Clinical trial NCT06986109: Effect of Subanaesthetic Dose of Ketamine on Depth of Anaesthesia Consistency
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Anesthesia
Keywords: ketamine
propofol
Bi-spectral index
closed-loop anaesthesia delivery system
Lead sponsor: Sir Ganga Ram Hospital
Sponsor class: OTHER
First posted: 2025-05-22
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: One hundred and six participants (53/group) aged 18-65 years, ASA physical status I-II, of either sex, and undergoing elective laparosocpic surgery will be randomly divided into one of the two groups:

Group I: Ketamine Group Prior to anaesthesia induction, a bolus dose of ketamine solution 0.05-ml/kg (concentration 5mg/ml) will be administered followed by continuous intraoperative ketamine infusion of 0.05-ml/kg /h along with automated propofol TIVA delivered using CLADS.

Group II: Placebo Group Prior to anaesthesia induction, an equivalent volume bolus (0.05-ml/kg) of 0.9% normal saline will be administered and it will be followed by continuous intraoperative 0.9% normal saline infusion at 0.05-ml/kg /h along with automated propofol TIVA delivered using CLADS.
Primary purpose: OTHER

Brief summary: General Anaesthesia (GA) is a medical state of controlled unconsciousness that inhibits two dimensions of consciousness: the content and the level of consciousness. This state is achieved using various anaesthetic agents, with propofol being one of the most commonly used intravenous anaesthetics. Propofol is a gamma amino butyric acid (GABAA) receptor agonist, which affects both the content and level of anaesthesia.

In some cases, anaesthesiologists may choose to use an adjuvant drug, ketamine, in subanaesthetic doses during inhalation GA and propofol total intravenous anaesthesia (TIVA). Ketamine is an N-methyl D-aspartate (NMDA) receptor antagonist and is primarily employed for its analgesic properties. Unlike propofol, ketamine selectively affects only the content of consciousness.

The combination of propofol and ketamine appears to have dual effects on the dimensions of consciousness, with propofol affecting both content and level, and ketamine affecting only the content. This combination is likely to complement and improve the consistency of intraoperative anaesthesia depth.

However, studies have shown that the administration of ketamine with propofol TIVA, delivered through an automated anaesthesia delivery system using electroencephalogram (EEG) feedback signals from NeuroSENSE processed electroencephalogram (pEEG) monitor, has not demonstrated any significant benefit over the use of propofol alone.

Till now, the only study on propofol-ketamine co-administration used an uncommon NeuroSENSE pEEG monitoring system. Closed loop anaesthesia delivery system (CLADS) is a more precise, efficient, and robust mechanism to facilitate automated administration of propofol TIVA which employs the standard bispectral index (BIS) pEEG monitoring to control propofol TIVA delivery. Further evidence is desirable on depth of anaesthesia consistency when ketamine is co-administered with propofol TIVA, using CLADS This randomised controlled study will compare the effect of subanaesthetic dose of ketamine versus placebo (normal saline) on anaesthesia depth consistency in patients undergoing elective laparoscopic surgery under automated propofol TIVA using CLADS. All patients undergoing elective laparoscopic surgery will be screened, and those found eligible will be enrolled. Enrolled patients will receive CLADS-controlled propofol TIVA as standard. In intervention are, patients will additionally receive subanaesthetic dose of ketamine (0.25-mg/kg bolus followed by maintenance infusion 0.25-mg/kg/h) (ketamine group); in control arm, patients will receive normal saline as placebo in addition to propofol TIVA (placebo group).

Detailed description: 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.

The proposed randomised-controlled study aims to compare the effect of addition of subanaesthetic dose of ketamine versus placebo on anaesthesia depth consistency in patients undergoing elective laparoscopic surgery under automated propofol TIVA using CLADS.

Eligibility criteria: Inclusion Criteria:

* ASA physical status I and II.
* Patients scheduled for elective laparoscopic surgery with estimated duration greater than 60-minutes.

Exclusion Criteria:

* Known uncontrolled cardiovascular disease (e.g., hypertension, systolic and diastolic dysfunction)
* Liver function abnormality (liver enzymes \>2 times the normal range)
* Kidney function abnormality (serum creatinine \>1.4 mg/dl)
* Known psychiatric or neurological disorder
* Known uncontrolled endocrine disorder (diabetes mellitus, hypothyroidism)
* Known allergy or hypersensitivity to the study drug
* Recent intake of sedative medication or anti-psychotic medication
* Substance abuse
* Anticipated need for postoperative ventilation
* Refusal to informed consent

Primary outcomes:
measure: Anaesthesia depth consistency
timeFrame: During the surgical procedure, an average of 360 minutes
Secondary outcomes:
measure: Performance characteristic of propofol delivery system determined by calculating the median performance error (MDPE)
timeFrame: During the surgical procedure, an average of 360 minutes
measure: Performance characteristic of propofol delivery system determined by calculating the median absolute performance error (MDAPE)
timeFrame: During the surgical procedure, an average of 360 minutes
measure: Performance characteristic of propofol delivery system determined by calculating the wobble
timeFrame: During the surgical procedure, an average of 360 minutes
measure: Performance characteristic of propofol delivery system determined by calculating the global score
timeFrame: During the surgical procedure, an average of 360 minutes
measure: Propofol induction dose (mg/kg)
timeFrame: From start of propofol injection till target BIS value of '50' is achieved, an average of 5 minutes after beginning of anesthesia
measure: Propofol maintenance dose (mg/kg/h)
timeFrame: From achieving target BIS value of '50' till skin closure, during the surgical procedure an average of 360 minutes
measure: Intraoperative haemodynamic instability
timeFrame: From beginning of anaesthesia till 10 hours intraoperatively
measure: Early recovery from anaesthesia (measured in minutes)
timeFrame: From end of anaesthesia till 20-minutes postoperatively
measure: Early recovery from anaesthesia (measured in minutes)
timeFrame: From end of anaesthesia till 20-minutes postoperatively
measure: Postoperative pain assesment
timeFrame: From the end of anaesthesia till 24-hours, postoperatively
measure: Postoperative nausea and vomiting
timeFrame: From the end of anaesthesia till 24-hours, postoperatively
measure: Postoperative sedation
timeFrame: From the end of anaesthesia till 24-hours, postoperatively
measure: Intraoperative awareness
timeFrame: From the end of anaesthesia till 48-hours, postoperatively
Other outcomes:
Locations:
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
state: Delhi
Study officials:
affiliation: Sir Ganga Ram Hospital, New Delhi, INDIA
name: Nitin Sethi, DNB
role: STUDY_CHAIR
affiliation: Sir Ganga Ram Hospital, New Delhi, INDIA
name: Amitabh Dutta, MD, PGDHR
role: STUDY_DIRECTOR
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