Introduction

Nitrous oxide (N2O) was first synthesised in 1772 by English scientist and philosopher Joseph Priestley [1, 2]. N2O is a stable, colourless, odourless gas at room temperature. Users derive a sensation of euphoria and dissociation from inhalation of the substance. It has a fast onset of effect and short duration of action. These properties are favoured in the use of N2O as a safe anaesthetic, especially in settings such as dentistry, obstetrics, paediatrics, and emergency. The exact mechanism of how N2O provides an analgesic and anxiolytic effect has not been well elucidated. Dopamine receptors, α-2 adrenergic receptors, opioid receptors, γ-aminobutyric acid type A (GABA-A) receptors and glutamatergic N-methyl-D-aspartic acid (NMDA) receptors have been proposed as sites of action [1, 3].

The first reported medical use of N2O was by the American dentist Horace Wells during his own tooth extraction in 1844 [4]. It is also used commercially, in the food industry as a mixing and foaming agent, and in the motor industry to increase combustion. Table 1. depicts industries where the gas is often used [8]. It is important to note however, that N2O is widely available to individuals in commercial quantities with few restrictions. Recreational users typically purchase steel bulbs, commonly referred to as ‘crackers’, ‘nangs’ or ‘whippits’, containing approximately 8 g of pressurised liquid N2O. This is equivalent to 4 L of gas under atmospheric conditions. These steel canisters are used commercially as a propellant in whipped cream dispensers and can be purchased cheaply and in abundance. N2O from the canister is discharged into a balloon then inhaled [1, 5, 6]. Some users inhale directly from the cartridge or from larger tanks hoping to achieve a more intense effect [7]. Its lack of a ‘hangover’, ability to be undetected in common drug testing kits, as well as its accessibility and affordability make N2O an increasingly popular substance.

Table 1 Commercial uses for nitrous oxide [8]
Full size table

English chemist Humphrey Davy coined the term ‘laughing gas’ in Victorian times when N2O was used by the aristocracy as a fashionable party drug. Early reports in the medical literature on N2O misuse were concerned with professionals who had ease of access to the gas, such as dentists and hospital personnel [1]. A survey in 1979 reported 20% of medical and dental students used N2O recreationally at the time [5]. It is now the fourteenth most popular recreational substance worldwide [9]. Despite the COVID-19 pandemic, it remains one of only two drugs showing increased usage globally [10].

The analgesic effect of inhaling N2O, coupled with poor recognition of complications, obscure the need for medical attention. The precise incidence and severity of injuries is unknown and is likely to be underestimated [10, 11]. The National Coronial Information System database for deaths across Australia identified 36 deaths from N2O use between 2010 and 2019 [12]. The number of calls pertaining to N2O to Australian Poisons Information Centre has increased sixfold between 2016 (n = 16) and 2020 (n = 111). There have also been increasing emergency department presentations due to N2O related injuries in Australia [6, 11]. There is often a delay in presentation and referral due to unfamiliarity with potential complications, fear of repercussions, and feelings of embarrassment [13].

Methods

A literature search was performed using PubMed, MEDLINE and Embase databases for English-language articles related to N2O and the pathophysiology, investigations, and treatment of resulting injuries. Articles were included based on keywords ‘nitrous oxide’ AND ‘cold injury’ OR ‘burn’ OR ‘frostbite’. Additional articles were retrieved from references as to identify any studies that may not have been captured in the primary literature search. A further search of the grey literature was conducted using World of Science and advanced Google search engines. As there is a limited body of publications on this topic, no restriction was placed on study design. Studies were excluded if the article pertained to other uses of N2O, for example, such as for analgesia in burns dressings or in agricultural practices.

