18.3 Toxidromes, ICU Delirium, and Hypertensive Encephalopathy (03.A.2–4)
Key Takeaways
- Recognize opioid, anticholinergic, sympathomimetic, serotonin syndrome, neuroleptic malignant syndrome, baclofen withdrawal, and alcohol/benzodiazepine withdrawal by vital signs, pupils, skin, and reflex pattern — not by a urine drug screen alone.
- Serotonin syndrome is hyperreflexic with clonus; NMS is lead-pipe rigid and bradyreflexic after dopamine blockade; baclofen (especially intrathecal) withdrawal can mimic sepsis or serotonin syndrome until the pump is restored.
- SCCM PADIS 2018: screen delirium with CAM-ICU or ICDSC, prefer light sedation with propofol or dexmedetomidine over benzodiazepines in most ventilated adults, and do not use antipsychotics routinely to prevent or treat ICU delirium.
- Hypertensive encephalopathy, PRES, RCVS, and ICH overlap in headache and seizure but split on imaging and BP strategy; do not apply an ICH systolic target of 140 mmHg blindly to every high-BP brain syndrome.
- For hypertensive encephalopathy/PRES without ICH, lower MAP by about 20–25% in the first hour with a titratable agent and avoid overshoot hypoperfusion.
Toxidromes, ICU Delirium, and Hypertensive Encephalopathy
Quick Answer: Match pupils, skin, tone, and reflexes to the toxidrome. Serotonin syndrome = clonus/hyperreflexia; NMS = rigidity/bradyreflexia after dopamine antagonists; intrathecal baclofen withdrawal = fever, spasticity, pruritus until the pump is restored. PADIS: CAM-ICU or ICDSC, light non-benzodiazepine sedation, no routine antipsychotics. Hypertensive encephalopathy / PRES: drop MAP ~20–25% in the first hour, not to a random 90/60. RCVS is thunderclap plus vasoconstriction. ICH is blood on CT with its own BP evidence.
Not every unresponsive neuro-ICU patient has a primary brain lesion. Independent OpenExamPrep teaching in this section covers toxic-metabolic encephalopathies, ICU delirium, and hypertensive encephalopathy as listed among Neurocritical care diseases in the ABPN Content Specifications. This guide is not an ABIM or ABPN product.
Toxidromes that look like primary coma
| Toxidrome | Pupils / skin | Vitals | Neurologic signature | Immediate therapy |
|---|---|---|---|---|
| Opioid | Pinpoint, often diaphoretic or just pale | Hypoventilation, bradycardia | Coma, low tone | Naloxone, airway |
| Anticholinergic | Mydriasis, dry flushed skin, dry mouth, urinary retention | Tachycardia, fever | Agitated delirium, picking, decreased bowel sounds | Physostigmine in selected pure cases; benzos for agitation; never as a “coma cocktail” substitute for glucose |
| Sympathomimetic (cocaine, amphetamine) | Mydriasis, diaphoretic | Hypertension, tachycardia, hyperthermia | Agitation, seizures, stroke/ICH risk | Benzodiazepines, cooling, BP control; avoid pure β-blockade in cocaine |
| Sedative-hypnotic / alcohol intoxication | Midsize or small, not classic pinpoint | Hypoventilation | Coma, nystagmus | Airway; not naloxone unless co-ingestion |
| Serotonin syndrome | Mydriasis, diaphoretic | Tachycardia, hyperthermia | Hyperreflexia, inducible or spontaneous clonus, especially lower limbs | Stop serotonergic drugs; benzos; cyproheptadine; cooling |
| NMS | Variable | Fever, autonomic instability | Lead-pipe rigidity, bradyreflexia, slower onset (days) | Stop dopamine antagonists; bromocriptine / dantrolene in severe cases; ICU support |
| Baclofen withdrawal (esp. intrathecal pump failure) | Often diaphoretic | Fever, hypertension, tachycardia | Rebound spasticity, seizures, pruritus; looks like sepsis or serotonin syndrome | Restore baclofen (enteral and/or IT); benzos; do not treat as infection alone |
| Alcohol / benzo withdrawal | Mydriasis, diaphoretic | Tachycardia, hypertension | Tremor, agitation, seizures, delirium tremens | Benzodiazepines (or phenobarbital adjunct); thiamine |
Hunter criteria for serotonin syndrome (in a patient on a serotonergic agent) include spontaneous clonus; inducible clonus plus agitation or diaphoresis; ocular clonus plus agitation or diaphoresis; tremor plus hyperreflexia; or hypertonia plus temperature >38 °C plus ocular or inducible clonus. That clonus/hyperreflexia split from NMS is the examination discriminator. NMS follows haloperidol, metoclopramide, or antipsychotic exposure (or sudden dopamine-agonist withdrawal in Parkinson disease) over days, with high CK and rigidity without the clonus show.
Intrathecal baclofen withdrawal is a neurocritical care original. A pump that runs dry, a catheter fracture, or a missed refill produces life-threatening hyperthermia and rigidity. Give baclofen back by the route that works and support the airway. Baclofen overdose is the opposite: hypotonic coma, hypothermia, and areflexia — do not reverse a pump for that picture.
Alcohol withdrawal seizures cluster at about 12–48 hours; delirium tremens at about 48–96 hours (later if benzodiazepines were on board). Benzodiazepines are first-line. Antipsychotics treat hallucinations but do not raise the seizure threshold. Benzodiazepine withdrawal can be delayed days after a long-acting agent stops and can last longer than alcohol withdrawal.
