Propofol

Propofol - The Resident's Guide to the Milk of Amnesia

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If there’s one drug you need to know inside and out, it’s this one - The Propofol. It’s in every OR, every GI lab, and every ICU. It’s elegant, fast, and powerful. But with great power comes great responsibility (and significant hypotension). Let's deep dive into it.

Starting with the fundamentals.

1. The "What": A Basic Profile

• Chemical Name: 2,6-diisopropylphenol. You don't need to know this for daily use, but it's great for a pimp session.
• Formulation: Propofol is highly lipophilic, so it's formulated in a white, oil-in-water emulsion. The classic formulation (Diprivan®) contains 10% soybean oil, 2.25% glycerol, and 1.2% egg phospholipide. This is why it’s called "propofol" or "milk of amnesia." Newer generic formulations have slightly different components (e.g., using medium-chain triglycerides), which can affect the incidence of pain on injection.
• Why the Lipid? The lipid carrier is essential for solubility but is also the source of its calories (1.1 kcal/mL) and a key player in its most dangerous side effect, Propofol Infusion Syndrome (more on that in Lesson 3).

2. The "How": Mechanism of Action (MOA)

The simple answer is "it's a GABA-A agonist," but that's not the whole story. For your exams and for understanding its unique effects, you need more depth.

• Primary Action: Propofol acts as a positive allosteric modulator of the GABA-A receptor. It binds to a site distinct from GABA and enhances the receptor's response to GABA. This increases the influx of chloride ions, hyperpolarizing the neuron and inhibiting firing. This is the main mechanism for its hypnotic and amnestic properties.
• Subunit Specificity: Propofol preferentially acts on GABA-A receptors containing the β2 and β3 subunits. This specificity is thought to contribute to its different profile compared to other GABAergics like benzodiazepines (which target the α subunit).
• GABA-Independent Effects: Propofol also inhibits the NMDA receptor and modulates certain calcium and potassium channels. These actions contribute to its neuroprotective effects (decreasing cerebral metabolic rate) and its potent cardiovascular depressant effects (vasodilation via decreased calcium entry into smooth muscle).

3. The "Journey": Pharmacokinetics (PK)

Propofol's PK is what makes it so beloved. Understanding it is key to mastering its use, especially for Total Intravenous Anesthesia (TIVA).

• Distribution: After an IV bolus, propofol rapidly distributes from the central compartment (plasma, highly perfused organs like the brain) to peripheral compartments (muscle, fat). This rapid redistribution is why a single bolus has such a quick onset and a relatively short duration of action.
  • V1 (Central Compartment): Small. This is why the initial plasma concentration is so high, leading to rapid loss of consciousness.
  • V2 & V3 (Peripheral Compartments): Large. V3 is the "fat sink." It fills up slowly and is responsible for the context-sensitive half-life.
• Metabolism: Propofol is extensively metabolized in the liver via conjugation (glucuronidation and sulfation) to inactive, water-soluble metabolites.
• The "Extra-Hepatic" Secret: The clearance rate of propofol can exceed hepatic blood flow. This proves that extra-hepatic metabolism is significant, with the lungs being a major site of first-pass uptake and metabolism. This is a classic board question!
• Context-Sensitive Half-Time: This is a crucial concept for TIVA. Unlike a fixed half-life, the time it takes for the plasma concentration to fall by 50% after a continuous infusion depends on the duration of the infusion. For propofol, this time remains remarkably short even after several hours, which is why it's ideal for long cases and facilitates rapid wake-up.

4. The "Effects": Pharmacodynamics (PD)

• Central Nervous System (CNS):
  • Hypnosis & Amnesia: Potent and dose-dependent.
  • Anti-emetic: A wonderful "side effect." It acts at the chemoreceptor trigger zone (CTZ).
  • Lack of Analgesia: CRITICAL. Propofol provides no pain relief. You must treat pain with opioids, ketamine, etc.
  • Seizure Threshold: It lowers the seizure threshold and can cause excitatory phenomena like myoclonus on induction. Paradoxically, it is also used to treat status epilepticus.
• Cardiovascular System (CVS):
  • Hypotension: This is its most significant side effect. It's caused by a combination of:
    1. Decreased Systemic Vascular Resistance (SVR): Direct arterial and venous vasodilation.
    2. Myocardial Depression: A direct negative inotropic effect.
    3. Blunted Baroreceptor Reflex: The body's natural compensatory tachycardic response is dampened.
• Respiratory System:
  • Apnea: Dose-dependent respiratory depression leading to apnea is the rule, not the exception. Be ready to mask ventilate.
  • Decreased Ventilatory Drive: Blunts the response to hypercarbia and hypoxia.