Fig. 1
figure 1

PRISMA diagram of study method

Full size image

Results

The search using the described strategy retrieved 122 results. After exclusion and removal of duplicates, and the addition of two studies hand-searched from reference lists, 26 articles were selected for full-text review. Four reports were excluded because manuscripts could not be located. One review article was removed as it employed data from other citations. Publications in languages other than English were excluded as qualitative information was difficult to interpret from these sources. Fifteen studies were included in the final analysis. Most of the articles included are case reports, reflecting the scarcity of more sophisticated studies on this topic.

There are 54 total cases included in the analysis. There is an equal ratio of males and females in this study (n = 16), with 22 cases not reporting the patient’s sex. Across the 24 cases reporting the patient’s age, the median age was 27.5 years. Patients waited an average of 0.5 days until first presentation, with an upper limit of 22 days until seeking medical attention. Aside from injury the oral cavity, oropharynx and larynx, the most common sites of injuries are hands and digits as well as inner thighs, due to the way canisters are held by users.

Discussion

Background

Frostbite injury as a complication of inhaled N2O anaesthesia has never been reported, however there are numerous reports of deaths due to malfunctioning equipment or incorrect usage, whereby patients were unintentionally given undiluted N2O [14, 15]. N2O does not cause respiration depression, but in high concentrations, the physiological response to hypoxia is inhibited. Thus, it is usually mixed 50:50 by volume with oxygen and delivered via a two-stage pressure demand valve to mitigate the risk of asphyxiation [16]. Patients inhale through a mouthpiece or mask to prevent direct contact between the gas and skin or mucous membranes. Effects of chronic nitrous oxide exposure can be prevented using appropriate scavenging equipment, ventilation systems, regular maintenance, and safe work practices.

Historical reports of N2O-associated burn injuries are primarily accidents involving anaesthetic staff in the operating room [17, 18]. Frostbite of the hand was reported in two cases due to inadvertent leakage of liquid N2O through a cylinder valve [19]. In 1996, Svartling et al. reported a threatened airway in a medical employee who suffered a blast of N2O to the face due to broken canister tubing [20]. Previous studies have reported frostbite of the oral cavity due to other volatile substances, such as dry ice and fluorocarbons [21]. Frostbite of the oral and pharyngeal mucosa secondary to intentional inhalation of N2O is a relatively new phenomenon. Upon release from a pressurized canister, the pressure of N2O decreases and as its volume quickly expands according to Boyle’s law. This rapid expansion of gas causes a significant drop in temperature to as low as -55 ˚C, a process described by the Joule-Thomson effect. When the cold N2O encounters moist mucosa, such as in the mouth or throat, it absorbs heat and leads to tissue damage. There are also reports of frostbite on hands, face, and thighs from direct contact with N2O tanks [13, 21].

Signs and symptoms

In cases of upper aerodigestive tract frostbite, patients typically arrive in the emergency department with a sore throat, odynophagia, and dysphonia [11]. In severe cases, airway obstruction and oxygen desaturation have been observed. Flexible nasoendoscopy was used in all reported cases to assess the upper aerodigestive tract. Common findings include erythema, blistering, and oedema of the oral and pharyngeal mucosa [11, 20] (Fig. 2). Within hours to days, this can progress to pseudomembrane formation, desquamation, and necrosis [22, 23]. Bagerman et al. recommended reassessing with nasoendoscopy when further swelling is suspected and after the first 24 hours [22]. Early intubation should be considered when a compromised airway is diagnosed, or when the mechanism of injury or endoscopic view suggests an anticipated increase in oedema [21]. In two cases, patients required awake transnasal fibreoptic intubation to secure the airway [16, 18]. In severe scenarios, emergency tracheostomies may be necessary [20].

Fig. 2
figure 2

Signs and symptoms of frostbite injury at different sites

Full size image

Pathophysiology

Frostbite is sustained after prolonged exposure to temperatures below 0 ˚C. Injury from N2O inhalation can occur within seconds and can penetrate deeper tissues [11]. The mechanism causing tissue damage is similar to that seen in deep burns [11]. Like any thermal injury, the severity depends on the duration of exposure, the specific temperature of the insult, and distance from the source of hazard [17]. Chan et al. describe a case in which a 950 psi automotive N2O canister was used, which has a higher potential for barotrauma [23]. However, significant oropharyngeal frostbite has been reported even at low pressures, such as from common whipped cream dispensers at 30 psi [12].

