Life-Threatening Thrombosis After Large Amounts of Nitrous Oxide Use

Abstract

This case report highlights the development of severe, life-threatening thrombotic complications after chronic recreational use of large quantities of nitrous oxide in a 21-year-old patient. In young patients presenting with thromboembolism and nitrous oxide abuse, swift identification of symptoms and management is critical.

Graphical abstract

History of Presentation

A 21-year-old woman, otherwise healthy, presented to the emergency department (ED) owing to a deteriorating general condition, pronounced breathlessness, dizziness, and bilateral limb paresthesia. The patient reported occasional recreational use of nitrous oxide in recent years, but over the 4 months preceding her illness, she had been using increasing amounts. In the 5-week period before the ED visit, she reported using 6 to 12 nitrous oxide canisters (amounting to approximately 600 g nitrous oxide per canister) daily. This quantity is equivalent to daily nitrous oxide anesthesia of approximately 10 to 20 hours (with 50% nitrous oxide and a respiratory minute volume of 6 L). In the ED, the patient did not exhibit any focal neurological deficits, had tachycardia (130 beats/min), and required 6 L oxygen to maintain saturation of >95%. Systolic blood pressure ranged between 90 and 110 mm Hg.

Learning Objectives

• •To understand the effect of nitrous oxide on homocysteine levels and its association with thrombosis.
• •To initiate the investigation and treatment of nitrous oxide-induced thrombosis. Adopt a standard thromboembolism treatment together with vitamin B₁₂ supplementation.
• •To maintain heightened awareness for symptoms consistent with a thromboembolic event in patients with a history of chronic nitrous oxide abuse.

Past Medical History

She had a history of depressive symptoms and was on combined oral contraceptives for several years. She had no previous history of thrombosis and was a nonsmoker.

Differential Diagnosis

Pulmonary embolism was suspected. In addition to that, pneumonia, paroxysmal nocturnal hemoglobinuria, and undiagnosed cancer were considered as the primary differential diagnosis.

Investigations

electrocardiography showed signs of right ventricular strain. Computed tomography scan of the pulmonary arteries revealed saddle embolism with features of right ventricular strain (Figure 1A and 1B). Laboratory tests showed elevated P-troponin T, 50 ng/L (reference value, <15 ng/L); P-N-terminal pro b-type natriuretic peptide, 4,600 ng/L (reference value, <300 ng/L); P-homocysteine, 78 μmol/L (reference value, <15 μmol/L); and S-cobalamin, 500 pmol/L (within the reference range).

Figure 1.

CT Scans

(A) Computed tomography (CT) scan showing saddle embolism; thrombus located at the bifurcation of pulmonary trunk. (B) Right ventricular enlargement on CT scan.

On day 2 of hospitalization, the patient experienced continued confusion, confabulation, and general weakness. The neurological condition worsened with the development of speech difficulties. An urgent computed tomography of the brain with venography on day 3 revealed a fresh left-sided central cerebral infarction. An echocardiogram showed a dilated right ventricle with a thrombus mass in the right ventricle and a right-to-left shunt at the atrial level.

Magnetic resonance imaging of the brain on day 4 revealed basilar artery thrombosis (Figure 2A), as well as confirming the presence of extensive left-sided ischemic infarctions.

Figure 2.

CT Angiography

(A) CT angiography showing thrombosis at the tip of the right sided basilar artery. (B) Status post thrombectomy demonstrating circulation in the basilar and posterior cerebral arteries. Abbreviation as in Figure 1.

Laboratory workup for coagulation disorders and thrombophilia was conducted on multiple occasions. In summary, tests revealed no cardiolipin antibodies and no beta-2-glycoprotein 1 antibodies of IgG, IgM, or IgA type. Lupus anticoagulant was negative. Tests for hereditary thrombophilia including antithrombin, protein C, protein S, mutation in the FV gene (APC resistance), and polymorphism in the FII (prothrombin) gene were negative. The high P-homocysteine value rapidly decreased from 78 μmol/L to 29 μmol/L after initiation of treatment and then normalized completely. Genetic analysis of methylenetetrahydrofolate reductase (MTHFR) polymorphism was performed, and the patient was homozygous for the MTHFR 1286 A>C variant that could lead to slightly elevated homocysteine levels. Other possible causes of thrombosis such as paroxysmal nocturnal hemoglobinuria were considered and excluded. Multiple radiological examinations and blood tests did not raise any suspicions of malignancy.

