Recommendations
Key Recommendations
If you suspect NMS, prioritise stopping or restarting/continuing the causative drug:[35][36]
Dopamine antagonists: discontinue the causative drug
Dopamine agonists: re-start/continue the causative drug.
Give supportive care, which should include:[35]
Rehydration
Use intravenous fluids if rhabdomyolysis is present or if the patient has more severe NMS.
Cooling
Sedation.
If rhabdomyolysis is present, consider urine alkalinisation and monitor the patient’s fluid balance, plasma sodium and potassium, urinary pH, and for the development of metabolic acidosis.[35] See Rhabdomyolysis.
Get urgent help from the critical care team 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 you suspect NMS, prioritise stopping or restarting/continuing the causative drug:[35][36]
Dopamine antagonists: discontinue the causative drug
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If possible, delay restarting withdrawn antipsychotic medication for at least 2 weeks following complete resolution of the NMS episode to reduce the risk of recurrence.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.
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]
Consider early referral to critical care.
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:
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.
Appropriate sedation, using an oral or intravenous benzodiazepine (e.g., diazepam or 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]
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 (e.g., bromocriptine, 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 (e.g., bromocriptine, amantadine) is not usually required, unless their usual dopamine agonist cannot be restarted/continued for any reason. See Immediate identification of causative drug above
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 (e.g., bromocriptine, 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.
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]
Seek advice from the patient’s mental health team before restarting antipsychotic medication.
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.
If feasible, avoid the antipsychotic that caused NMS, and depot formulations. Some experts recommend a second-generation antipsychotic, with lower risk of extrapyramidal adverse effects, in preference to a first-generation antipsychotic.
Always start the antipsychotic at a low dose and slowly titrate while monitoring the patient closely to assess for signs of recurrence.[24][67][68]
Manage recurrence of NMS in the same way as the initial presentation: withdrawal of dopamine antagonist (or continuation/restarting of dopamine agonist) medication, supportive therapy, and adjunctive use of pharmacological treatments if needed.
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