Pancytopenia Caused by Nitrous Oxide Toxicity: Two Cases Report

Recreational nitrous oxide (N 2 O) is increasingly common among young people, leading to attendant health disadvantages. Related complications primarily involve the hematological and neurological systems. We report two relatively uncommon cases of pancytopenia due to substantial N 2 O inhalation. One possible cause is that N 2 O toxicity results in vitamin B12 inactivation and an insufficient intake of nutrients. The patient’s symptoms partially improved after cessation of N 2 O inhalation and supplementation with vitamin B12. In conclusion, if the patients presented with unexplained bone marrow failure, a history of prolonged N 2 O exposure should be considered, which would greatly help in early diagnosis, therapy


Introduction
N 2 O is widely used for anesthesia and as an analgesic in surgery.The related complications primarily involve hematological and neurological systems.We reported two cases of pancytopenia due to substantial N 2 O inhalation, which was relatively uncommon.We hope that the report can provide a reference value for the diagnosis and treatment of long-term N 2 O exposure.
Recreational nitrous oxide (N 2 O) is a worldwide health problem with increasing incidence.A study from the 2014 Global Drug Survey confirmed N 2 O as a very common addictive drug, in particular in the UK and the US (38.6% and 29.4% lifetime prevalence) [1].
However, this overuse is more likely to develop acute (hypoxia, barotrauma) and chronic complications (peripheral nervous system complications, anemia) [2].
We reported two cases of pancytopenia due to substantial N 2 O inhalation over two months, which was uncommon in China.Written consent to publish the case report was obtained from the patients.numbness, walking disability, and fecal incontinence.The patient reported a 2-month history of smoking N 2 O.In the initial phase, she inhaled approximately three canisters weekly.When the patient tried to quit the inhalation of N 2 O, she was often depressed and developed suicidal thoughts.Subsequently, the inhalation volume increased substantially and she inhaled 5-7 canisters daily.Ten days before admission, general fatigue, numbness, walking disability and fecal incontinence occurred.She was not eating for five consecutive days because of nausea, vomiting, and anorexia before admission.In addition, no significant medical history was noted.
In the ED, physical examination revealed that the temperature was 37.8°C, tachycardic to 110 beats per minute, tachypneic to 22 breaths per minute, and the blood pressure and oxygen saturation were normal.She had multiple oral ulcers and the muscle strength of both lower limbs was grade 4/5.Initial laboratory analysis results showed pancytopenia with hemoglobin of 109g/L, red blood cell count of 3.62×10 The hemoglobin declined gradually and the lowest hemoglobin was 69 g/L on the second day of admission.The peripheral blood smear reminded the red blood cell distribution width was increased (18.6%).Further details are provided in Table-1.The cranial magnetic resonance imaging (MRI) was normal.Regrettably, electromyography (EMG) was not performed.
The patient presented with history, exam findings, and labs that all supported the major diagnosis of N 2 O exposure-induced pancytopenia.The primary treatment goal is complete abstinence from N 2 O.The patient, combined with vitamin B1 and folic acid supplements, was treated with intramuscular vitamin B12 during admission.The antibiotic was used to treat possible infections.Owing to the factor that she suffered from emotional disturbances, some anxiolytic and antidepressant medications have been administered.
The patient showed improvement in sleep, diet, numbness, and limb muscle strength after one week of treatment.The psychiatric symptoms of anxiety, decreased energy, and depressed thoughts were partially improved and she still has the psychological craving for N 2 O.

