3.3 Anesthetics, Sedatives, Analgesia, and Paralytics

Airway, ICP, and EEG goals collide at the sedative pump. A TBI patient needs enough drug to stop fighting the ventilator without erasing the examination you need in two hours. A refractory status patient needs burst suppression. A recovering SAH patient needs to be awake enough to catch delayed cerebral ischemia. This section covers propofol, midazolam, dexmedetomidine, ketamine, opioids, neuropathic analgesics, and neuromuscular blockade—including why paralysis is incompatible with a valid brain-death exam.

Analgosedation as the default strategy

Pain drives tachycardia, hypertension, and ventilator dyssynchrony. Analgosedation means assess and treat pain first, then add a hypnotic only as needed, aiming for the lightest sedation that meets the physiologic goal (PADIS-style ICU practice). In a neuro ICU, exceptions are high ICP with dyssynchrony, need for neuromuscular blockade, and anesthetic-depth treatment of RSE. Use a structured pain scale in the communicative patient and behavioral pain tools in the ventilated patient.

Opioids used at the bedside include fentanyl (fast on/off, hepatic clearance, serotonin-syndrome caution with some co-meds), hydromorphone, and morphine. Morphine releases histamine and has a renally cleared active metabolite (morphine-6-glucuronide); it is a poor choice in kidney failure. Remifentanil is ultra-short and ester-metabolized, useful when you need a neurologic exam on short notice. Opioids do not treat ICP directly; hypoventilation from opioid excess raises PaCO2 and can raise ICP.

Gabapentin and pregabalin help neuropathic pain after spinal cord injury, Guillain-Barré syndrome, and perioperative nerve injury. Both are renally cleared; overdosing a patient on CRRT or fluctuating GFR causes profound sedation that is mistaken for new brainstem injury. Low-dose ketamine infusions (often 0.1–0.5 mg/kg/h) are opioid-sparing analgesics; anesthetic-range ketamine is a different intent (RSE or induction).

Propofol and PRIS

Propofol is a GABA-A agonist in lipid emulsion. Onset is seconds to a minute; offset after a short infusion is minutes, but context-sensitive half-time lengthens with prolonged infusion. It lowers ICP, lowers MAP through vasodilation and myocardial depression, and is a strong anticonvulsant that can achieve burst suppression. The emulsion provides calories (about 1.1 kcal/mL for 1% propofol) that count in the nutrition plan.

Propofol infusion syndrome (PRIS) is the high-stakes toxicity. Risk rises with high dose (commonly discussed thresholds around >4–5 mg/kg/h, or roughly >67–83 mcg/kg/min) and long duration (often >48 hours), especially with catecholamine infusions, corticosteroids, carbohydrate deprivation, critical illness, and in children. Features include unexplained anion-gap metabolic acidosis, rhabdomyolysis, hyperkalemia, hyperlipidemia, hepatomegaly, renal failure, Brugada-like electrocardiographic changes, and cardiac failure. Treatment is stop propofol, support the circulation (including extracorporeal support in refractory shock), correct electrolytes, and consider renal replacement for acidemia and potassium. Do not keep escalating propofol through worsening lactate because the EEG still shows a few spikes—change agents.

Avoid propofol as a prolonged high-dose strategy in known mitochondrial disease. Green urine is a benign cosmetic effect of phenols, not PRIS.

Midazolam, dexmedetomidine, and ketamine

Midazolam is a benzodiazepine with rapid onset. Infusions used for ICU sedation or RSE accumulate in adipose tissue. The active metabolite 1-hydroxymidazolam accumulates in renal failure; hepatic failure slows parent clearance. After days of infusion, a patient can remain comatose long after the pump is off. Tachyphylaxis is expected in status protocols, which is why doses climb and why a second anesthetic is often added. Midazolam modestly lowers MAP and can lower ICP if it stops agitation and dyssynchrony. It is not a daily wake-up-and-exam drug after a large cumulative dose.

Dexmedetomidine is a central alpha-2 agonist. It produces arousable sedation, modest analgesia, and little respiratory depression. Bradycardia and hypotension are the dose-limiting effects; bolus dosing is more arrhythmogenic than a slow infusion. Dexmedetomidine does not provide burst suppression or reliable deep sedation for high ICP or RSE. It is useful around ventilator weaning, for light sedation when you still need a neurologic exam, and in some delirium-sparing pathways. It is the wrong sole agent for a herniating patient.

