytic, analgesic, and amnestic properties, rapid onset and recovery, and, in particular, needle-free application. Numerous studies have reported that N2O can be used safely and effectively as a procedural sedation and analgesia (PSA) agent. However, N2O can lead to the irreversible inactivation of vitamin B12, which is essential for humans; although rare, this can be fatal in some patients.

INTRODUCTION

Many patients experience dental fear and anxiety (DFA), which imposes a significant level of stress in dentists who must treat such patients [123]. While there are various non-pharmacological methods for dealing with DFA, these methods may not be effective in patients with severe DFA; therefore, pharmacological approaches including sedation and general anesthesia (GA) may be unavoidable in treating some patients [4]. Although there is very little difference in the prevalence of DFA between adults and children [12], adults are able to avoid their DFA by canceling or delaying their own dental appointments, whereas children often do not have such options. Moreover, children are often unable to repress their expression of fear, which may manifest as excessive crying and/or physical struggle. These reasons led to the early adoption of sedation in pediatric dentistry. According to a survey of the members of International Association of Paediatric Dentistry (IAPD) and European Academy of Paediatric Dentistry (EAPD), the pharmacological method most often used for behavioral control was GA (52%), followed by N2O-only sedation (46%) and oral sedation (44%) [5]. The objective of this review was to investigate the properties of N2O as a PSA agent and identify the adverse events (AEs) associated with N2O.

N2O FOR PROCEDURAL SEDATION AND ANALGESIA

Since its initial introduction in 1844 by an American dentist named Horace Wells for pain control during tooth extraction, N2O has been widely used in dentistry to control the pain and distress in patients [6]. N2O is an odorless and colorless gas with anxiolytic, analgesic, and amnestic properties, along with rapid onset and recovery, which represent the ideal characteristics of a sedative [67]. Moreover, as a major advantage of using N2O is the mitigation of needle phobia [7], it is therefore commonly to achieve PSA in pediatric patients. In particular, N2O is used for simple venipuncture [8], with Pasarón and colleagues [9] reporting that 98% of patients who underwent PSA by N2O did not even remember the injection. In other words, patients who are sedated by the inhalation of N2O through a mask are not only very receptive to being injected by a needle owing to the anxiolytic and analgesic effects of N2O (often being completely unaware of needling itself), but they may also not remember the injection. Undoubtedly, these characteristics of N2O make it a very appealing sedative for patients who have a significant phobia of needles. However, PSA with N2O alone may not provide a sufficient analgesic effect in procedures that can cause severe pain, such as fracture reduction or foreign body removal [10].

In many countries, including the US, Australia, and France, there have been reports on the safe use of N2O as a PSA agent, where it is also used in diverse areas, including dentistry, radiology, orthopedics, and the emergency department (ED) [91112131415]. Unlike Korea, N2O can be used in the US and France without a dentist, doctor, or anesthesiologist present [111416]; naturally, nurses who can perform N2O sedation are registered nurses who have completed N2O certification courses [17].

There have been many studies in France on the safety and efficacy of N2O as a PSA agent [14151819]. However, because the use of N2O in France is based on a 50% N2O/O2 premix one-bottle system [14], those studies from France were excluded in this review owing to the potential for slight differences to the two-bottle system used in Korea.

There is a risk of diffusion hypoxia after cessation of N2O [20], which may be minimized by using O2 together with N2O where 100% O2 is supplied after cessation of N2O [21]. Moreover, the N2O inhalation sedation unit most widely used today (MDM, Matrx, NY, USA) has a minimum O2 concentration setting of 25%–30% and has an O2 fail-safe system, in which the unit automatically shuts off the supply of N2O when the oxygen pressure drops below a certain preset level [22]. Although there is no specific formula or a general rule for how long 100% O2 should be supplied after cessation of N2O, longer sedation times typically requires a longer time to remove the sedative effect [22]. Some studies have reported no difference in recovery under room air versus 100% O2 supply [23]. However, a 2010 study by Zier et al. [24] reported that three out of six atypical AEs were associated with apnea/O2 desaturation after recovery under room air when patients were supplied with 100% O2 for 2–3 minutes after cessation of N2O. Meanwhile, Malamed [22] reported that 100% O2 should be supplied for at least 3–5 minutes for the complete elimination of N2O from the body, after which the patient should be re-evaluated to determine whether additional 100% O2 should be supplied.