Direct injury involves the formation of extracellular ice crystals at temperatures below 2˚ C which causes mechanical damage in cell structure [9, 18, 19, 22]. This also leads to concomitant changes in the osmotic gradient. Cell dehydration and cell death results from intracellular fluid shifts to the newly hyperosmolar extracellular space [22]. The degradation and inhibition of enzymes, protein damage, and the formation of cellular vacuoles also directly cause cell rupture [23].

Indirect effects ensue as the body seeks to restore blood flow through vasodilation, leading to repeated freeze-thaw cycles and additional tissue ischaemia [12, 20]. This triggers the release of inflammatory mediators, such as prostaglandin f2α, histamines, bradykinin, and thromboxane, which eventually lead to transient vasoconstriction, platelet aggregation, formation of thrombi, and ischaemic necrosis [12]. This is complemented by the generation of anti-tumour antibodies, leading to B cell activation and a T cell-mediated immune response. Mitochondrial damage and activation of the caspase pathway also promote apoptosis [23]. Vascular stasis and endothelial damage can contribute to increased capillary permeability, tissue oedema and necrosis as early as two hours after thawing [22]. In well-controlled settings, this principle can be employed as an effective treatment modality, for example in direct cryotherapy using N2O for oral pathologies such as mucocoeles, leukoplakia and vascular malformations [24].

Management

Securing the airway is paramount. Those experiencing airway symptoms are often treated with supplemental oxygen and nebulised adrenaline. Close monitoring and repeated examinations are advisable as progressive swelling and sloughing of the mucosa can continue to pose a risk to the airway. Prophylactic corticosteroids such as dexamethasone and methylprednisolone have been recommended to reduce airway oedema, inflammation, and tissue damage [11, 16]. An animal study demonstrated some effect of cortisone administration in suppressing cold-induced vascular changes and necrosis in rats [25]. Empirical antibiotics are also reported to counter local immunosuppression in exposed tissues. Dose and duration of therapy vary, but often utilised broad-spectrum combinations such as cefuroxime and metronidazole, or amoxicillin and clavulanic acid [11, 16]. Hydrogen peroxide gargles and topical sucralfate have also been used as adjunctive medical treatments, but are of unproven benefit [16, 18]. Most reports indicate that symptoms usually resolve by days three to five after injury, at which point patients no longer require analgesia and can tolerate oral intake [11].

Complications

Long-term sequelae of upper aerodigestive tract frostbite are sparsely published. Kuspis and Krenzelok reported lip and tongue necrosis that required resection in a patient with extended exposure to fluorinated hydrocarbons [26]. Svartling et al. described a patient requiring multiple surgical debridement of necrotic tissue. Two months later, trismus became apparent and scarring and fibrosis of the oral mucosa were confirmed on biopsy and histological examination [20]. Unintended submucosal fibrosis have also been reported in patients who received N2O cryotherapy of oral lesions [19].

Stricture of the airway is a theoretical long-term consequence, although the trachea appears to be resistant to frostbite. In animal models, the application of N2O is known to be associated with extensive damage to epithelial cells but minimal damage to fibroblasts, allowing for collagen regeneration [24]. In one study, freezing of the canine oesophagus was observed to eventually develop strictures. In contrast, freezing canine tracheas resulted in local necrosis followed by rapid regeneration of the mucosa and perichondrium, returning to normal within 28 days [22]. However, there are no in vitro reports in the literature and there remains a significant risk of upper airway obstruction due to massive mucosal and soft tissue swelling.

