In this episode, I’ll discuss the recognition and treatment of serotonin syndrome (SS), malignant hyperthermia (MH), and neuroleptic malignant syndrome (NMS).



Muscular rigidity, significant hyperthermia, and autonomic instability are all common features of serotonin syndrome, malignant hyperthermia, and neuroleptic malignant syndrome. A thorough review of the patient’s current and recent medications is the best way to tell the difference between these 3 conditions.

Serotonin syndrome

Seretonin syndrome can result from an overdose or drug interaction involving one or more of the many drugs that increase serotonergic activity.

The Hunter Criteria is often used for the diagnosis of serotonin syndrome. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:

1. Spontaneous clonus

2. Inducible clonus PLUS agitation or diaphoresis

3. Ocular clonus PLUS agitation or diaphoresis

4. Tremor PLUS hyperreflexia

5. Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Serotonin syndrome is very similar to neuroleptic malignant syndrome. A thorough review of the patient’s current and recent medications and history of present illness is essential for differentiating between the two syndromes. SS develops over 24 hours, whereas NMS develops over a period of days. SS is accompanied by neuromuscular hyperreactivity (tremor, hyperreflexia, and myoclonus); NMS is accompanied by sluggish neuromuscular responses (rigidity and bradyreflexia).

Cases of serotonin syndrome that I’ve seen have included an opioid plus two serotonergic medications. I once encountered a young adult female in my emergency department with confusion, hyperthermia, tachycardia, tremor, hyperreflexia, and diaphoresis. She was on therapeutic doses of citalopram and hydrocodone, but had taken three cyclobenzaprine 10 mg tablets for her severe back pain. The team initially thought she was having an anticholinergic reaction from the extra cyclobenzaprine. I was able to point out that the patient was diaphoretic so anticholinergic toxicity was unlikely, and that cyclobenzaprine is also a serotonergic agent (in fact it is structurally nearly identical to amitriptyline). We gave the patient cyprohpetadine and lorazepam and she recovered quickly.

Treatment of serotonin syndrome

In addition to supportive care, benzodiazepines are given to eliminate agitation, tremor, clonus, and elevations in heart rate and blood pressure. Start with 1 or 2 mg of IV lorazepam or midazolam and titrate the dose to effect. Cyproheptadine, an anti-serotonergic antihistamine can be given as well. Give 12 mg orally or by orogastric tube as the initial adult dose.

Malignant hyperthermia

Malignant hyperthermia occurs rarely after exposure to halogenated volatile anesthetics and depolarizing muscle relaxants (succinylcholine). It’s classic presentation is increased concentrations of end-tidal carbon dioxide, rigor mortis-like muscle rigidity, tachycardia, hyperthermia, and acidosis.

The onset of MH in the postoperative period is extremely rare. Cases thought to be postoperative MH have been described as isolated rhabdomyolysis in otherwise asymptomatic patients, and there is controversy as to whether these represent MH at all.

A great resource that I have called upon many times when MH was in the differential diagnosis is the Malignant Hypethermia Association of the United States (MHAUS). At their website, mhaus.org, you can find a 24/7 hotline for use in emergency situations. Calling the hotline will put you in touch with an expert anesthesiologist within minutes to advise you in selecting the best treatment for your patient. I’ve called this hotline several times, and I’ve been impressed with the assistance given.

Treatment of malignant hyperthermia

In addition to supportive ventilator strategies, dantrolene should be given immediately to patients with MH. Dantrolene is the only known antidote for MH. It should be administered as a loading dose of 2.5 mg/kg IV, with subsequent bolus doses of 1 mg/kg IV until the signs of acute MH abate. Be prepared for the development of hyperkalemia (refer to episode 34 for the treatment of severe hyperkalemia).

Neuroleptic malignant syndrome

The slow onset of neuroleptic malignant syndrome (mental status changes occurring over one to three days) generally distinguishes it from MH or SS. NMS does not generally occur during administration of general anesthesia. NMS is defined by its association with a class of medications that block dopamine transmission and 4 distinctive findings: fever, rigidity, mental status changes, and autonomic instability.

Medications associated with NMS are the dopamine blocking agents such as neuroleptic medications (haloperidol, olanzapine, etc…) and antiemetics (metoclopramide, droperidol, proclorperazine, and promethazine). NMS is also seen in patients treated for parkinsonism in the setting of withdrawal of levodopa or dopamine agonist therapy, as well as with dose reductions and when switching from one agent to another.

Treatment of neuroleptic malignant syndrome

Aggressive supportive care in NMS is essential. It is likely that mechanical ventilation, IV fluids, antihypertensives, and benzodiazepines will be required. Maximally aggressive surface cooling should be used, including cooling blankets and axillary ice packs. The use of endovascular cooling has not been evaluated for the treatment of NMS, but if it was my family member as the patient, I’d be pushing hard for this intervention to get the patient’s temperature down.

Recommended treatments for NMS are based upon case reports and clinical experience, not upon data from clinical trials. Commonly recommended medications are dantrolene, bromocriptine, and amantadine. Their use is controversial and largely unsupported. However due to lack of other proven treatments and high morbidity and mortality of the disorder, it is likely one or more of these medications will be requested for a patient who develops NMS.

Dantrolene doses of 1 to 2.5 mg/kg IV are typically used and can be repeated to a maximum dose of 10 mg/kg/day. Efficacy includes reduction of heat production and rigidity, effects are reported within minutes of administration. The duration of treatment required is unclear, with recommendations ranging from a few to 10 days of treatment.

Bromocriptine, a dopamine agonist, is given to restore lost dopaminergic tone. Start with 2.5 mg by mouth or gastric tube every six to eight hours and titrate up to a maximum of 40 mg/day. Continue bromocriptine for 10 days after NMS is controlled and then taper slowly.

Amantadine has dopaminergic and anticholinergic effects and is used as an alternative to bromocriptine. I’ve never used it for this purpose. The starting dose is 100 mg by mouth or gastric tube and is titrated upward as needed to a maximum of 200 mg every 12 hours.

The MHAUS website also has a section for neuroleptic malignant syndrome, and there is a separate hotline that can be used to contact a clinician with expertise in NMS. I’ve used this hotline once before. It took a little longer than the MH hotline to reach the clinician, but they were very helpful with giving specific treatment recommendations.

Summary

A thorough review of current and recent medications helps to differentiate MH, SS, and NMS. Malignant hyperthermia is extremely rare in the postoperative setting, and serotonin syndrome has a faster onset and neuromuscular hyperactivity while neuroleptic malignant syndrome has a slower onset and neuromuscular hypoactivity.

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