ICU delirium: PADIS, not a haloperidol standing order
Delirium is an acute disturbance of attention and awareness that fluctuates. Hypoactive delirium is easy to miss and is associated with worse cognition and longer stays. The 2018 SCCM PADIS guidelines (Pain, Agitation/sedation, Delirium, Immobility, Sleep) tell you to routinely screen with a validated tool: CAM-ICU (Confusion Assessment Method for the ICU) or ICDSC (Intensive Care Delirium Screening Checklist), after a sedation score such as RASS. CAM-ICU requires acute/fluctuating change, inattention, and either disorganized thinking or an altered level of consciousness.
Prevention is the ABCDEF bundle: assess/treat pain, both SAT and SBT, choice of sedation, delirium monitoring, early mobility, family engagement. For most ventilated adults, PADIS suggests light sedation and propofol or dexmedetomidine rather than benzodiazepines. Use dexmedetomidine when agitation is blocking a wean. Do not routinely give typical or atypical antipsychotics to prevent delirium, and PADIS does not support antipsychotics as routine treatment of ICU delirium (they remain reasonable for dangerous agitation after non-drug measures and for specific psychiatric indications). Benzodiazepines stay indicated for alcohol/benzo withdrawal and some seizure indications — that is not a contradiction of “avoid benzos as default sedation.”
Fix the reversible causes: hypoxia, shock, infection, sodium, glucose, urine retention, restraint, sleep disruption, and the medication list (anticholinergics, extra benzos, high-dose opioids). A “new coma” that is actually hypoactive delirium plus residual midazolam is an exam favorite.
Hypertensive encephalopathy, PRES, RCVS, and ICH
These four share headache, seizure, and high blood pressure in some patients. They are not interchangeable.
Hypertensive encephalopathy is acute cerebral hyperperfusion when BP exceeds the upper limit of autoregulation (shifted even higher in chronic hypertension). Papilledema may be present. CT may be near-normal or show edema. Treat as a hypertensive emergency: ICU, arterial-line-level monitoring, titratable nicardipine, clevidipine, or labetalol. Lower MAP by about 20–25% in the first hour, then toward roughly 160/100 mmHg over the next 2–6 hours, then toward baseline over 24–48 hours. Overshoot — a crash from 230 systolic to 110 — causes watershed ischemia in a brain whose autoregulatory floor has moved up. Nitroglycerin is a poor choice when ICP physiology matters because venodilation can raise cerebral blood volume.
Posterior reversible encephalopathy syndrome (PRES) is vasogenic edema, classically parieto-occipital T2/FLAIR hyperintensity with increased ADC (vasogenic, not cytotoxic), though atypical frontal, brainstem, and cerebellar patterns exist. Triggers: abrupt hypertension, eclampsia, calcineurin inhibitors, some chemotherapies, autoimmune disease. Treatment is the cause plus the same controlled BP reduction — not a malignant-MCA craniectomy reflex and not high-dose steroids as if it were ADEM unless an inflammatory mimic is proven.
Reversible cerebral vasoconstriction syndrome (RCVS) presents with thunderclap headache, often recurrent over days, sometimes after vasoconstrictive drugs or postpartum. Angiography shows segmental vasoconstriction that reverses in about 3 months. Convexity SAH, PRES-overlap edema, and rarely infarction occur. Imaging of vessels (CTA/MRA/DSA) is the discriminator from isolated PRES. Nimodipine is commonly used; avoid further vasoconstrictors (triptans, binge sympathomimetics).
Intracerebral hemorrhage is blood on CT. BP care follows ICH evidence (INTERACT2, ATACH-2, AHA/ASA 2022 ICH guidance): uncontrolled hypertension promotes hematoma growth; intensive targets below about 130 mmHg systolic in ATACH-2 increased renal adverse events. For many mild-to-moderate ICH patients with SBP 150–220 mmHg, lowering toward 140 mmHg is a studied range — that is not the same order set as “drop MAP 25%” for encephalopathy without a hematoma, and it is not a license to overshoot to 90 mmHg systolic.
Worked stems
A transplant recipient on tacrolimus has seizures, BP 190/110, and posterior T2 hyperintensity with high ADC. Think PRES; lower BP in a 25% first-hour fashion and call the transplant team about the calcineurin inhibitor — not hypertonic saline as if this were cytotoxic MCA edema.
A patient with an IT baclofen pump is febrile, rigid, and delirious. Cultures are pending. The first disease-specific move is restore baclofen and inspect the pump, not “culture and wait” as the only plan.
Exam traps
Calling NMS serotonin syndrome because of fever. Using CAM-ICU never and calling all agitation “ICU psychosis” treated with scheduled haloperidol. Dropping SBP from 240 to 90 in hypertensive encephalopathy. Treating RCVS thunderclap as migraine with a triptan. Applying ICH 140 targets to PRES without blood, or ICH patients to 90 mmHg “to protect the brain.” Independent practice at /practice/abim-neurocritical-care should mix these four vascular-looking encephalopathies.
Which pairing best separates serotonin syndrome from neuroleptic malignant syndrome?
A patient with an intrathecal baclofen pump develops high fever, rebound spasticity, pruritus, and delirium. What is the priority besides ABCs?
According to SCCM PADIS 2018-style ICU practice, which delirium plan is most appropriate in a ventilated adult without alcohol withdrawal?
SBP is 230 mmHg with headache, confusion, and no hemorrhage on CT. MRI shows posterior T2 hyperintensity with increased ADC. Which BP plan is most appropriate?