Pulmonary embolus associated with a rare provoking factor: recreational nitrous oxide use
- Aroon Bhardwaj Shah and
- Sindhu Bhaarrati Naidu
- Respiratory, Barts Health NHS Trust, London, UK
- Correspondence to Dr Aroon Bhardwaj Shah; aroon.bhardwajshah@nhs.net
Abstract
Pulmonary embolism (PE) is a common acute presentation which may be provoked by multiple factors. We present the unique case of a young man with no underlying health conditions who was diagnosed with bilateral PE which we believe was provoked by chronic use of nitrous oxide (NO), a potentially under-recognised risk factor for PE. NO is a substance that is commonly used recreationally, particularly among young adults in the UK. It has been shown to increase serum homocysteine levels which may create a prothrombotic state.
Our patient had raised serum homocysteine levels on admission. He was anticoagulated and discharged with advice to stop nitrous oxide use. We recommend asking patients about recreational drug use when screening for provoking factors for PE so as to offer appropriate treatment and counselling.
Background
Pulmonary embolism (PE) is a common acute cardiovascular presentation with a UK annual incidence estimated at 34.2 per 100 000 and an estimated mortality rate of 22.6%.1 It also presents a significant economic burden with one European study noting that 27.8% of patients had not returned to work 1 year later.2
PE may be provoked or unprovoked.3 British Thoracic Society guidelines recommend looking for any underlying causes of PE, particularly in those who are under 50 years old, to determine duration of anticoagulation and prevent future thrombotic events.4 PE may also be the first presentation of an underlying pathology such as malignancy and identifying such possible provoking factors is an important part of management.
One possible provoking factor is nitrous oxide (NO). Alongside its medical uses, NO is also used recreationally owing to its hallucinogenic and euphoric effects. While the sale of NO as an intoxicant is now illegal, it remains easy to purchase and is now the second most prevalent drug abused among young adults aged 16–24.5 Regular recreational NO use has many documented harms, including neurological deficits.6 This is likely due to the oxidation of B12 into an inactive form.6 7 This may also lead to a prothrombotic state by inhibiting methionine synthase and thus increasing serum homocysteine levels.8
We present the case of a young man where chronic recreational NO use led to a prothrombotic state and presentation with PE to highlight an under-diagnosed provoking factor.
Case presentation
A man in his 20s with no known medical conditions presented to the emergency department following a syncopal episode at home. Prior to the collapse, he had been feeling feverish and had a mild cough and light-headedness. He was walking down the stairs when he lost consciousness for less than 1 min. He felt breathless thereafter. He reported no chest pain and had otherwise been well. There was no relevant family history. He initially denied smoking any substances including tobacco and use of alcohol or recreational drugs. He felt that the episode was due to poor oral intake since fasting for a religious festival.
His observations were: pulse rate 118 beats per minute, blood pressure 117/80 mm Hg, respiratory rate 24 breaths per minute, oxygen saturation 95% on room air and temperature 36.4°C. His examination was otherwise unremarkable.
A CT pulmonary angiogram (CTPA) confirmed bilateral PE (see figure 1). On the advice of the haematology team, further tests were performed but did not reveal any provoking factors (see table 1). The patient reported no family history of thrombotic disorders or further risk factors for thromboembolic events such as recent immobility.
Image from the CT pulmonary angiogram (CTPA) performed on 18 May 2021 demonstrating filling defects in the lobar branches of the pulmonary arteries (arrows indicate the grey areas which are filling defects).
Investigations performed to look into potential risk factors for pulmonary embolism
| Investigations | Results |
|---|---|
| Plasma homocysteine levels | 92.2 µg/L |
| Alpha fetoprotein (AFP) | <2000 units/L |
| CA 15–3 | 12 700 units/L |
| CA 19-9 | <9000 units/L |
| Carcinoembroynic antigen (CEA) | <1 µg/L |
| Prostate-specific antigen (PSA) | 0.48 µg/L |
| Cardiolipin antibody screen | Negative |
| Lupus anticoagulant | Weakly positive by dilute APTT only (patient on Xa inhibitor) |
| Protein C function | 58 IU/dL |
| Factor V Leiden | Homozygous wildtype |
| Prothrombin 2010 gene screen | Homozygous wildtype |
| Antithrombin III activity | 104 IU/dL |
| Ultrasound scan abdomen pelvis testes | Gall bladder polyps, otherwise unremarkable |
Investigations
Of note, his admission blood tests showed an elevated D-dimer of 14.13 (>0.5) and raised troponin of 72 ng/L (>14). His admission ECG demonstrated a sinus tachycardia with lateral T-wave inversion. A CTPA demonstrated ‘filling defects in the lobar branches of the pulmonary arteries on both sides, suggestive of bilateral pulmonary emboli’ (see figure 1). There was no evidence of right ventricular strain on echocardiogram. His COVID-19 test was negative.