The most common AE associated with using PSA with N2O is vomiting [9121324]. Burnweit et al. [25] reported that preoperative fasting is a cause of nausea and vomiting. In a retrospective review of 12 years of cases from a single institution, the rate of vomiting among patients who were asked to eat something light during 2 hours before the procedure was 0.7%, which was lower than the vomiting rates found in other studies (Table 1) [9]. In the study by Babl et al. [13], which required at least 2 hours of preoperative fasting, 5.7% presented with vomiting. In Zier & Liu's study 2.2% presented with vomiting [12]. In Zier & Liu's study, four hours of preoperative fasting was required for patient who underwent N2O procedure during the first 4 months of the study; a light meal during the 4 hours before the procedure was advised for the 6 months; and no fasting-related requirement was given for the rest of the study period as the interim analysis on the first two periods revealed no difference in AE rates. In addition, this study also reported that frequency of minor AEs (MAEs) increased with longer treatment time or deeper sedation [9]. Meanwhile, Zier and Liu reported that the frequency of AEs increased with a longer duration of N2O supply [12].

Table 1

Study of adverse events of nitrous oxide/oxygen procedural sedation and analgesia

Study	Country	Total number of patients	Nitrous oxide: oxygen ratio	Serious adverse events, %	Minor adverse events, %	Vomiting, %
Babl et al. (2008) [13]	Australia	762	Up to 70:30	0.3	8.3	5.7
Zier & Liu (2011) [12]	USA	7,802	Up to 70:30	0.14	5.0	2.2
Pasarón et al. (2015) [9]	USA	1,058	Up to 60:40	0	1.8	0.7

Recently, laryngospasm was reported after PSA with only N2O/O2 [26]. As laryngospasm does not occur under minimal or moderate sedation, only when the patient is under deep sedation or light GA [22], this indicated that 70% N2O induced deep sedation, close to GA, for the patients in this case. Because drug reactions vary greatly between patients, N2O (1 MAC = 105-107, MAC: minimal alveolar concentration) may induce deep sedation in some patients, sufficient to cause laryngospasm [27]. Moreover, because dental treatments regions coincied with upper airway space, there is a high risk of airway irritation during dental treatment. Thus, reactions of a patient must be carefully observed to titrate the concentration of N2O.

In addition, other serious AEs (SAEs), including stabbing central chest pain, O2 desaturation, apnea > 15 seconds, stridor, and tonic-clonic seizure have been reported (Table 2); these SAEs occurred when a high concentration of N2O, from over 50% to nearly 70%, was used [13242628]. The 2011 survey of 311 members of IAPD and EAPD reported one case of N2O-related death, but did not give specific details [5].

Table 2

Description of serious adverse events during nitrous oxide/oxygen procedural sedation and analgesia

Study	Patient's age	Percentage of nitrous oxide	Description of serious adverse events	Notes
Babl et al. (2015) [26]	16 months	70%	Laryngospasm
Babl et al. (2008) [13]	11 years	70%	Stabbing central chest pain
	12 years	70%	Desaturation	2.5 mg Morphine sulfate IV 1 hour before PSA
Zier et al. (2010) [24]	2 years	50%	Apnea >15 seconds (on return to room air)	Trisomy 21 After cessation of N2O, 100% O2 3 min
	16 months	65–70%	Desaturation to 89% (on return to room air)	After cessation of N2O, 100% O2 2 min
	3 years	70%	Unresponsive/desaturation to 89% (On return to room air)	After cessation of N2O, 100% O2 3 min
	2 months	70%	Stridor
Zier et al. (2010) [28]	12 months	1st: 70% for 4 min	Tonic-clonic seizure for 3 min just after the 3rd administration
		2nd: 50% for 8 min
		3rd: 65%
	2 years	60% 9 min	Tonic-clonic seizure	One probable nonfebrile seizure history
				After cessation of N2O, during administration of 100% O2
	17 months	70% 4 min	Tonic-clonic seizure	Two febrile and one nonfebrile seizure history
				Familial history for febrile seizures

IV: Intravenous injection, PSA: Procedural sedation and analgesia, N2O: nitrous oxide, O2: Oxygen, min: minutes.

