Neuroleptic malignant syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acute episode

1st line – stop dopamine antagonist or restart/continue dopamine agonist

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1st line –

stop dopamine antagonist or restart/continue dopamine agonist

If you suspect NMS, prioritise stopping or restarting/continuing the causative drug:[35][36]

Dopamine antagonists: discontinue the causative drug
- Dopamine antagonists commonly associated with NMS include most antipsychotics.[35] However, other dopamine antagonists/modulators that may contribute to NMS include metoclopramide, lithium, tolcapone, amantadine, and certain (particularly tricyclic) antidepressants.[1][2][3][29]
Dopamine agonists: re-start/continue the causative drug.

This list of causative drugs is not exhaustive, and you should consult your drug formulary for a complete list of drugs where NMS or NMS-like symptoms have been reported.

Practical tip

If possible, delay restarting withdrawn antipsychotic medication for at least 2 weeks following complete resolution of the NMS episode to reduce the risk of recurrence. See ‘ after resolution of NMS’ below for more information.

Plus – supportive therapy

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Plus –

supportive therapy

Treatment recommended for ALL patients in selected patient group

Ensure the patient has a patent airway and is adequately ventilated.[35]

Alert the critical care team urgently if the patient:[35]

Has moderate or severe NMS
Has severe hyperthermia (rising temperature >38.5℃ despite conventional cooling methods); severe hyperthermia is associated with a high mortality rate and requires aggressive intervention
Has compromised ventilation due to severe rigidity
Is in a coma
Develops acute renal failure or severe hyperkalaemia.

If the patient has dysphagia, consider insertion of a nasogastric tube for the administration of fluids, nutrition, and pharmacological therapy.[12]

Rehydration

Give fluids to all patients with NMS.[35] Most patients are dehydrated in the acute phase of the illness; therefore, administration of fluids and prevention of volume depletion are essential.

Aggressive hydration with intravenous fluids is recommended if the patient has more severe NMS or rhabdomyolysis.[35] Specific fluid management for rhabdomyolysis is covered under Management of rhabdomyolysis below.
Ensure the patient is adequately perfused and aim for a urine output of 0.5 mL/kg/hour, as long as rhabdomyolysis is not present.[35]

Cooling

Use physical cooling measures; antipyretics such as paracetamol or ibuprofen do not appear to be effective in NMS.[57] Take into account the patient’s overall condition as well as their degree of hyperthermia when making a decision about the method of cooling. However, in general, if the patient has:

Mild to moderate hyperthermia:
- These patients may respond to conventional cooling methods such as:[35]
  - Mist and fan techniques
  - Ice packs to the patient’s groin and axillae
  - External cooling devices.
Severe hyperthermia (rising temperature >38.5°C despite conventional cooling methods):
- Instigate urgent additional cooling methods with regular monitoring of the patient’s core temperature (at least every 30 minutes), in line with your local protocols.
- Additional cooling methods include:[35]
  - Internal or invasive measures such as cold fluid lavage (such as gastric, bladder, or peritoneal) or intravascular cooling techniques
  - Ice baths (although these are rarely used in practice).

Management of rhabdomyolysis

If the patient has rhabdomyolysis (creatine kinase >5 times the upper limit of normal range):[35]

Give intravenous fluids as soon as possible to maintain a urine output of ≥1 mL/kg/hour.[35]
Monitor the patient’s fluid balance, plasma sodium and potassium, urinary pH, and for the development of metabolic acidosis.[35] Be alert to severe hyperkalaemia.[35]
Consider urine alkalinisation using sodium bicarbonate, in addition to intravenous fluids if these are insufficient, to prevent or reduce the severity of renal failure that is due to rhabdomyolysis.[35] This is not commonly used in practice as many patients with rhabdomyolysis will be referred early to critical care. If the patient is undergoing urinary alkalinisation:
- Check the patient’s urinary pH every hour, and plasma sodium and plasma potassium every 1 to 2 hours.[35]
- If needed, replace potassium intravenously to maintain the plasma potassium around 4 to 4.5 mmol/L.[35]
- Aim to increase the urine pH to >7.5.[35]
Seek urgent advice from the critical care team if the patient develops acute renal failure or severe hyperkalaemia. Haemodialysis, haemodiafiltration, or haemofiltration may be required.[35]

See Rhabdomyolysis .

