A serotonergic collision on a respiratory ward
A 61-year-old retired teacher with osteoarthritis and no psychiatric history is admitted with community-acquired pneumonia. He has taken sertraline 100 mg each morning for six years after a depressive episode and tramadol 200 mg daily in divided doses; both are continued on admission. Because of a suspected resistant organism the medical team adds linezolid 600 mg twice daily. On the third day the nurses report that he is restless, sweating profusely, and 'talking nonsense'. Temperature 38.4 °C, pulse 118 regular, BP 168/94, respiratory rate 22, saturation 95% on air. He is agitated, with dilated pupils, a coarse tremor of the outstretched arms, symmetrical hyperreflexia at the knees and ankles, and sustained ankle clonus; bowel sounds are hyperactive with two loose stools. There is no neck stiffness and the chest is resolving. Creatine kinase 380 U/L, white cell count 11.2, sodium 136, C-reactive protein falling. He keeps pulling out his cannula.
1. What is the most likely diagnosis, and which clinical features let you separate it from the alternatives?
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Diagnosis: serotonin toxicity (serotonin syndrome) precipitated by the combination of sertraline, tramadol and linezolid. Linezolid is a reversible, non-selective monoamine oxidase inhibitor, so adding it to two serotonergic drugs is a textbook triple interaction; the timing (within 72 hours) fits.
Features that do the discriminating work
- Neuromuscular: inducible and sustained clonus and symmetrical hyperreflexia, especially in the legs - the hallmark. Tremor and myoclonus may coexist.
- Autonomic: fever (usually <38.5 °C unless severe), tachycardia, hypertension, diaphoresis, mydriasis, diarrhoea.
- Mental state: agitation, confusion, insomnia - not a true psychosis.
Against the alternatives
- Neuroleptic malignant syndrome: lead-pipe rigidity, hyporeflexia, bradykinetic confusion, CK usually in the thousands, onset over days after a dopamine antagonist. Here there is clonus and hyperreflexia, no rigidity, and a modest CK.
- Anticholinergic toxicity: dry flushed skin, absent bowel sounds, urinary retention, normal reflexes and no clonus.
- Alcohol withdrawal: tremor and hallucinosis but not clonus, mydriasis and hyperreflexia together; take a collateral drinking history.
- Sepsis and delirium: the chest is improving and CRP is falling, but infection should still be excluded rather than assumed.
- Malignant hyperthermia and encephalitis: no anaesthetic exposure; no meningism, focal signs or seizure.
The Hunter criteria are satisfied by spontaneous or inducible clonus plus agitation and diaphoresis in a patient taking a serotonergic agent.
2. Outline your management in the first 24 hours, including what must be stopped and which drugs you would avoid.
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Stop the offending agents immediately. Sertraline, tramadol and linezolid all go. Contact microbiology for an alternative antibiotic covering the pneumonia; discuss the MAOI effect of linezolid explicitly, because it will not wash out for days after stopping.
Supportive care is the main treatment
- Quiet, low-stimulation environment with continuous observation; avoid physical restraint, which raises temperature and CK and can cause rhabdomyolysis.
- Intravenous fluids to maintain urine output; correct electrolytes.
- Benzodiazepines (e.g. diazepam 5–10 mg orally or IV, repeated) for agitation, tremor and autonomic overactivity; they are first-line and reduce hyperthermia.
- Active cooling if temperature exceeds 38.5 °C; paracetamol alone is inadequate.
- Monitor CK, renal function, coagulation and ECG (QT) at least daily; watch for rhabdomyolysis, disseminated intravascular coagulation and acute kidney injury.
Serotonin antagonist. If benzodiazepines and supportive care do not control the syndrome, give cyproheptadine (5-HT2A antagonist), typically 12 mg then 2 mg every 2 hours up to about 32 mg/day, by nasogastric tube if necessary.
Avoid. Antipsychotics (dopamine blockade worsens the picture, and chlorpromazine adds anticholinergic and hypotensive risk), and never restart a serotonergic combination without checking interactions. Escalate to high-dependency care for temperature above 38.5 °C, rising CK, rigidity, seizures or falling consciousness. Recovery is usually within 24–72 hours of withdrawal once the MAOI effect has passed, but he must not be discharged on the same combination.
3. Three days later, still on the ward, he develops lead-pipe rigidity, hyporeflexia, fever of 39.8 °C, labile blood pressure, sweating and confusion, with CK 8000 U/L, after haloperidol was started for agitation. How does this change your diagnosis and plan?
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Diagnosis: neuroleptic malignant syndrome. The discriminating features are the reverse of before - generalised lead-pipe rigidity, hyporeflexia rather than clonus, fever above 39 °C, autonomic instability with labile blood pressure, fluctuating consciousness, a CK in the thousands, and onset over 1–3 days after a dopamine antagonist. It is a clinical diagnosis; CK and white cell count support it but do not define it. Exclude sepsis, heat stroke and a recurrence of serotonin toxicity (tramadol and linezolid should already have been stopped, and clonus was previously present).
Immediate actions
- Stop haloperidol and any other dopamine antagonist, including antiemetics such as metoclopramide.
- Transfer to a high-dependency setting: cooling, intravenous fluids, monitoring of CK, potassium, renal function and coagulation (rhabdomyolysis and acute kidney injury are the killers).
- Treat with dantrolene 1–2.5 mg/kg IV repeated to a total of about 10 mg/kg/day, and/or bromocriptine 2.5 mg orally two to three times daily, titrated; evidence is observational but these are standard.
- Benzodiazepines for agitation; thromboprophylaxis; broad-spectrum sepsis cover until cultures are back.
If refractory. Electroconvulsive therapy is effective for NMS that does not respond to drug treatment, particularly with persistent hyperthermia or marked rigidity.
After recovery. Wait at least two weeks after resolution before considering any antipsychotic, reintroduce only a low-potency agent at a low dose with close monitoring, and document NMS prominently in the record. Review why he became agitated in the first place - delirium from the pneumonia or the interaction - rather than treating the agitation reflexively.