VITAMIN B12 INACTIVATION BY N2O

N2O may cause irreversible inactivation of vitamin B12 [29], an essential nutrient that acts as a cofactor in the folate and methionine cycles in humans [30]. However, because the human body is unable to synthesize vitamin B12, it must be obtained through the consumption of foods of animal origin [31].

Vitamin B12 deficiency may cause megaloblastic anemia in the peripheral blood and bone marrow, subacute combined degeneration (SCD) of the spinal cord, polyneuropathy, optic nerve injury, glossitis, dementia, thrombosis, and/or infertility [31323334]. In children, the possibility of Vitamin B12 deficiency should be carefully monitored as it can impair the development of the brain and the overall growth, which may lead to permanent disabilities [3536].

Vitamin B12 deficiency may be caused by various factors, including genetic factors such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, impaired vitamin B12 absorption (observed in pernicious anemia, inflammatory bowel diseases such as Crohn's disease, a history of partial/total gastrectomy or ileal resection, gastric subacidity, and the use of metformin), insufficient dietary consumption of vitamin B12 (in vegetarians/vegans, or infants breastfed by mothers with vitamin B12 deficiency), as well as repeated occupational or recreational exposure to N2O [31373839].

However, when vitamin B12 deficiency is subclinical, such patients may appear to be healthy and consequently classified as ASA class I without any suspicion; indeed, they may even have a previous history of uneventful N2O anesthesia or sedation [40]. Caution should be taken as the use of N2O on such patients may result in fatal outcomes [40].

The first case of hematological changes as a result of prolonged N2O use was a report by Goilmsen in 1955 [41]. At the time of the report, prolonged N2O use was not identified as the cause; this was subsequently determined by Lassen et al. in 1956 [42]. In this study, GA, which included the use of N2O, for the treatment of tetanus, was performed over several days and severe bone marrow depression was found 4-17 days after the use of N2O [42]. Since then, there have been numerous case reports of N2O toxicity (Table 3) [323740434445464748]. Symptoms appeared from after 2 days to even after 2 months, with the initial symptoms including symmetric paresthesia or numbness in the limbs, which gradually spread to the trunk to cause gait unsteadiness. In most patients, the injection or oral supplements of vitamin B12 may be effective to alleviate the symptoms, but sensory impairment and other sequelae may persist. In particular, N2O toxicity may be fatal in pediatric patients who are still in a developmental stage [3740].

Table 3

Summary of case studies on nitrous oxide toxicity

Study	Patient's age	Concentration and duration of exposure to N2O	Time of onset of symptoms	History or undiagnosed disease	Treatment	Consequences
Lassen et al. (1956) [42]	10 years	14 days	14th day	-	-	-
	11 years	12 days	6–10th day	-	-	-
	15 years	17–18 days	17–18th day	-	-	Mortality (on 29th day)
	53 years	16 days	16th day	-	-	Mortality (on 16th day)
Koblin and Biebuyck (1986) [43]	25 years	1st: 90 min, 1980, Mar.	2 months later	Ileal resection for Crohn's disease	Cyanocobalamin injection	Reversible
		2nd: 1982, Apr.
	58 years	90 min	6 weeks later	Pernicious anemia	Cyanocobalamin injection	Reversible
Hadzic et al. (1995) [44]	47 years	70% for 8 hours	6 weeks later	Pernicious anemia	Cobalamin injection	Reversible
Rosener and Dichgans (1996) [45]	50 years	66% for 2 hours	4 weeks later	Vegetarian diet	Cyanocobalamin injection	Reversible
McNeely et al. (2000) [37]	6 months	-	2 weeks later	Breast feeding vegetarian mother	Vitamin B12 supplementation	Developmental delay
Ilniczky et al. (2002) [32]	52 years	-	1 week later	Macrocytic, hyperchromic anemia with decreased serum levels of vitamin B12	IM injection of vitamin B12	Reversible
	57 years	-	2 months later	Borderline anemia with decreased serum levels of vitamin B12	IM injection of vitamin B12	Reversible
Selzer et al. (2003) [40]	3 months	1st: 60% for 45 min	25 days after 2nd anesthesia	MTHFR deficiency	-	Mortality (46 days after 2nd anesthesia)
		2nd: 60% for 270 min (4 days after 1st anesthesia)
Lacassie et al. (2006) [46]	52 years	1st: 50% for 200 min for	2 weeks after 1st anesthesia	Polymorphism of MTHFR	Vitamin B12 and folic acid supplementation	Reversible
		2nd: 50%, 105 min (8 weeks after 1st anesthesia)
Singer et al. (2008) [47]	27 years	-	2 months later	Pernicious anemia	IM injection of vitamin B12	Reversible
Renard et al. (2009) [48]	46 years	-	2 days later	Borderline anemia	IM injection of vitamin B12	Reversible

