Total Intravenous Anaesthesia (TIVA)

Definition

Historical Background

Components of TIVA

Pharmacokinetics of Key Drugs

Propofol

• Highly lipophilic; rapid redistribution after bolus
• Three-compartment pharmacokinetic model
• Initial distribution half-life: 2-8 minutes
• Slow distribution half-life: 30-70 minutes
• Elimination half-life: 4-23.5 hours
• Volume of distribution at steady state: 150-700 L
• Central compartment volume: 6-40 L (smaller in elderly due to reduced cardiac output)

• Clearance: 1.5-2.2 L/min (exceeds hepatic blood flow)
• Hepatic oxidation to 1,4-diisopropyl quinol, followed by glucuronide conjugation
• Extrahepatic metabolism confirmed (kidney accounts for ~30% of clearance; lungs contribute 20-30% first-pass)
• Propofol inhibits CYP3A4 (even at 3 mcg/mL, reduces CYP3A4 activity by ~37%)

• For infusions up to 8 hours, CSHT remains <40 minutes
• Since the required decrease in concentration for awakening is <50%, recovery remains rapid even after prolonged infusion - this makes propofol ideal for TIVA

Simulation of propofol-remifentanil interaction at skin incision and time to recovery (Miller's Anesthesia, 10e)

Remifentanil

• Ultra-short-acting synthetic mu-opioid agonist
• Ester hydrolysis by nonspecific plasma and tissue esterases (independent of hepatic/renal function)
• Context-sensitive half-time: 3-5 minutes (does NOT increase with infusion duration)
• Elimination half-life: ~8-20 minutes
• Dose: 0.05-2 mcg/kg/min by infusion
• Uniquely, neonates have more rapid clearance than older children due to larger volume of distribution and esterase activity

Target-Controlled Infusion (TCI)

Principle - BET Scheme

1. Bolus: Initial bolus to rapidly achieve target concentration in the central compartment
2. Elimination infusion: Constant rate infusion to replace drug lost by elimination
3. Transfer infusion: Exponentially declining infusion to replace drug redistributing to peripheral compartments

Effect-Site (Ce) vs. Plasma (Cp) Targeting

• Plasma TCI (Cp target): Targets the plasma concentration; effect-site concentration lags behind due to the blood-brain equilibration delay (ke0)
• Effect-site TCI (Ce target): Targets the biophase/effect-site concentration; produces faster onset by temporarily overshooting plasma concentration

Propofol TCI Models

Remifentanil TCI

• Minto model: Uses age, weight, height, and lean body mass; accounts for age-related changes in pharmacokinetics

Induction and Maintenance Doses

Advantages of TIVA

1. Reduced PONV - Propofol has intrinsic antiemetic properties; avoiding volatile agents significantly reduces postoperative nausea and vomiting
2. Safe in malignant hyperthermia (MH) susceptible patients - TIVA avoids all triggering volatile agents and succinylcholine; it is the technique of choice in MH-susceptible individuals
3. Better maintenance of surgical field - Reduces bronchospasm; ideal for airway surgery, ENT, and sinus surgery (TIVA with remifentanil reduces coughing and improves surgical conditions)
4. Smooth induction and emergence - No excitation on induction; rapid, clear-headed recovery
5. Reduced pollution - No theatre pollution from volatile agents
6. Better neurophysiologic monitoring - TIVA (propofol + remifentanil) causes less suppression of evoked potentials (MEP, SSEP) compared to volatile agents; preferred for spine and neurosurgery
7. Use in remote locations - Can be administered without an anaesthetic machine
8. Facial nerve monitoring - Propofol + remifentanil provides reliable conditions for facial nerve monitoring during ear surgery (Choe et al.)
9. Reduced airway reactivity - Propofol suppresses laryngeal reflexes; ideal with LMA
10. Anti-epileptic properties - Propofol useful in patients with epilepsy
11. Opioid-free TIVA variants - Reduces PONV further in bariatric surgery beyond triple prophylaxis

