›Then 1 mg IM once weekly until there is no further improvement, commonly 6 to 12 weeks
›Then maintenance 1 mg IM every 1 to 3 months while any exposure risk or malabsorption remains
›No fixed maximum dose, as the schedule is limited by response plateau rather than a cumulative ceiling
›Cyanocobalamin alternative
›Cyanocobalamin 1 mg IM on the same loading and maintenance schedule where hydroxocobalamin is unavailable
›Avoid cyanocobalamin in coexisting tobacco amblyopia or Leber hereditary optic neuropathy
›Oral high-dose cobalamin
›Oral cyanocobalamin 1 to 2 mg daily is an option only for maintenance after neurological recovery in a reliable patient with no malabsorption
›Parenteral dosing is preferred whenever there is myelopathy, neuropathy or doubt about adherence
›Pretreatment sampling
›Ensure B12, methylmalonic acid, homocysteine, folate and full blood count were drawn before the first dose
›Do not delay the first dose for results when myelopathy is present
Haematologic support and repletion monitoring
›Support the marrow during recovery and anticipate hypokalaemia and fluid overload
›Folate and iron
›Folic acid 5 mg PO daily started only with or after cobalamin, never before
›Ferrous sulfate 200 mg PO two to three times daily if iron deficiency coexists or emerges as reticulocytosis begins
›Potassium monitoring
›Measure potassium at baseline and at least daily for the first 3 to 5 days of repletion
›Brisk erythropoiesis drives potassium into new cells and can cause life-threatening hypokalaemia
›Replace to keep serum potassium above 3.5 mmol per litre, orally or intravenously depending on severity
›Transfusion
›Reserve red cell transfusion for haemoglobin below 70 g per litre with symptoms, or haemodynamic compromise
›Transfuse single units slowly with reassessment, as chronic megaloblastic anemia carries a high risk of pulmonary oedema
›Furosemide 20 to 40 mg IV with each unit if there is any fluid overload concern, and avoid over-transfusion
›Expected response and its brakes
›Homocysteine falls within 1 to 2 days and methylmalonic acid within 1 to 2 weeks
›Reticulocytosis peaks at day 5 to 7 and haemoglobin normalises over about 8 weeks
›Mean corpuscular volume may rise transiently before falling
›Thrombocytosis
›Rebound thrombocytosis during recovery adds to the existing thrombotic risk
›Encourage early mobilisation and use mechanical thromboprophylaxis while mobility is limited
Thromboembolism management
›Treat confirmed thrombosis and lower the homocysteine that drives it
›Initial anticoagulation
›Low molecular weight heparin such as enoxaparin 1 mg per kg SC every 12 hours
›Reduce to 1 mg per kg once daily if creatinine clearance is below 30 ml per minute
›Use anti-factor Xa monitoring in pregnancy, extremes of body weight and renal impairment
›Omit or delay the first dose if there is active bleeding or an imminent neuraxial procedure
›Apixaban 10 mg PO twice daily for 7 days then 5 mg PO twice daily as an oral option in non-pregnant patients
›Unfractionated heparin infusion when fine control is needed
›Unfractionated heparin IV bolus 80 units per kg
›Followed by infusion 18 units per kg per hour
›Adjust by 2 to 4 units per kg per hour against activated partial thromboplastin time or anti-factor Xa every 6 hours
›Move to smaller adjustments once two consecutive levels are therapeutic to avoid oscillation
›Hold the infusion for 1 hour and reduce the rate for supratherapeutic levels
›Omit the bolus if bleeding risk is high or a fall with occult injury is possible
›Prefer this route when bleeding risk is high or an invasive procedure may be needed
›Definitive therapy for high-risk pulmonary embolism
›Systemic alteplase 100 mg IV over 2 hours, or a weight-based accelerated regimen, for haemodynamic collapse
›Weigh against recent head strike, fall or trauma from intoxication
›Homocysteine lowering
›Cobalamin and folate replacement is the specific treatment for the hyperhomocysteinaemic prothrombotic state
›Duration of anticoagulation follows standard provoked-event guidance once nitrous oxide is stopped
Supportive, neurological and substance use care
›Manage neuropathic pain, bladder dysfunction, mobility and the underlying use disorder
›Neuropathic pain
›Gabapentin 300 mg PO at night, titrated by 300 mg every 1 to 3 days in three divided doses, usual maximum 3600 mg per day
›Reduce the increment and the ceiling in renal impairment, for example a maximum near 1400 mg per day if creatinine clearance is 30 to 59 ml per minute
›Amitriptyline 10 to 25 mg PO at night as an alternative, avoiding it with significant urinary retention
›Duloxetine 30 mg PO daily increasing to 60 mg PO daily as a further option
›Bladder and bowel care
›Intermittent or indwelling catheterisation for retention with a post-void residual above 300 ml
›A bowel regimen with a stimulant laxative and a stool softener for neurogenic constipation
›Mobility and safety
›Early physiotherapy and occupational therapy for gait retraining and falls prevention
›Pressure area care and thromboprophylaxis while mobility is limited
›Psychiatric symptoms
›Psychosis and mood symptoms often improve with cobalamin over days to weeks
›Olanzapine 5 to 10 mg PO daily for persistent agitation or psychosis, with attention to the QT interval
›Substance use disorder
›Brief intervention and motivational interviewing in the department
›Referral to addiction services and treatment of comorbid depression or anxiety
›Explicit counselling that continued use carries an irreversible neurological risk
Monitoring response and managing treatment failure
›Define the expected trajectory and have a structured response when the patient does not improve
›Monitoring cadence
›Full blood count and reticulocytes at day 5 to 7, then weekly until haemoglobin normalises
›Potassium daily for 3 to 5 days, then as clinically indicated
›Repeat methylmalonic acid and homocysteine at 1 to 2 weeks to confirm the biochemical response
›Serial neurological examination documenting power, gait, sphincter function and any sensory level
›Therapy is not working
›Confirm complete abstinence, as continued covert nitrous oxide use is the most common reason for non-response
›Re-image the spine to exclude an evolving compressive lesion if signs progress
›Recheck copper and caeruloplasmin and reconsider HIV and inflammatory myelopathy
›If there is no haematologic response by 2 weeks, reconsider coexisting iron deficiency, thalassaemia, myelodysplasia or an incorrect diagnosis
›Escalate to neurology and consider repeat cerebrospinal fluid analysis and nerve conduction studies
›Setting expectations
›Neurological recovery is slow over months and may be incomplete, especially with a long history and a marked baseline deficit
›Early cessation and early replacement are the strongest predictors of good recovery