On the advice of the haematology team, tumour markers such as alpha-fetoprotein (AFP) test and an ultrasound of his abdomen, pelvis and testes were performed to look for an occult cancer. No such provoking factor was found (see table 1). A prothrombotic workup was also performed (see table 1). The only finding of note was his lupus anticoagulant was weakly positive via dilute APTT only. This test result was likely due to the patient being on a factor Xa inhibitor which can cause false positives.9 10
His serum homocysteine level was markedly raised at 92.2 umol/L (>15 umol/L).
Treatment
The patient was initially treated with treatment dose low molecular weight heparin and remained cardiovascularly stable throughout. He was subsequently switched to a direct oral anticoagulant.
Outcome and follow-up
The patient was counselled on the potential dangers of further NO abuse prior to discharge and was offered the support of drug and alcohol services to stop.
Three months later, the patient reported no residual symptoms including breathlessness or chest pain. He also reported that he had successfully stopped using NO. He has been reviewed by the anticoagulation team and will remain on a direct oral anticoagulant until his next appointment in the haematology clinic. The biochemistry team also advised monitoring of homocysteine levels could be considered; in this case homocysteine levels were not measured at follow-up.
Discussion
Here we have presented the case of a young man with confirmed chronic recreational NO use and high homocysteine levels, thus leading to a prothrombotic state and the development of bilateral PE.
The association between high homocysteine levels and the propensity to clot has been demonstrated.8 11–13 One meta-analysis found that treatment with vitamins such as folic acid, vitamin B6 and B12 can effectively reduce serum homocysteine levels.14 However, a randomised controlled trial in adults over 55 years old with cardiovascular risk factors found that while treatment with vitamins reduced homocysteine levels, there was no impact on the incidence of venous thromboembolic events.15 In our patient, vitamin therapy was not considered. He was instead initially treated with anticoagulation and support to stop using NO so as to reduce his homocysteine levels.
Of note, while chronic NO abuse may lead to a prothrombotic state by increasing homocysteine levels, nitric oxide is a short-acting vasodilator that has effects on smooth muscle and leads to decreased pulmonary vascular resistance.16 The European Society of Cardiology and European Respiratory Society jointly recommend its use in patients with pulmonary hypertension as the standard of care for vasoreactivity testing.17 NICE guidelines recognise nitric oxide as the main treatment in neonates with pulmonary hypertension,18 a systematic review has found it is effective in treating perioperative or postoperative pulmonary hypertension in patients undergoing cardiac or pulmonary surgery,16 and it has been found to be beneficial in many other scenarios including possibly in acute pulmonary embolism.19
The association between blood clots and chronic NO use has been previously described. We describe three reports globally of young men between the ages of 19 and 35 who developed arterial and venous thromboses after prolonged NO use. One man, who was also found to have a heterozygous factor II mutation which increases the risk of venous thromboembolic events, developed an aortic arch thrombosis, deep vein thrombosis and PE.12 Another man with multiple risk factors for thrombosis in addition to chronic recreational NO use was diagnosed with a PE.13 More recently, a man who was admitted to hospital with a 4- to 5-week history of severe peripheral neuropathy from chronic NO use has developed bilateral central PE that was attributed to both NO use and reduced mobility.20 All of these men had high homocysteine levels.
In the above cases there are other identifiable risk factors which increase the risk of thrombosis alongside chronic NO abuse. Uniquely here, we present the case of a young man with no underlying medical conditions or other prothrombotic risk factors other than chronic NO use, who was diagnosed with bilateral PE. This may provide further evidence that chronic NO use is an independent provoking factor for thrombotic events.
The current British Thoracic Society and European Society of Cardiology guidelines recommend a thorough clinical assessment to assess patients for risk factors for venous thromboembolism.4 21 Given its association with thrombosis and prevalence of use among young adults, we advocate asking young patients about recreational drug use to screen for possible provoking factors. Homocysteine levels may be tested to confirm a prothrombotic state. Patients can be counselled and supported with stopping NO use. During follow-up, homocysteine levels may be monitored to screen for ongoing NO use and thus ongoing risk for thrombosis. This may help to determine anticoagulation duration.
NO is commonly used recreationally, and healthcare professionals should sensitively screen for its use and be aware of possible complications in order to treat patients holistically.
Patient’s perspective
I was surprised to find out that I had a lung clot, this was my first hospital admission. I wasn’t aware that laughing gas could cause this and it surprised me to find it out. I thought it wouldn’t be possible for young people to get ill from it. I no longer have laughing gas because of this.
Learning points
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Recreational nitrous oxide use is common, particularly among young adults, and doctors should take a recreational drug history from their patients.
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Nitrous oxide abuse could be a provoking factor for pulmonary embolus.
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Serum homocysteine level may help to confirm current and ongoing nitrous oxide abuse.
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Patients should be counselled on the risks of ongoing nitrous oxide use.
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Patients with ongoing nitrous oxide use may benefit from prolonged anticoagulation.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to acknowledge and express our appreciation to the patient who has provided us with a unique perspective and who has kindly agreed for this to be published to contribute to medical learning.
Footnotes
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Contributors SN conceptualised presenting the case report. Both ABS and SN managed the case, acquired patient data and composed, edited and approved the final case report. ABS liaised with the patient for consent and contributory statements.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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