Recent advancements in total intravenous anaesthesia and anaesthetic pharmacology

ABSTRACT

Target-controlled infusion pumps and depth of anaesthesia monitors have made total intravenous anaesthesia (TIVA) easy, safe, and precise. The merits of TIVA were highlighted during the coronavirus disease 2019 (COVID-19) pandemic, confirming its potential further in the post-COVID clinical practice as well. Ciprofol and remimazolam are newer drugs that are being tried with a hope to upgrade the practice of TIVA. While research on safe and effective drugs continues, TIVA is being practised with a combination of drugs and adjuncts to overcome the disadvantages of each and to provide complete and balanced anaesthesia with additional benefits in recovery and pain relief postoperatively. Modulation of TIVA for the special population groups is still under process. Advancement in digital technology with mobile apps has increased the scope of TIVA in day-to-day use. The formulation and update of guidelines can establish a safe and efficient practice of TIVA.

INTRODUCTION

Pharmacokinetics and pharmacodynamics of popular intravenous drugs like propofol and newer and shorter acting agents like remifentanil coupled with the development of pharmacokinetic models and advanced technology in infusion pumps have made a significant impact in the evolution of total intravenous anaesthesia (TIVA).[1] Target-controlled infusion (TCI) pumps and depth of anaesthesia monitors have made TIVA easy, safe, and precise. However, TIVA can also be practised with routine infusion pumps and even when these sophisticated models of equipment are not available. TIVA may be provided either with insertion of an endotracheal tube or supraglottic airway device, nasal or oral airway, or oxygen alone without insertion of any airway device.[2] The practice of TIVA started initially in the fields of neurosurgery, day care surgery, as a supplementation to regional or local anaesthesia, and for sedation/analgesia in diagnostic/therapeutic procedures. In recent times, it has proven to be beneficial in oncosurgery, paediatric and geriatric surgery, cardiac surgery, and non-operating room anaesthesia (NORA).[3] We did a literature search on latest trends in TIVA by searching various databases. The information so compiled is presented in this article.

NEWER DRUGS/COMBINATIONS IN TOTAL INTRAVENOUS ANAESTHESIA

An ideal drug for TIVA should have rapid onset of action, rapid recovery, be potent and lipid soluble, and be stable in solution, with no perivascular sloughing if extravasated. It should be water-soluble to minimise toxicity associated with the solvent, not be absorbed by plastic, be devoid of adverse effects, be cost -effective, and, most importantly, it should be compatible with other agents such that it can be mixed without any complication.[2,4] While the search for such an ideal drug continues, TIVA is being practised with a combination of drugs to overcome the disadvantages of each. The combination of various classes of drugs and adjuncts in TIVA is necessary for complete and balanced anaesthesia [Table 1]. It decreases the dose of individual drugs, thereby reducing the side effects of all drugs in a mixture.[5]

Table 1.

Some useful IV drug combinations used for TIVA and postoperative analgesia

Combination of TIVA	Doses/Concentration	Clinical Applications
Remifentanil and propofol	Remifentanil in concentration of 50 µg/ml (1 mg in 20 ml propofol)	Most widely used in the world for TIVA by TCI. 50% reduction in dose of propofol is seen. Can be used for up to 36 h
Propofol and fentanyl	Propofol (1% and 2%) and fentanyl (10–50 µg/ml)	No significant degradation of emulsion within 20 h. 50% reduction is seen in dose of propofol
KPD (ketamine + propofol + dexmedetomidine)	1:1:1 initially then maintenance with 0.5:0.5:0.5 (mg: mg:µg/kg/h) Or Dexmedetomidine 0.7 µg/kg/h in RL Or Propofol 6–8 mg/kg/h in 100 ml NS	Combination of all these drugs permit lower dose of each agent and reduces adverse reactions Dexmedetomidine reduces shivering caused by propofol Excellent analgesia and anaesthesia Haemodynamically stable, rapid recovery
Ketofol (ketamine and propofol)	1:1 mixture is stable 100 mg ketamine: 100 mg propofol 0.5 mg/kg followed by another 0.5 mg/kg after about 30–60 s Maintenance 0.25 mg/kg as needed	Widely used by anaesthesiologists for short procedures
Ketodex (ketamine and dexmedetomidine)	1 µg/kg of dexmedetomidine and 1–2 mg/kg of ketamine. This could be followed by 1–2 µg/kg/h of dexmedetomidine infusion with supplemental bolus doses of 0.5–1 mg/kg of ketamine as needed	Paediatric patients for radiological and endoscopic procedures
Ketomed (ketamine and midazolam)	1 mg/kg ketamine+0.1 µg/kg midazolam	Non–operating room anaesthesia
MDF (midazolam, dexmedetomidine, and fentanyl)	0.05 mg/kg midazolam+1 µg/kg dexmedetomidine+1 µg/kg fentanyl bolus and half the previous dose if required	Widely used in COVID-19 Short surgical procedures, commonly used as adjunct
PDF (propofol, dexmedetomidine, and fentanyl)	1 mg/kg propofol+1 µg/kg dexmedetomidine+1 µg/kg fentanyl bolus and half the previous dose if required	Short surgical procedures, widely used in COVID-19
DML (dexamethasone, magnesium sulphate [MgSO4], and lidocaine)	8 mg dexamethasone+1 gm MgSO4+1.5 mg/kg lidocaine	Reduces postoperative nausea and vomiting, reduces doses of IV anaesthetic agents, improves quality of TIVA, recovery and discharge
FLK (fentaketacaine)	100 µg fentanyl+100 mg lidocaine+100 mg ketamine in 500 ml RL, given in dose of 0.5:0.5:0.5 (µg: mg: mg/kg/h) for maximum of 24h	Used as drip after major surgery of duration >3 h
Ketacaine drip	100 mg ketamine+100 mg lidocaine in 500 ml RL Given in dose of 0.5:0.5 (mg: mg/kg/h)	Used after routine surgery of duration <3 h
Etomidate and fentanyl/remifentanil	IV etomidate 0.3 mg/kg+IV fentanyl 1 µg/kg bolus. Maintenance with intermittent bolus etomidate 0.1 mg/kg when needed	Useful in haemodynamically unstable patient for short surgical procedures To be cautious about adrenocortical suppression; if low cortisol level/geriatric patient, dose of etomidate to be reduced to 0.2 mg/kg Pharmacokinetic model for TCI of etomidate not yet available

