Propofol at the Receptor Level
1. Primary receptor target
* **Propofol is a positive allosteric modulator of the GABA-A receptor.**
* **GABA-A receptor** = ligand-gated chloride channel.
* Pentamer (usually 2 α, 2 β, 1 γ subunits).
* When **GABA** binds → channel opens → Cl⁻ influx → neuronal membrane **hyperpolarises** → decreased excitability.
---
2. Propofol’s mechanism
* Propofol binds to **β subunits** of the GABA-A receptor.
* **Low concentrations:** enhances the effect of GABA by increasing **channel opening events**.
* **Higher concentrations (induction doses):** can **directly activate** the receptor, even in the absence of GABA.
---
3. "Slowing of GABA receptor dissociation" explained
Normally:
* GABA binds → channel opens briefly → GABA dissociates (unbinds) → channel closes.
With propofol:
* Propofol **stabilises the receptor in its “open” conformation**.
* This means that **once GABA is bound, it stays bound longer** (slows dissociation).
* Result: **longer chloride channel open times** → more Cl⁻ influx → stronger neuronal inhibition.
Think of it like this:
* GABA = the **key** that opens the door.
* Propofol = the **doorman** holding the door open longer before the key slips out.
---
4. Other receptor effects (minor but clinically relevant)
* **Glycine receptors:** weak agonism → adds to inhibition.
* **NMDA receptors:** mild inhibition (less glutamate excitation).
* **Nicotinic ACh receptors:** some inhibitory action.
* Together, these extras may contribute to its **amnestic** and **immobility** properties.
---
5. Clinical implications of GABA-A action
* **Rapid onset/offset**: due to lipophilicity and redistribution.
* **Sedation/hypnosis**: cortical depression from enhanced inhibition.
* **Anticonvulsant**: suppresses epileptiform discharges.
* **Antiemetic**: exact mechanism unclear but linked to GABAergic effects in the chemoreceptor trigger zone.
* **Respiratory depression**: GABA-mediated suppression of medullary centres.
* **Cardiovascular depression**: vasodilation and decreased sympathetic tone partly from GABA-A modulation in brainstem.
Propofol — what you must own What it is (fast mental model)
* **IV hypnotic** in a 1% lipid emulsion (10 mg/mL; ~1.1 kcal/mL).
* **Primary effects:** rapid unconsciousness, strong **antiemetic**, decreases **CMRO₂/CBF/ICP**, depresses **SVR** and **myocardial contractility**, dose-dependent **apnoea**.
* **Kinetics:** onset 30–45 s; peak ~90 s; context-sensitive half-time short at brief infusions, lengthens with prolonged ICU use.
---
Practical dosing (adult)
### Induction (OR)
* **Standard haemodynamics:** 1–2 mg/kg IV (often 1–1.5 mg/kg with opioid).
* **Cardiac/low EF/AS/elderly:** 0.25–0.5 mg/kg in **small aliquots** (e.g., 20–30 mg every 30–45 s) while supporting with **norepinephrine/phenylephrine** and opioid.
* **DLT/bronchial manipulations (thoracic):** prefer deeper opioid + lidocaine ± lower propofol bolus to avoid hypotension.
### Maintenance/TIVA (anaesthesia)
* **50–200 mcg/kg/min** (3–12 mg/kg/h) titrated to response, often with **remifentanil/fentanyl**.
* For cardiac cases: anticipate **vasodilation**—keep a low-dose vasopressor ready.
### Procedural sedation
* **Bolus** 0.25–0.5 mg/kg, then **25–75 mcg/kg/min**; titrate slowly, **airway ready**.
### ICU sedation
* **Start 5–20 mcg/kg/min**, typical range **5–50 mcg/kg/min**.
* **Avoid >4 mg/kg/h (≈67 mcg/kg/min) for >24–48 h** due to **Propofol Infusion Syndrome (PRIS)** risk.
* Check **triglycerides** at baseline then q48–72 h; account for **calorie load** in TPN/feeds.