Case-2:
A 26-year-old male patient was found confused, irritable, babbling, with general fatigue on the couch by his mother, he looks decadent and sloppy.The family members and friends reported that he presented with a two-month history of inhaling N 2 O and inhaled several canisters daily.Physical examination revealed that his heart rate, respiratory rate, blood pressure, and peripheral oxygen saturation were normal.
He had redness and ulceration of the skin involving bilateral thigh tattoo areas of skin.There were many rashes on the chest wall skin.He was unable to walk and presented hypoesthesia of the skin.The muscle strength of both lower limbs was grade 3/5.Initial laboratory analysis results showed pancytopenia with hemoglobin of 100 g/L, MCV 88.8 fL, white blood cell count 2.26 × 10 9 /L, neutrophils 0.99 × 10 9 /L, and platelets 55 × 10 9 /L.Subsequently, reticulocyte count was decreased to 0.0177 × 10 12 /L.The details were provided in Table-1.The further medical examination included a negative viral screen (HIV, hepatitis B, and C), a negative autoimmune screen, and normal thyroid hormones.The test showed a serum iron of 6.5 umol/L (normal range, 10.6-36.7 umol/L), transferrin saturation of 27.3% (20-55%), transferrin of 1.12 g/L (2.5-4.3 g/L), and ferritin of 1327 ng/ml (24-336 ng/ml).Serum vitamin B12 level increased to over 1550 Pg/ml (180-914 Pg/ml).Head and neck MRI were normal and a T2weighted MRI of the cervical spine didn't show inverted V-shaped hyperintensity.
The major diagnosis of N 2 O exposure induced pancytopenia.The primary treatment included supplements of vitamin B12, vitamin B1, and folic acid.The antibiotic was used to treat skin ulcers with infection.The hematological test showed clear improvement, but he was unable to walk independently at discharge.Rehabilitation therapy was commenced in the rehabilitation hospital.Onemonth follow-up after discharge showed that the patient was emotional stability, and whose sleep and diet have been even normalized, he was able to walk without the help of crutches, but the numbness of his feet and hands remains.

Discussion and Conclusions
N 2 O is widely used for anesthesia and as an analgesic, but now it is increasingly used as a recreational drug.The N 2 0 influences hematopoiesis similar to that found in the case of vitamin B12 deficiency.N 2 O can inactivate vitamin B12/ cobalamine due to prolonged or repeated exposure, which is a crucial co-factor in metabolic pathways involved in myelin and DNA synthesis [3].The related complications primarily involve hematological and neurological systems [4].A systematic review reported on 100 patients of N 2 O exposure with a median age of 27 years.The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%).At least one hematological abnormality was retrieved in 71.7% of cases.However, this review did not report cases related to pancytopenia [4].
In our study, the cases of two patients had an identifiable history of inhalation of N 2 O and were found to be pancytopenia.Intriguing is the rarity of such reports everywhere.Three case reports of N 2 O toxicity resulting in pancytopenia have been reported previously to our knowledge.Felicity Norris et al [5] reported a female patient had non-specific neurological and gastrointestinal symptoms.She was diagnosed initially with pyelonephritis.Subsequently, she was found to be an N 2 O use disorder and started Vitamin B12 supplement daily on day six of admission.Another case reported a pregnant patient presented after prolonged N 2 O exposure with altered mental status and pancytopenia.However, there may be other reasons for pancytopenia in this patient including pregnancy, and possible viral infection [6].Vozy et al. reported a 16-year-old girl who presented with secondary bone marrow failure following an allogeneic haploidentical stem cell transplant.This was mainly because of the heavy use of N 2 O (analgesia) over a prolonged period [7].
In addition, we summarized two cases of pancytopenia in our hospital.presented with symptoms of loss of appetite.Case-1 even presented with vomiting and anorexia which were relatively infrequent and she was not eating for five consecutive days before admission, which may further deteriorate toxic effects such as anemia.Secondly, both patients showed signs of infection.Due to pancytopenia, the patients were immunosuppressed and prone to infection.They were administered with antimicrobials.Thirdly, the primary treatment was administrated with supplements of vitamin B12.The white blood cell count, neutrophils, and platelet levels of patients returned to normal and anemia was partially ameliorated before discharge.The recovery speed was much faster than damage to the spinal cord.Furthermore, they all showed typical neurological damage, mainly manifested by decreased limb muscle strength and sensory disturbance.Regrettably, electrodiagnostic testing such as EMG and nerve conduction study were not performed.One possible reason was their symptoms improved in the early stage of treatment.Summarily, N 2 O was widely used under the name 'narcotic balloon' or 'happy balloon' with its attendant health disadvantages.Physicians particularly included ED physicians, anesthesiologists and psychiatrists should be aware of the pathophysiological, symptoms, and treatment of recreational N 2 O exposure.The related complications primarily involve hematological and neurological systems.Pancytopenia is not so frequent when using N 2 O for patients with normal hematopoiesis [6].If the patients presented with unexplained bone marrow failure, a history of N 2 O use should be considered, which would greatly help in early diagnosis, therapy, and the reduction of unnecessary costs.