Disadvantages of TIVA

1. Risk of intraoperative awareness - No reliable exhaled agent monitoring; reliance on PK models which may be inaccurate; BIS/processed EEG monitoring strongly recommended
2. Venous access dependent - Disconnection, dislodgement, or extravasation can cause awareness or drug toxicity
3. Propofol infusion syndrome (PRIS) - Rare but life-threatening complication with high-dose, prolonged infusions (>4 mg/kg/h for >48h); characterised by metabolic acidosis, rhabdomyolysis, cardiac failure, lipaemia
4. Injection pain - Propofol causes burning on injection (50-70% if given into small peripheral vein); using large antecubital vein, lidocaine pretreatment, or using lipid formulations mitigates this
5. Haemodynamic effects - Propofol causes vasodilation and myocardial depression, especially at induction; caution in hypovolaemic and elderly patients
6. Cost - Higher cost than inhalational anaesthesia for routine cases
7. Pharmacokinetic variability - TCI models are population-based averages; individual variability (obesity, elderly, hepatic disease, cardiac failure) can lead to under- or overdosing
8. Supports microbial growth - Propofol's lipid emulsion supports bacterial and fungal growth; strict aseptic handling required; discard within 12 hours of opening
9. Apnoea - High-dose propofol causes respiratory depression and apnoea
10. Dose calculation complexity - Manual TIVA requires careful calculation of infusion rates

Indications for TIVA

• Malignant hyperthermia susceptibility (absolute)
• Airway surgery (shared airway, laser surgery, microlaryngoscopy)
• ENT surgery - sinus surgery, middle ear surgery, thyroidectomy
• Neuroanaesthesia with neurophysiological monitoring
• Neurosurgery requiring cerebral protection (propofol reduces CMRO2)
• Patients prone to PONV
• Remote anaesthesia (MRI, radiotherapy, catheterisation labs)
• Robotic and laparoscopic surgery
• Paediatric anaesthesia (where TIVA is feasible and MH risk exists)
• Day-case and ambulatory surgery

Monitoring During TIVA

Depth of Anaesthesia Monitoring

• BIS (Bispectral Index): Most widely used; value 40-60 = adequate anaesthesia; <40 = deep; >60 = risk of awareness
• Entropy (State Entropy / Response Entropy)
• Narcotrend

• Continuous ECG
• SpO2 pulse oximetry
• NIBP (or IBP in high-risk patients)
• Capnography (EtCO2)
• Neuromuscular monitoring (if muscle relaxants used)
• Temperature monitoring

TIVA in Special Populations

Elderly Patients

• Reduced central compartment volume - higher peak plasma concentrations after bolus
• Reduced clearance and cardiac output
• Reduce induction dose of propofol by 30-50%
• Schnider model incorporates age as a covariate and is preferred

Obese Patients

• Marsh model using total body weight overestimates required dose
• Use adjusted body weight or Eleveld model
• Effect-site TCI with Schnider model risks negative lean body mass calculations

Paediatric Patients

• TIVA increasingly used; propofol + remifentanil are the main agents
• Remifentanil clearance is paradoxically more rapid in neonates (esterase-based clearance; not liver/kidney dependent)
• Propofol not licensed for sedation in paediatric ICU (<16 years) due to risk of PRIS

Hepatic/Renal Impairment

• Propofol clearance minimally affected by liver disease (extrahepatic metabolism predominates)
• Remifentanil is safe in renal and hepatic failure (ester hydrolysis)

Propofol Infusion Syndrome (PRIS)

• Dose >4 mg/kg/h (>67 mcg/kg/min)
• Duration >48 hours
• High carbohydrate, low fat intake
• Concomitant catecholamine or steroid infusion
• Sepsis, brain injury

• S - Severe metabolic acidosis (lactic/anion gap)
• C - Cardiac failure (new right bundle branch block, ST changes, arrhythmias)
• A - Acute rhabdomyolysis
• L - Lipaemia (hypertriglyceridaemia)
• P - Pancreatic enlargement / pancreatitis

TIVA vs. Inhalational Anaesthesia - Key Comparison

Closed-Loop TIVA

Summary Points for Exam

1. TIVA = all anaesthetic components given IV; no volatile agents
2. Gold standard regimen: propofol + remifentanil ± muscle relaxant
3. Propofol is ideal for TIVA: rapid onset, short CSHT (<40 min for 8h infusions), antiemetic
4. Remifentanil: ester hydrolysis, CSHT 3-5 min regardless of infusion duration
5. TCI uses BET schemes based on 3-compartment PK models
6. Common TCI models: Marsh (simple, total body weight) and Schnider (includes age, LBM; better for elderly)
7. Plasma TCI vs Effect-site TCI - effect-site gives faster onset by overshooting plasma concentration
8. TIVA is technique of choice in malignant hyperthermia and neurosurgery with neurophysiological monitoring
9. Main risk: intraoperative awareness - always use processed EEG (BIS 40-60)
10. PRIS: high-dose, prolonged propofol - present with lactic acidosis, cardiac failure, rhabdomyolysis
11. Propofol: injection pain, supports microbial growth, CYP3A4 inhibitor, extrahepatic metabolism (30% renal, 20-30% pulmonary)
12. TIVA reduces PONV significantly - benefit particularly in bariatric, ENT, and gynaecological surgery