Management

The patient was initially treated with low-molecular-weight heparin and oral cyanocobalamin 2 mg ×2 and admitted with preparation for thrombolysis in case of deterioration. Thrombolysis was, however, deemed contraindicated upon the discovery of cerebral infarction. The patient underwent pulmonary endovascular thrombectomy.

The patient continued to receive a heparin infusion, but despite this, in addition to the above-mentioned thrombosis, the thrombosis extended from the popliteal vein to the femoral vein in the left leg and a thrombus extending to the muscle vein from the popliteal vein in the right leg, thrombosis in the femoral artery and iliac artery in the right leg, as well as splenic and renal infarctions, were identified. Basilar artery thrombosis revealed by magnetic resonance imaging of the brain was treated with intracranial endovascular thrombectomy (Figure 2B).

The patient improved gradually, but was wheelchair bound, dysphagic and had peripheral nerve paresis. After 14 days of hospitalization, she was transferred to a neurorehabilitation center.

Discussion

We report a case of severe and life-threatening extensive thrombosis after chronic nitrous oxide abuse. There are scarce reports of thromboembolic complications after extensive nitrous oxide abuse, but the phenomenon may be under-reported.^1,2 The patient was on combined oral contraceptives, but, aside from this, no other risk factors for thromboembolic disease were found. Coagulation investigations revealed no apparent abnormalities.

Vitamin B₁₂ is essential for the function of methionine synthase, an enzyme in the methionine cycle; a process where homocysteine is converted to methionine, necessary for myelin formation.³ If methionine synthase binds oxidized vitamin B₁₂, a nonfunctioning complex is formed, and methionine synthesis stops. The interrupted methionine cycle causes an accumulation of homocysteine leading to hyperhomocysteinemia, which is typical with pronounced nitrous oxide abuse. Elevated homocysteine levels are assumed to increase the propensity for atherosclerosis and have a prothrombotic effect.³ Hereditary homocystinuria, often resulting in homocysteine levels of >100 μmol/L, is a known risk factor for both arterial and venous thromboses.⁴ Lower levels of hyperhomocysteinemia have also been suspected to be associated with an increased risk of both venous and arterial thromboembolism, although these findings have been questioned recently.⁵ A mildly elevated homocysteine level (>15 μmol/L) is quite common and may, for example, be seen in primary deficiency of vitamin B₆ and vitamin B₁₂, as well as in cases of MTHFR polymorphism. Moreover, smoking, various malignant diseases, kidney failure, hypothyroidism, diabetes, obesity, hypercholesterolemia, hypertension, and medication with statins, methotrexate, and fenofibrate can lead to altered homocysteine levels.⁶ The uncertainty regarding the association between hyperhomocysteinemia and thromboembolism might specifically relate to conditions with relatively mild homocysteine elevation.⁷ High levels (>60 μmol/L), in contrast, are usually seen only in homocystinuria or in nitrous oxide abuse.⁸ The patient was positive for MTFHR 1286 A>C, 1 of 2 known variants of reduced activity of MTFHR (the other being MTFHR 677 C>T) that can lead to elevated homocysteine levels. MTHFR polymorphism is a very common (approximately 60%-70% in the population) genetic variation, and the patient’s polymorphism has an allele frequency of 34% in the Swedish population, meaning that >10% of the population is homozygous.⁹ The association between MTHFR polymorphism and thrombosis has been strongly questioned, and currently discouraged as part of thromboembolism workup.⁹ However, one can speculate whether the risk of thromboembolic events in the setting of significantly elevated homocysteine is higher with extensive nitrous oxide abuse in the presence of an MTHFR polymorphism. The homocysteine level in our reported patient was first measured 24 hours after the ED visit and after initiation of treatment, indicating that the homocysteine level might have been much higher initially as it is known that homocysteine levels sharply decrease in the absence of nitrous oxide.¹⁰

Follow-up

The patient received continuous treatment and follow-up at the neurorehabilitation unit and anticoagulation center. Three months after the onset of illness, the patient's motor skills had improved, homocysteine levels remained normal, and no new thromboses were diagnosed.

Conclusions

Recreational use of nitrous oxide has become increasingly popular which is at least in part owing to its widespread availability, low cost, and ease of use. The Netherlands and UK have recently criminalized the sale of nitrous oxide to the public. We believe that restrictions such as these are necessary in more countries to reduce the adverse effects of nitrous oxide abuse.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.