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Summary

• Propofol is a GABA-A modulator with other effects on NMDA and calcium channels.
• Its rapid onset is due to quick distribution to the brain.
• Its rapid offset after a bolus is due to redistribution, not metabolism.
• Metabolism is hepatic and extra-hepatic (lungs!).
• Key Effects: Amnesia/hypnosis (yes), analgesia (no), anti-emesis (yes).
• Key Side Effects: Hypotension (SVR drop + myocardial depression) and apnea. Be prepared!

In our next lesson on Propofol, we'll move from theory to practice and discuss how to actually use propofol safely and effectively in the OR. We'll cover induction techniques, managing side effects, and the basics of TIVA.

Next: Beyond the Bolus - Mastering Propofol in the Real World →

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Beyond the Bolus - Mastering Propofol in the Real World

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In our first post, we covered the science behind propofol. Now, let's talk about the art. How do you take this knowledge and apply it to the patient in front of you? This post is all about the practical, in-the-moment decisions that define a good anesthesiologist.

1. Induction: The Art of the "Go"

Induction with propofol is a delicate balance. Too much, and you're chasing hypotension for 10 minutes. Too little, and your patient is coughing on the LMA or remembering the experience.

• Standard Dosing: The textbook range is 1-2.5 mg/kg. But this is just a starting point.
• The Golden Rule: Titrate! Unless it's a rapid sequence induction on a healthy, fasted patient, there is almost never a reason to "slam" the full dose.
• Factors That MUST Modify Your Dose:
  • Age: The elderly are exquisitely sensitive. An 85-year-old may only need 0.5-1 mg/kg. Their decreased initial distribution volume and clearance mean a little goes a long way.
  • Hemodynamic Status: That patient with a low EF and baseline MAP of 65? Start with 20-30 mg and see what happens. Have a phenylephrine or vasopressin infusion ready before you push.
  • Opioid Co-administration: Giving fentanyl 30-60 seconds before the propofol dramatically reduces the required dose. This is a classic technique to blunt the hemodynamic response to laryngoscopy.
  • Pre-medication: Did the patient get midazolam in pre-op? Factor that in.
  • ASA/Comorbidities: The sicker the patient (ASA III/IV), the smaller the starting dose.

Pro-Tip: For a smooth induction on a relatively healthy patient, give 1-1.5 mg/kg slowly over 30-60 seconds while watching the heart rate and blood pressure. You'll often see the HR dip slightly and the BP start to fall just as the patient loses consciousness. This is your cue to stop.

2. Maintenance: TIVA and TCI

While many use propofol just for induction, it's a mainstay for maintenance, especially with TIVA.

• Manual TIVA: You can start a maintenance infusion after induction. A typical starting rate is 100-150 mcg/kg/min. You then titrate up or down based on hemodynamics and signs of anesthesia depth (movement, HR/BP response to stimulus, BIS if you use it).
• Target-Controlled Infusion (TCI): This is where propofol shines. TCI pumps use patient-specific data (age, weight, height) and pharmacokinetic models (like Marsh or Schnider) to target a specific plasma or effect-site concentration of propofol.
  • Marsh Model: Older, simpler, uses total body weight. Can lead to higher-than-intended concentrations in obese or elderly patients.
  • Schnider Model: More complex, uses lean body mass, and is often considered more accurate, especially for effect-site targeting.
  • Why TCI is great: It allows for precise control and predicts wake-up time. You set a target concentration (e.g., 4-6 mcg/mL for maintenance), and the pump does the math.

3. Taming the Beast: Managing Common Side Effects

You will face these every day. Have a plan.

