Effect of Subanaesthetic Dose of Ketamine on Depth of Anaesthesia Consistency During Propofol Total Intravenous Anaesthesia Administered by Closed-loop Anaesthesia Delivery System in Adults Undergoing Elective Laparoscopic Surgery: a Randomised Controlled Study

General Anaesthesia (GA) is a state of controlled unconsciousness that negatively affects a person's subjective experience or interaction with the external environment. GA inhibits two dimensions of consciousness: the content and the level of consciousness. The content of consciousness relates to a person's awareness or subjective experience, while the level of consciousness reflects the degree of wakefulness or arousal. Intravenous anaesthetics, such as propofol, which affect both the content and level of anaesthesia, are used for total intravenous anaesthesia (TIVA). Recently, there has been renewed interest in exploring the addition of anaesthetic adjuvants (ketamine, dexmedetomidine, lignocaine) that affect either the content or level of consciousness, or both, to propofol TIVA.

Propofol is a commonly used anaesthetic for administering TIVA. It acts on gamma-aminobutyric acid (GABAA) receptors in the brain, resulting in hyperpolarisation and inhibition of electrical activity in the neuronal circuits involving the cortex and the thalamus. It simultaneously activates the sleep-generating ventrolateral preoptic nuclei (VLPO) of the hypothalamus. The resultant effect is the depression of both the content and level of consciousness. Propofol causes a transition in electroencephalogram (EEG) waves from high-frequency, low-amplitude beta waves (13-25 Hz) and gamma oscillations (26-80 Hz) of the awake state to high-amplitude, slow delta waves (1-4 Hz) and alpha oscillations (9-12 Hz)

Ketamine is a dissociative anesthetic often used in subanesthetic doses alongside both inhalation general anesthesia (GA) and propofol total intravenous anesthesia (TIVA) due to its numerous benefits, including postoperative pain relief, reduced postoperative nausea and vomiting (PONV), and decreased shivering. It works by antagonizing the N-methyl D-aspartate (NMDA) receptor on the GABAergic inhibitory interneurons in the brain, leading to the disinhibition of excitatory or arousal-promoting neurons in the cortex. Additionally, it inhibits the VLPO nuclei of the hypothalamus. As the dose of ketamine increases, NMDA receptors on excitatory glutaminergic neurons are blocked, resulting in unconsciousness. Unlike propofol, ketamine's EEG signature is characterized by high-frequency, low-amplitude beta (13-25Hz) and gamma oscillations (25-32Hz). This unique mechanism of action, which selectively affects the content of consciousness, leads to a cataleptic state marked by dysphoria, hallucinations, and delirium.

The coadministration of propofol and ketamine has shown an additive effect on hypnosis. Additionally, evidence suggests that ketamine, like propofol, disrupts corticocortical neural activity affecting feedback neural circuits from the frontal to parietal cortex while preserving feedforward neural activity. The EEG signature of ketamine co-administered with propofol resembles that of propofol but with an augmented peak frequency of alpha wave oscillation. The propofol-ketamine combination, which appears to have both dual and solitary effects on dimensions of consciousness, is likely to improve intraoperative anesthesia depth consistency. Administering ketamine with propofol through an automated anesthesia delivery system using EEG feedback signals from the NeuroSENSE processed electroencephalogram (pEEG) monitor (NeuroWave Systems, Ohio, USA) (depth of hypnosis (DoH) index: WAVCNS index, value: '0' to '100') has demonstrated that a subanesthetic dose of ketamine maintains equivalent anesthesia depth consistency similar to when propofol is administered alone. Therefore, adding subanesthetic doses of ketamine to propofol TIVA neither compromises the automated system performance nor affects anesthesia depth consistency. Further evidence is desirable regarding propofol-ketamine TIVA administered by objective automated systems incorporating a feedback-loop mechanism using the bispectral index (BIS) (Medtronics, Minneapolis, USA) pEEG monitor (DoH index: BIS score, value: '0' to '100'), whose working algorithm differs from that of the WAVCNS index. One such automated system using the BIS pEEG monitor is the closed-loop anesthesia delivery system (CLADS). The use of CLADS in patients undergoing cardiac and non-cardiac surgery has demonstrated robust anesthesia depth consistency with propofol TIVA.

The investigators hypothesize that administration of subanaesthetic dose of ketamine will improve the intraoperative anaesthesia depth consistency as compared to placebo in adults undergoing elective laparoscopic surgery under automated propofol TIVA using CLADS.