---
## Quick infusion math (10 mg/mL)
**Formula:**
mL/h = (Weight kg × Rate mcg/kg/min) ÷ 166.7
Examples (70 kg):
* 75 mcg/kg/min → **31.5 mL/h**
* 100 mcg/kg/min → **42 mL/h**
* 125 mcg/kg/min → **52.5 mL/h**
I’ve put a handy table you can keep open during shifts (weights 50–90 kg; rates 50–150 mcg/kg/min). It’s right above in your workspace.
---
## Haemodynamic + respiratory effects (what to expect & fix)
* **Hypotension (common):** ↓SVR, venodilation, mild negative inotropy.
* **Prevent:** preload optimization (small crystalloid), slow titration, start **norepinephrine** “primed” at 0.02–0.05 mcg/kg/min in fragile patients.
* **Treat:** vasopressor (phenylephrine bolus 50–100 mcg or norepi), reduce dose, consider switching to volatile or **etomidate/ketamine** for induction next time.
* **Apnoea/hypoventilation:** especially with bolus + opioid.
* **Prevent:** oxygenation, staged dosing, airway equipment ready; capnography when sedating.
* **Bradycardia:** vagotonia or co-admin drugs; atropine if symptomatic.
---
## Neuro & cardiac surgery angles
* **Neuro:** ↓ICP/CMRO₂—useful if ICP concerns (watch CPP if MAP falls).
* **Cardiac:** great for blunting sympathetic responses but **vasoplegia-prone**—use small aliquots and early vasoactive support, especially in **poor LV/RV** or severe **AS**.
---
## ICU pearls
* **Light sedation targets** (e.g., RASS −1 to 0); daily sedation holds.
* **Nutrition:** adds **~1.1 kcal/mL**—subtract from feed plan.
* **Triglycerides:** hold/adjust if >4.5–5.6 mmol/L (400–500 mg/dL) or rising fast.
* **Green/white urine** benign; **pancreatitis** rare—consider lipase if abdominal pain + hypertriglyceridaemia.
---
## Propofol Infusion Syndrome (PRIS) — must recognise
* **Risk factors:** high dose (>4 mg/kg/h), **>48 h**, catecholamines, steroids, critical illness, sepsis, young age, mitochondrial disease.
* **Features:** otherwise-unexplained **lactic acidosis**, **rhabdomyolysis/CK↑**, **hyperkalaemia**, **AKI**, **arrhythmias** (Brugada-like ECG), **cardiac failure**, hepatomegaly.
* **Actions (don’t delay):**
1. **Stop propofol immediately.**
2. Switch to **dexmedetomidine** or **midazolam** ± opioid.
3. Treat complications: fluids, bicarbonate for severe acidaemia, vasopressors/inotropes, **CRRT** for AKI/rhabdo, consider **ECMO** in refractory cardiac collapse.
4. Frequent gases, CK, K⁺, lactate, triglycerides.
---
## Dosing cautions & special populations
* **Elderly/frail/low EF/severe AS:** reduce dose by 25–50%; go slow; pressor ready.
* **Obesity:** dose induction to **LBW/AdjBW**, then titrate to effect; monitor ventilation closely.
* **Pregnancy:** crosses placenta—can cause neonatal depression at induction; generally **compatible with breastfeeding**.
* **Hepatic/renal impairment:** no formal adjustment, but **increased sensitivity**—titrate carefully.
* **Paediatrics:** avoid **prolonged ICU infusions** (historical fatal reports); peri-op use is common with appropriate monitoring.
---
## Compatibility, prep & infection control
* **Concentration:** most commonly **1% (10 mg/mL)**; some centres also use 2% (20 mg/mL) to reduce carrier volume.
* **Pain on injection:** lidocaine 20–40 mg IV just before/through same cannula (avoid mixing in syringe if your policy disallows).
* **Lines:** dedicated line preferable; **do not** co-infuse with blood products or most drugs.