• Pain on Injection: Up to 80% of patients complain of this. It's thought to be due to propofol activating the kinin cascade.
  • Best Method: Lidocaine pretreatment. Give 20-40 mg of IV lidocaine (with a tourniquet) 1-2 minutes before the propofol injection (Bier's block).
  • Good Method: Mix 20-40 mg of lidocaine directly into the propofol syringe.
  • Other tricks: Use a large-bore IV, preferably in the antecubital fossa. Injecting slowly helps. Colder propofol hurts more.
• Hypotension: The #1 problem.
  • Prevention: Fluid loading (if not contraindicated), smaller induction dose, co-administration of an opioid, and having a vasopressor drawn up and ready.
  • Treatment: First-line is usually a direct-acting vasopressor like phenylephrine (40-100 mcg boluses) to counteract the SVR drop. If there's significant myocardial depression, ephedrine (5-10 mg) or an epinephrine infusion may be needed. Don't be shy—treat it early and aggressively.
• Apnea: Expect it. Have your mask ready, a good seal, and be prepared to ventilate. The duration of apnea is directly related to the dose and the use of co-administered opioids.

4. Resident Pearls & Pro-Tips

• The "Propofol Shuffle": That brief, non-purposeful movement some patients make on induction? It's a known phenomenon, likely a subcortical excitatory effect. Don't panic and give more drugs; it usually resolves in seconds.
• The Anti-emetic Boost: A small 20-30 mg bolus of propofol at the end of a case (especially with a volatile-based anesthetic) can be a powerful anti-emetic for PONV-prone patients.
• The "Propofol Scalp": For awake craniotomies, a subcutaneous injection of diluted propofol along the scalp incision line provides excellent, long-lasting local anesthesia.
• Recognizing Depth: Without a BIS monitor, you learn to read the patient. A rising HR/BP in response to a surgical stimulus means "lighten up" (increase vapor or propofol rate). Sudden hypotension and bradycardia with no surgical stimulus might mean you're "too deep."

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Summary

• Induction is titration, not a race. Adjust dose for age, cardiac status, and pre-meds.
• TIVA/TCI allows for precise control and rapid wake-ups. Know the basics of the models.
• Pain on injection: Pretreat with lidocaine (Bier's block is best).
• Hypotension: Prevent it (fluids, smaller dose) and treat it aggressively (phenylephrine is your friend).
• Apnea: Be ready to ventilate. It's not a complication, it's an expectation.

In our final post on Propofol, we'll tackle the advanced topics: the terrifying Propofol Infusion Syndrome, special populations, and debunking the egg/soy allergy myth.

Next: The Deep Dive - Propofol's Dark Side and Delicate Touch →

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The Deep Dive - Propofol's Dark Side and Delicate Touch

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We've covered the basics and the daily practice. Now, let's enter the territory of senior residents, fellows, and board examiners. This is the high-yield, "pimp" material that separates the good from the great. We're talking about the scary stuff, the special cases, and the common misconceptions.

1. The Big Bad Wolf: Propofol Infusion Syndrome (PRIS)

PRIS is rare but devastating. You must have a high index of suspicion, especially in the ICU or for very long, complex cases.

• What is it? A rare but often fatal metabolic derangement characterized by severe metabolic acidosis, rhabdomyolysis, and cardiac failure leading to refractory bradycardia and asystole.
• Pathophysiology: The exact mechanism is not fully understood, but it's thought to be a direct mitochondrial toxicity. Propofol impairs fatty acid oxidation and the electron transport chain within the mitochondria, leading to a switch to anaerobic metabolism and cellular energy failure. The lipid emulsion itself may exacerbate this by overwhelming the body's lipid-clearing mechanisms.
• Risk Factors (The "4 H's"):
  1. High Dose: Infusion rates > 4-5 mg/kg/hr (some say >80 mcg/kg/min).
  2. High Duration: Infusions lasting > 48 hours.
  3. High-Risk Patients: Critical illness, sepsis, severe head injury, catecholamine/vasopressor infusions, glucocorticoid use, and young children.
• Clinical Signs (What to Look For):
  • Cardiac: Sudden, refractory bradycardia progressing to asystole (this is often the first sign).
  • Metabolic: Unexplained, high anion gap metabolic acidosis with a rising lactate.
  • Muscular: Rhabdomyolysis (rising CK, myoglobinuria, tea-colored urine).
  • Other: Hyperkalemia, acute renal failure, hepatomegaly, and severe lipemia (a milky appearance to the blood).
• Prevention & Treatment:
  • Prevention is KEY: Limit dose and duration. Be extremely cautious with high-risk patients. Consider an alternative agent (e.g., midazolam, dexmedetomidine) for long-term sedation.
  • Treatment: There is no antidote. You must:
    1. IMMEDIATELY STOP THE PROPOFOL.
    2. Provide aggressive supportive care.
    3. Treat the acidosis (bicarbonate).
    4. Initiate renal replacement therapy (CRRT) early to clear metabolites and manage the hyperkalemia and renal failure.
    5. For refractory cardiac failure, ECMO may be the only lifesaving option.