TIVA=Total intravenous anaesthesia, COVID=Coronavirus disease, TCI=Target-controlled infusion, IV=Intravenous, RL=Ringer lactate, NS=Normal saline

Propofol and remifentanil remain the most appropriate and near-ideal drugs for TIVA. Remifentanil is effective in reducing propofol requirements by up to 50%. Its combination with propofol is highly effective and constitutes the most common drug combination by TCI model worldwide because of the low context-sensitive half-life. Propofol reduces the dose of remifentanil by its analgesic properties and by reducing hyperalgesia caused by remifentanil.[2]

Various adjuncts are being administered during TIVA to reduce the intra- and postoperative complications. Dexamethasone, an anti-inflammatory drug, in a single dose of 8 mg reduces postoperative nausea and vomiting by 30% in propofol-based TIVA, with good quality of recovery and discharge.[6–8] Lidocaine used in a bolus dose of 1–1.5 mg/kg with infusion of 1.5 mg/kg/h reduces TIVA dose by 10%–20% during the maintenance phase.[9,10] Magnesium sulphate used as an adjunct in TIVA reduces propofol, dexmedetomidine, atracurium, and postoperative narcotic consumption. Used in a bolus dose of 30–50 mg/kg with maintenance dose of 10 mg/kg/h, it improves the quality of postoperative analgesia. Its anti-hypertensive, bronchodilator, anti-arrhythmic, anti-shivering, and anti-seizure effects are an added advantage.[3,4] Esmolol 1 mg/kg bolus over 60 s during preoxygenation is able to reduce the total induction dose by 18.5%.[11,12] Perioperative esmolol infusion has been shown to reduce the total anaesthetic and analgesic requirements and postoperative pain.

The new addition of remimazolam in the armamentarium of TIVA is promising for procedural sedation and anaesthesia. It is pharmacologically a benzodiazepine, but is differentiated by its ester group and rapid metabolism by tissue esterases to a significantly less active metabolite. Its rapid pharmacokinetics and pharmacodynamics with relatively small effects of covariates such as age, gender, race, obesity status, American Society of Anesthesiologists (ASA) physical status, and weight will make it a perfect addition in TIVA medication regimens.[13]

Ciprofol, a new intravenous anaesthetic, is a gamma- aminobutyric acid (GABA) receptor agonist and is a novel 2,6-disubstituted phenol derivative like propofol with improved pharmacokinetic and pharmacodynamic characteristics. It has a rapid rate of onset and recovery in preclinical experiments. It is five times more potent than propofol, does not cause pain on intravenous injection, and provides better haemodynamic stability. It is better in prolonged infusion due to rapid clearance. It can be given in initial doses of 0.4 mg/kg for 30 s followed by a supplemental intravenous bolus dose of 0.1 mg/kg for 10 s. The maintenance infusion dose is 0.1–0.3 mg/kg/hour.[14]

NEWER TECHNIQUES IN TOTAL INTRAVENOUS ANAESTHESIA

TIVA can be administered by various techniques like intermittent bolus, fixed rate or manually controlled infusion, or TCI. These techniques are heterogeneous in nature and vary significantly in their safety and efficacy. Advancements have been made in different areas along with the use of specialised infusion sets and mobile applications to make it a safe technique.

