Total Intravenous Anaesthesia - MD Anaesthesia Pg Exam - 30 marks

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Total Intravenous Anaesthesia (TIVA)

MD Anaesthesia PG Exam Answer - 30 Marks

Definition

Total Intravenous Anaesthesia (TIVA) is a technique of general anaesthesia in which all anaesthetic agents are administered exclusively by the intravenous route, without the use of any volatile inhalational agents. The components of anaesthesia - hypnosis, analgesia, and muscle relaxation - are all delivered intravenously.

Historical Background

The concept of intravenous anaesthesia dates to 1656, when Christopher Wren administered opium intravenously via a quill. Modern TIVA became practical only with the introduction of propofol in the 1980s and the development of target-controlled infusion (TCI) systems. Kruger-Thiemer first described the theoretical framework for achieving steady-state blood concentrations using multi-compartment pharmacokinetic models, later clinically implemented by Schwilden and colleagues. The bolus-elimination-transfer (BET) scheme became the cornerstone of TCI design.

Components of TIVA

Component	Drug(s)
Hypnotic	Propofol (most common), Ketamine, Midazolam, Etomidate
Opioid/Analgesic	Remifentanil (preferred), Fentanyl, Sufentanil, Alfentanil
Muscle Relaxant	Vecuronium, Rocuronium, Cisatracurium

The propofol + remifentanil combination is the gold standard TIVA regimen due to their complementary pharmacokinetics.

Pharmacokinetics of Key Drugs

Propofol

Propofol (2,6-di-isopropyl phenol) is the cornerstone of TIVA.

Distribution:

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)

Metabolism:

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%)

Context-Sensitive Half-Time (CSHT):

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

Remifentanil + Propofol interaction: When added to a propofol plasma concentration of 2 mcg/mL, remifentanil concentration required for suppression of surgical stimuli follows a synergistic interaction. The optimal combination is propofol ~2.5 mcg/mL and a lower remifentanil concentration to minimize recovery time.

Target-Controlled Infusion (TCI)

TCI is a computer-controlled infusion system that uses pharmacokinetic models to calculate and deliver drug infusions targeting a clinician-specified plasma or effect-site concentration.

Principle - BET Scheme

The Bolus-Elimination-Transfer (BET) scheme works via:

Bolus: Initial bolus to rapidly achieve target concentration in the central compartment
Elimination infusion: Constant rate infusion to replace drug lost by elimination
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

Model	Key Features
Marsh	Simple three-compartment; uses total body weight; commonly used in clinical practice
Schnider	Uses age, total body weight, height, lean body mass; includes effect-site; more refined for elderly
Eleveld	Most recent; allometric scaling; better accuracy across a wide range of body weights including obese patients

Schnider model limitation: Uses the James equation for lean body mass calculation, which yields negative values in morbidly obese patients - making it invalid in this population.

For obese patients: Adjusted body weight (ABW = ideal weight + 40% × [total - ideal weight]) with Marsh or Schnider models, or the Eleveld model, provides best accuracy.

Remifentanil TCI

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

Induction and Maintenance Doses

Agent	Induction	Maintenance
Propofol (manual)	1-2.5 mg/kg IV	4-12 mg/kg/h (66-200 mcg/kg/min)
Propofol TCI (Cp)	Target 4-8 mcg/mL	Target 3-6 mcg/mL
Remifentanil infusion	0.5-1 mcg/kg/min	0.05-2 mcg/kg/min
Ketamine	1-2 mg/kg IV	1-3 mg/kg/h

Advantages of TIVA

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

Disadvantages of TIVA

Risk of intraoperative awareness - No reliable exhaled agent monitoring; reliance on PK models which may be inaccurate; BIS/processed EEG monitoring strongly recommended
Venous access dependent - Disconnection, dislodgement, or extravasation can cause awareness or drug toxicity
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
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
Haemodynamic effects - Propofol causes vasodilation and myocardial depression, especially at induction; caution in hypovolaemic and elderly patients
Cost - Higher cost than inhalational anaesthesia for routine cases
Pharmacokinetic variability - TCI models are population-based averages; individual variability (obesity, elderly, hepatic disease, cardiac failure) can lead to under- or overdosing
Supports microbial growth - Propofol's lipid emulsion supports bacterial and fungal growth; strict aseptic handling required; discard within 12 hours of opening
Apnoea - High-dose propofol causes respiratory depression and apnoea
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

Monitoring depth of anaesthesia is particularly important in TIVA because there is no end-tidal volatile agent concentration to guide dosing.

Processed EEG monitors:

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

BIS target range during TIVA: 40-60. An adequate TIVA requires BIS monitoring as TCI models alone cannot guarantee adequate depth in every individual.

Standard monitoring (AAGBI minimum):

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)

A rare but potentially fatal complication associated with high-dose propofol infusion.

Risk factors:

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

Features (SCALP mnemonic):

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

Management: Stop propofol immediately, haemodynamic support, renal replacement therapy if needed.

TIVA vs. Inhalational Anaesthesia - Key Comparison

Parameter	TIVA	Inhalation
PONV	Significantly lower	Higher
Emergence quality	Smoother, less agitation	More agitation possible
MH safety	Safe	Contraindicated in MH
Theatre pollution	None	Present
Intraoperative awareness	Higher risk (no exhaled monitor)	Lower risk (MAC-based monitoring)
Cost	Higher	Lower
Neurophysiology	Better EP preservation	Volatile agents suppress EPs
Recovery	Rapid (propofol CSHT <40 min)	Variable with long volatile use

Closed-Loop TIVA

An advanced development where processed EEG feedback (BIS) is used to automatically adjust the TCI target concentration - creating a truly automated anaesthetic delivery system. Research demonstrates small improvements in haemodynamic control and BIS stability with closed-loop advisory display systems compared to standard TCI.

Summary Points for Exam

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

Sources: Miller's Anesthesia 10th edition; Barash Clinical Anesthesia 9th edition; Morgan & Mikhail Clinical Anesthesiology 7th edition; Scott-Brown's Otorhinolaryngology

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