2. Special Populations: A Delicate Touch

• Pediatrics: Propofol is used, but PRIS is a major concern, especially in children under 3 or with critical illnesses. The FDA warning is prominent. Dosing is weight-based, and vigilance is paramount.
• Elderly: We've said it before, but it's worth repeating. They are sensitive. Use ideal body weight for dosing, reduce the dose by 30-50%, and give it slowly. Their clearance is reduced, and they are prone to hypotension and prolonged sedation.
• Cardiac Patients: Propofol is a double-edged sword. It's excellent for attenuating the sympathetic response to intubation, but it can cause catastrophic hypotension. The strategy is:
  • Preload: Optimize with fluids.
  • Afterload: Have a potent vasopressor (phenylephrine, norepinephrine) infusing or ready to bolus.
  • Contractility: Have an inotrope (epinephrine) available if needed.
  • Dose: Use micro-boluses (10-20 mg) until the desired effect is achieved.
• Neuroanesthesia: Propofol is a staple here. It is a potent cerebral vasoconstrictor, decreasing both Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate of Oxygen Consumption (CMRO2). This makes it useful for providing a "quiet" brain for aneurysm clipping or tumor resection. It also lowers ICP. The debate over "neuroprotection" is ongoing, but its ability to match metabolic supply and demand is well-established.
• Obesity: Dosing should be based on Lean Body Weight (LBW) or Ideal Body Weight (IBW), not Total Body Weight (TBW), for induction and maintenance. Using TBW leads to massive overdosing, as the initial distribution volume (V1) does not scale with fat mass.

3. Contraindications & Debunking Myths

• True Allergy: A true IgE-mediated allergy to propofol is exceedingly rare. When it occurs, it's usually an allergy to the isoflurane used in some formulations, not the propofol itself.
• The Egg & Soy Allergy Myth: This is a classic board question and a common point of confusion.
  • The Theory: Propofol is formulated with egg lecithin and soybean oil, so patients with allergies should avoid it.
  • The Reality: Most food allergies are to the proteins in egg whites or soy, not the fats (lipids). The purification process for propofol removes virtually all protein.
  • The Consensus: For patients with a known severe allergy to eggs or soy, many institutions still recommend avoiding it out of an abundance of caution. However, for patients with a history of atopy or a mild intolerance, propofol is generally considered safe. Always check your institution's policy and discuss with the attending if you are unsure.
• Hypertriglyceridemia: This is a real contraindication. Propofol is a lipid emulsion. Infusing it into a patient with a baseline triglyceride level > 400-500 mg/dL can worsen the condition and precipitate pancreatitis. Monitor triglyceride levels if you anticipate a long infusion (>48 hours).

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Summary

• PRIS is real and deadly. Think of it with high doses (>4-5 mg/kg/hr) and long durations (>48 hrs) in sick patients. Watch for refractory bradycardia, metabolic acidosis, and rhabdomyolysis.
• Special Populations: Dose down for the elderly and cardiac patients. Use lean body weight for the obese. Be extremely cautious with PRIS in children.
• Egg/Soy Allergy: The risk is likely overstated for most allergies, but follow institutional policy for severe, known allergies.
• Hypertriglyceridemia: A true contraindication. Monitor levels for long infusions.

Propofol is more than just a drug; it's a tool. Understanding its science, its practical application, and its dangers is the first step toward mastering the art of anesthesia. Use it wisely, use it safely, and never stop learning.

← Back to Introduction of Propofol

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