Consider – benzodiazepine

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Consider –

benzodiazepine

Additional treatment recommended for SOME patients in selected patient group

Appropriate sedation, using an oral or intravenous benzodiazepine (e.g., diazepam, lorazepam), should be given if the patient is agitated or has severe hyperthermia (rising temperature >38.5℃ despite conventional cooling methods).[35][36]

In practice, other considerations for giving a benzodiazepine include the patient’s level of consciousness and their ability to tolerate treatments such as cooling.
Benzodiazepines can improve subjective distress and peripheral muscle tone.[36]

Intravenous benzodiazepines should only be given if there is access to full resuscitation equipment for the administration of basic and advanced life support.[35][58]

An oral or intravenous route is generally preferred over an intramuscular route, because regular intramuscular administration may complicate interpretation of the creatine kinase levels.[36]
- If the patient has severe hyperthermia, a benzodiazepine may be given via an infusion to help reduce muscle activity.[35]
Adverse effects include respiratory depression and/or worsening delirium.[30]

Primary options

diazepam: consult specialist for guidance on dose

lorazepam: consult specialist for guidance on dose

Consider – dopamine agonist or dantrolene

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Consider –

dopamine agonist or dantrolene

Additional treatment recommended for SOME patients in selected patient group

If the patient has more severe NMS that has not responded to supportive therapy and withdrawal of their dopamine antagonist (or continuation/restarting of their dopamine agonist) medication, consider a dopamine agonist (bromocriptine or amantadine) or dantrolene to reduce NMS-associated hyperthermia and rigidity.

In practice, if NMS has been caused by cessation of the patient’s usual dopamine agonist, an additional dopamine agonist (bromocriptine or amantadine) is not usually required, unless their usual dopamine agonist cannot be restarted/continued for any reason. See first-line treatment above ( stop dopamine antagonist or restart/continue dopamine agonist).

Always seek advice from a senior or specialist colleague before starting these drugs.

There is not enough evidence to give specific guidance on their use. However, they are used often in the treatment of NMS despite the limited evidence of their effectiveness.[24][40][41][59]

Dopamine agonists

Dopamine agonists (bromocriptine or amantadine) are preferred by some specialists over dantrolene if the NMS was caused by a hypodopaminergic state (such as withdrawal of antiparkinsonian medication).

If considering using dopamine agonists: discuss individual cases with your local poison information service.[35]
Avoid bromocriptine if the patient is agitated.[35]
Dopamine agonists are administered orally, or by a nasogastric tube in patients with dysphagia.[12][13][30]
One systematic case series analysis suggests that bromocriptine may be more effective in the treatment of severe NMS than supportive care.[60]
In practice, if the patient is being treated with bromocriptine for NMS due to a hypodopaminergic state, continue this until NMS symptoms have resolved before gradually tapering the dose.

Dantrolene

Both the UK National Poisons Information Service and the British Association for Psychopharmacology state that dantrolene is generally used if the patient has severe or rapidly progressive NMS.[35][36] It may aid resolution of NMS-associated muscular rigidity and hyperthermia.[55]

Dantrolene is given orally or intravenously, but should be used with caution if the patient has abnormal liver function tests.[35]
- Dantrolene is associated with hepatic injury, particularly if it is given at a high dose for a prolonged period.[35] Therefore, it should be stopped as soon as symptoms of NMS have resolved.
One systematic case series analysis suggests that dantrolene may be more effective in the treatment of severe NMS than supportive care.[60]
Although dantrolene is used in practice, some studies show that a combination of dantrolene with other drugs for the treatment of NMS is associated with protracted clinical recovery.[41][59]

Practical tip

Dantrolene is very difficult to administer; one member of the team should be dedicated solely to this task.

Dantrolene is usually found in the fridge in most theatre recovery suites, because it is used for malignant hyperpyrexia.

Primary options

bromocriptine: consult specialist for guidance on dose

amantadine: consult specialist for guidance on dose

dantrolene: consult specialist for guidance on dose

Consider – electroconvulsive therapy

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Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Electroconvulsive therapy (ECT) may be used if the patient has severe or refractory NMS.[36]

Case reports and one systematic case series analysis suggest that ECT may be effective in the treatment of NMS (particularly if severe), even after failed pharmacotherapy, but can often be impractical.[60][61][62][63][64]
Be aware that convulsions induced by ECT might lead to further elevation of the patient’s creatine kinase level, which in turn may contribute to worsening renal failure.[65][66]

ONGOING

after resolution of NMS

1st line – re-start any withdrawn medication

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Neuroleptic malignant syndrome

acute episode

stop dopamine antagonist or restart/continue dopamine agonist

Practical tip

supportive therapy

Rehydration

Cooling

Management of rhabdomyolysis

benzodiazepine

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

dopamine agonist or dantrolene

Dopamine agonists

Dantrolene

Practical tip

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

electroconvulsive therapy

after resolution of NMS

re-start any withdrawn medication

Neuroleptic malignant syndrome

Treatment algorithm

acute episode

stop dopamine antagonist or restart/continue dopamine agonist

Practical tip

supportive therapy

Rehydration

Cooling

Management of rhabdomyolysis

benzodiazepine

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

dopamine agonist or dantrolene

Dopamine agonists

Dantrolene

Practical tip

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

electroconvulsive therapy

after resolution of NMS

re-start any withdrawn medication