Systemic toxicological effects

N2O oxidises the cobalt ion in vitamin B12 from a valence state of 1 + to a valence state of 3+, effectively rendering it inactive [7, 27, 29]. Thus, patients with pre-existing vitamin B12 deficiency are particularly susceptible to injury. Vitamin B12 is essential in converting homocysteine to methionine, and 5-methyltetrahydrofolate to tetrahydrofolate. Both methionine and tetrahydrofolate are vital in the synthesis of DNA and myelin. N2O is also postulated to impair cytokines and growth factors that regulate myelin integrity [7]. Individuals with N2O abuse may exhibit neurotoxicity through myelopathy, peripheral neuropathy, and autonomic dysfunction [27].

Megaloblastic anaemia, observed in 35–50% of N2O abusers, is a natural consequence of impaired DNA synthesis affecting the high turnover of haematologic cells [7]. Just a few hours of exposure can cause megaloblastic changes in the bone marrow, and a few days of exposure can cause agranulocytosis [28]. Furthermore, deficiency of methionine synthase results in elevated homocysteine, which is associated with endothelial dysfunction, oxidative stress, increased platelet activation, thrombin production, and impaired fibrinolysis [28]. A systematic review identified fourteen users who suffered thromboembolic events in the absence of any other risk factors [9]. Other vascular complications of N2O abuse include peripheral arterial disease, ischaemic heart disease, stroke, pulmonary embolism and intestinal ischaemia [3]. Indraratna et al. reported a case of a young patient presenting with acute myocardial infarction, attributable to N2O use [29].

N2O is readily soluble and rapidly expands gas-filled cavities in the body. Pneumothoraces and pneumocardia have both been reported due to a rapid change in intraalveolar pressure after inhaling pressurised N2O [3]. Seizures and cardiac arrythmias can also result from the hypoxic effects of inhalation. Psychiatric symptoms such as psychosis or cognitive impairment can present as encephalopathy or act as a cofactor in the evolution of N2O misuse [7]. Hyperpigmentation on the dorsal surfaces of fingers, toes, and trunk has also been reported [7, 28].

The mainstay of treatment is the abstinence from N2O inhalation. Vitamin B12, folic acid, and methionine supplementation have been used in patients with systemic complications, although there is no consensus on the dosing regime, and the evidence supporting their efficacy is limited [27]. Recovery from N2O toxicity appears to be slow and incomplete despite aggressive treatment [5, 30]. Ongoing rehabilitation, psychiatric medicine expertise and social supports are instrumental to the holistic care of the patient.

Strengths and limitations

This study is the first review on inhaled N2O with a focus on frostbite injury, and allows clinicians to identify emerging trends, presentations, and outcomes. The diverse perspectives represented from different countries provide a broader insight into this condition. Limitations must be acknowledged, such as the retrospective nature of this study and the risk of missing data and selection bias. Owing to the poor reporting on substance use and recognition of symptoms, this review is largely limited to case reports and case series, which are inherently prone to bias. The reporting was not standardised across all cases and there was insufficient information, particularly regarding management and long-term sequelae. Lastly, this review was limited to English-only articles, while N2O use is also pervasive in the non-Anglophone world. Quantitative data could not be accurately reviewed, and description of qualitative data was inconsistent. The paucity of articles should not serve as a reflection of the prevalence or importance of this topic.

Conclusions

Nitrous oxide (N2O) is gaining popularity as a substance of abuse. The adverse effects of exposure to N2O, often inadequately recognised despite ubiquitous use, are primarily documented through case reports. There exists a distinct pattern of injury, affecting specific patient cohorts and anatomical areas, suggesting the potential for targeted treatment guidelines and public health interventions. This review highlights the emerging phenomenon of N2O-related frostbite and systemic complications, and challenges the common perception that N2O is harmless. A high index of suspicion and prompt treatment are of utmost importance to ensure patient safety and to mitigate long-term sequelae.