Min: minutes, IM: Intramuscular, MTHFR: 5,10-Methylenetetrahydrofolate Reductase.

Previously, reports on N2O toxicity have been related to GA, recreational abuse, and occupational exposure [4950515253]. However, the important factor was not whether N2O was used for GA or PSA, but the degree of exposure to N2O: that is, the concentration of N2O used and how long and often the patient was exposed to N2O were important [545556]. In addition, as mentioned above, patients with diagnosed or undiagnosed vitamin B12 deficiency may experience symptoms from a single exposure to N2O. Even in those patients with no signs of vitamin B12 deficiency, repeated occupational exposure or recreational abuse may place them at high-risk of N2O toxicity.

N2O interferes with the process of transformation from homocysteine and methionine through the inactivation of vitamin B12; consequently, it causes elevation of the plasma homocysteine concentration [57]. In 2008, Nagele et al. [58] reported that exposure to 66% N2O for over 4 hours resulted in a significant increase in postoperative plasma homocysteine concentration levels, whereas in 2013, Hakimoglu et al. [59] reported that postoperative plasma homocysteine concentration level was significantly higher when the duration of GA with 60% N2O was > 3 hours than when it was < 3 hours. Amos et al. [60] reported that megaloblastic bone-marrow change occurred in patients who underwent GA with N2O for ≥ 2 hours, which was affected more by the general condition of the patient than the length of N2O exposure. Moreover, in the deoxyuridine (dU) suppression test for the assessment of abnormalities in DNA synthesis, all 15 patients who did not undergo GA with N2O showed normal results, whereas 39 of 42 patients who underwent GA with N2O showed abnormal results, and this difference was detected for patients who were exposed to N2O for a minimum of 1 hour.

It is not simple for experts to recognize and diagnose vitamin B12 deficiency in a clinical setting [31]. However, since patients with vitamin B12 deficiency sometimes present with neurological symptoms or anemia and as over 98% of them have increased serum methylmalonic acid and total homocysteine levels, a preoperative evaluation of these parameters may be helpful for the identification of patients at risk of N2O toxicity.

Although there are differences in prevalence based on ethnicity, the number of patients with risk factors for N2O toxicity is a low proportion of the total population [61]. Indeed, relevant information often goes unmentioned in contraindications for PSA with N2O. Nevertheless, based on cases reported from time to time, this factor should not be underestimated. If screening is possible prior to PSA, the use of a suitable alternative sedative would be preferable. Moreover, if related symptoms occur after PSA with N2O, early detection and appropriate treatment may reverse such symptoms. Therefore, it is necessary to provide an introduction and warnings about possible initial symptoms to patients who may not have been screened.

CONCLUSION

Since the introduction of clinical anesthesiology, N2O has been used for sedation and analgesia, and it remains a popular option. The rate of SAEs after PSA with only N2O is low (0–0.3%), with vomiting being the most common AE. Cases of laryngospasm after a high-dose of N2O have been reported, and even a few cases of death. Furthermore, in patients who are repeatedly exposed to N2O or have vitamin B12 deficiency, various neurological symptoms may result from N2O-induced vitamin B12 inactivation. In summary, while sedation with N2O rarely presents with SAEs, further investigation on understanding of N2O-related AEs and their triggers may prove to be beneficial towards patients with greater risk.