* **Asepsis:** lipid emulsion supports bacterial growth. **Discard open vials/syringes after 6 h**; change **infusion tubing at 12 h** (follow your hospital policy/manufacturer).
* **Allergy myths:** egg/soy allergy is **not an absolute contraindication** (lecithin content is tiny); true **propofol anaphylaxis** → avoid.
---
## Drug interactions (clinically relevant)
* **Synergy** with **opioids**, **benzodiazepines**, **volatile agents** → lower doses needed; more hypotension/respiratory depression.
* **Antihypertensives** add to hypotension.
* **Clevidipine/intralipid**: additional lipid calories.
---
## Monitoring & endpoints
* **During induction/sedation:** ECG, NIBP/arterial line, SpO₂, capnography; airway equipment ready.
* **ICU:** RASS target, TGs q48–72 h, daily gas/lactate where indicated, nutrition accounting, watch CK/K⁺ if doses creeping up.
---
## What to write on your pocket card (one-liners)
* **Induction cardiac:** 0.25–0.5 mg/kg in aliquots; norepi ready.
* **TIVA:** 75–150 mcg/kg/min + opioid; watch SVR.
* **ICU:** 5–50 mcg/kg/min; **avoid >4 mg/kg/h >24–48 h.**
* **PRIS:** acidosis + rhabdo + arrhythmia → **STOP**, switch sedative, treat aggressively.
* **Math:** mL/h = (kg × mcg/kg/min) / **166.7** (10 mg/mL).
# CMRO₂ (Cerebral Metabolic Rate of Oxygen)
**Definition:**
CMRO₂ is the **rate at which the brain consumes oxygen**, usually expressed as **mL O₂/100 g brain tissue/min**.
* **Normal value:** about **3–3.5 mL O₂/100 g/min** (≈ 50 mL/min for the whole brain).
* The brain, although ~2% of body weight, takes up **~20% of resting O₂ consumption**.
---
## Determinants of CMRO₂
CMRO₂ reflects the **energy needs of neurons**, mainly for:
* Maintaining **Na⁺/K⁺ ATPase** (ion gradients, action potentials).
* Neurotransmission, synaptic activity.
It depends on:
* **Neuronal activity** (higher activity → higher metabolism).
* **Temperature** (hypothermia ↓ CMRO₂ ~6–7% per °C drop).
* **Anaesthetic/sedative drugs** (propofol, barbiturates, volatile agents ↓ CMRO₂).
* **Seizures, fever, agitation** ↑ CMRO₂.
---
## Relationship to CBF
* The brain normally **matches blood flow (CBF) to metabolic demand (CMRO₂)** — this is **cerebral autoregulation**.
* If CMRO₂ rises (e.g., seizure), CBF increases.
* If CMRO₂ falls (e.g., with propofol), CBF decreases.
* Exception: some drugs (volatile anaesthetics) can cause **uncoupling** (↓ CMRO₂ but vasodilation → ↑ CBF).
---
## Clinical relevance in anaesthesia/ICU
* **Propofol, barbiturates, etomidate**: ↓ CMRO₂ → ↓ CBF → ↓ ICP → useful in raised ICP/neuro cases.
* **Ketamine**: historically thought to ↑ CMRO₂ and ICP, but newer data show this may be less dramatic.
* **Hypothermia**: ↓ CMRO₂ → neuroprotection (used in CPB, post–cardiac arrest).
* **Hyperthermia, seizures, agitation**: ↑ CMRO₂ → risk of cerebral hypoxia/ischaemia if CBF cannot keep up.
* **Neurocritical care monitoring**: CMRO₂ can be inferred from jugular bulb oximetry, cerebral oximetry (NIRS), or invasive cerebral metabolism monitors.
---
## Quick memory anchor
* **CMRO₂ = brain’s “oxygen bill”**
* Drugs like **propofol** “cut the bill” by lowering metabolism.
* Fever, seizures, agitation “spike the bill.”
* Perfusion (CBF) must always be adequate to pay the bill, or ischaemia results.
.
No comments:
Post a Comment