Ketamine is an NMDA-receptor antagonist. At induction or RSE doses it usually supports heart rate and blood pressure (endogenous catecholamine release), causes hypersalivation, and can cause emergence phenomena. Older teaching that ketamine is forbidden in high ICP is not how ventilated neuro ICUs use it: if PaCO2 is controlled, clinically important ICP surges are uncommon, and ketamine can be ICP-neutral or helpful by supporting MAP and CPP. It is an anticonvulsant via NMDA blockade and a standard RSE adjunct when propofol or midazolam is limited by blood pressure or PRIS risk. Theoretical ICP concern still matters in a spontaneously breathing, hypoventilating patient.

Neuromuscular blockade: train-of-four, the exam, and organ failure

Nondepolarizing paralytics (vecuronium, rocuronium, cisatracurium) stop skeletal muscle, including the diaphragm. They do not stop the brain. They hide seizures, hide herniation signs, and make a neurologic examination uninterpretable. If you must paralyze for ventilator dyssynchrony, shivering during temperature management, or last-resort ICP control, start continuous EEG when the exam is gone, and use the lowest dose that achieves the goal.

Train-of-four (TOF) ulnar-nerve monitoring delivers four stimuli. Four equal twitches imply little residual blockade; zero of four is deep blockade. Many ICUs titrate to 1–2 twitches when paralysis is required. TOF at the face can underestimate blockade if facial muscles recover earlier; use a consistent site and interpret in clinical context.

Brain-death / death by neurologic criteria testing cannot proceed while a paralytic is active. Confirm recovery with TOF 4/4 (and usually a clinical twitch or adequate time plus a drug level strategy per hospital policy) before the examination and apnea test. Residual paralysis produces absent movement and absent breathing effort that mimic brain death. The same rule applies to deep sedatives: document that confounding drugs have been reduced or reversed to a degree that does not explain the findings. Details of the 2023 AAN/AAP/CNS/SCCM examination live in the brain-death chapter; the pharmacology point is that cisatracurium at 08:00 makes an 09:00 brain-death exam invalid.

Cisatracurium is eliminated by Hofmann elimination and ester hydrolysis—largely organ-independent. It is the usual choice in hepatic failure, renal failure, or both. Laudanosine, a metabolite, is a theoretical pro-convulsant at extreme accumulation. Vecuronium undergoes hepatic metabolism to an active 3-desacetyl metabolite that is renally cleared, so recovery is prolonged in liver or kidney failure. Rocuronium is intermediate; sugammadex can reverse rocuronium or vecuronium when you need an urgent exam and the drug is still on board, with usual binding and re-paralysis cautions. Succinylcholine is used for rapid sequence intubation, not for infusions; avoid it in denervating disease, burns after the first day, and rhabdomyolysis because of hyperkalemia.

Comparing agents against ICP, MAP, and seizures

Worked bedside scenarios

A 28-year-old with RSE is on propofol 80 mcg/kg/min for 60 hours. Lactate is 6 mmol/L, creatine kinase is rising, and the arterial line shows progressive shock. This is PRIS until proven otherwise: stop propofol, support MAP with catecholamines or mechanical support, and switch the EEG goal to midazolam, ketamine, or pentobarbital.

A 70-year-old with cirrhosis is paralyzed on vecuronium so the ventilator will cycle. Twelve hours after the infusion stops, TOF is 0/4 and the team is asked to declare brain death because there is no cough. Do not examine for death by neurologic criteria. Wait for recovery or use cisatracurium next time if paralysis is unavoidable, and confirm TOF 4/4.

A SAH patient on dexmedetomidine 1.4 mcg/kg/h still has ICP 32 mmHg and is coughing on the tube. Dexmedetomidine is past its job description. Deepen with propofol or a midazolam bolus, treat pain, consider a brief paralytic only with EEG, and reassess whether an EVD or osmotic bolus is the real missing therapy.

Exam traps

Using dexmedetomidine as the sole sedative for herniation. Infusing propofol at PRIS-range doses for days because it is convenient. Declaring brain death on a paralyzed patient. Choosing vecuronium in hepatorenal failure when cisatracurium is available. Treating gabapentin accumulation as a new brainstem stroke. Forgetting that opioids plus hypoventilation raise ICP through CO2. Claiming ketamine is always contraindicated in high ICP in a controlled, ventilated patient.