Advancement in target-controlled infusion techniques

TCI technology is constantly evolving, with innovations in drug delivery devices, pharmacokinetic modelling, and computer technology. In advanced closed-loop anaesthesia delivery system (CLADS), a controller allows a change in dose either manually or automatically based on the feedback from clinical or physiological monitors.[15] In order to achieve precise dosing, improved haemodynamic stability, and faster recovery, a reliable feedback is very important.[16] Advancements in TCI techniques are aimed to achieve reliable feedback either from physiological monitoring or through processed electroencephalogram (pEEG) monitoring, which have shown some promise in improved haemodynamic stability and faster recovery.[16] Knowing the median effective effect-site concentration of the drug being used in TCI for a particular type of surgery can be useful and can guide the anaesthesiologist during drug infusion; for example, a median effective effect-site concentration of 3.38 μg/ml of propofol is required to prevent patient movement during uterine dilatation and curettage.[17]

Sedasys, a computer-assisted personalised sedation system, integrates continuous physiologic monitoring with patient feedback to control the depth of sedation. This technique is found to be very effective for non–operating room sedation as it intends to maintain constant sedation, thereby reducing the risk of apnoea, haemodynamic instability, and loss of responsiveness.[18]

pEEG monitoring can be used to monitor the effect of the anaesthetic drug on the cerebral cortex, thereby reducing the incidence of awareness during TIVA.[19] Studies have shown that propofol requirement can be significantly reduced by titrating the dose to a processed EEG score.[20] It is also recommended to use this monitor whenever muscle relaxants are used with TIVA.[21]

iControl-RP and McSleepy are two automated CLADS. In iControl-RP, in addition to bispectral index (BIS), peripheral oxygen saturation, heart rate, respiratory rate, and blood pressure are monitored and drug delivery is altered automatically based on these parameters. In McSleepy, all three components of general anaesthesia, like hypnosis, analgesia, and neuromuscular blockade, are monitored using BIS, Analgoscore, and train of four testing, respectively. Studies have shown better control of hypnosis and faster extubation with McSleepy system compared to manually administered anaesthesia.[22]

Specialised infusion sets

Specialised extension sets should be used during TIVA for better clinical effectiveness and patient safety. These sets should have a Luer-lock connector at each end, an anti-syphon valve on the drug delivery line, and an anti-reflux valve in the fluid administration line. In order to reduce dead space, one should also make sure that drug and fluid lines are placed as close to the patient as possible.[21]

Mobile apps

iTIVA and TIVAManager are computer programs created for monitoring plasma concentrations of anaesthetic drugs and guide the administration of TIVA. iTIVA is a pharmacokinetic/pharmacodynamic simulation programme based on mathematical models and calculates a dose required to achieve the target plasma, or effect-site concentration. As infusion schemes are obtained from published models, there are chances of wide variation in the plasma concentrations and clinical effects achieved. Currently, its use is limited to educational purposes to demonstrate pharmacokinetic principles. TIVA Manager has got added advantages like monitoring of concentrations of anaesthetics and planning of anaesthesia with TCI, availability of a wide range of pharmacokinetic/pharmacodynamic models, better optimisation of anaesthesia course by assessing the effect of administered drug, and availability of data for scientific investigations and education.[19,23]

TOTAL INTRAVENOUS ANAESTHESIA IN THE SPECIAL POPULATION

In spite of the technical advancements in TIVA, research regarding its use in the extremes of population, especially elderly patients, remains sparse. There are specific pharmacokinetic and pharmacodynamic differences in paediatric and geriatric patients compared to adults. Knowledge of these differences in drug behaviour becomes imperative for the successful and safe administration of TIVA in this population group.

Total intravenous anaesthesia in children

In the past, manual infusion regimens were used to maintain a target concentration in paediatric TIVA.[24] But as soon as it became clear that the maintenance doses being employed were insufficient, greater thought was given to developing a model that catered to paediatric requirement. Hence, two paediatric TCI programs of Kataria[25] and Paedfusor[26] came into practice. Others have been described too, like the Rigby Jones, Davis, and Minto models. The Kataria model can be used for ages above 3 years or those weighing more than 15 kg, whereas Paedfusor can be used for ages as low as 1 year or those with weight as low as 5 kg. Although the Paedfusor model is extensively researched, one should still be careful with the bolus doses as there may be some overestimation of the doses. This is particularly true for children who are haemodynamically unstable. Unlike in the adults, the child TCI models do not have effect-site prediction of the plasma concentration. Thus, loss of consciousness should be ascertained before doing an airway intervention. For obese children, since the dose calibration does not exactly follow a linear increase, it is practical to calculate the ideal body weight and add 20% to it. To reduce the risk of propofol infusion syndrome in neonates, it is suggested to keep the infusion rates to less than 10 mg/kg/h if infusions are required for more than eight hours.[27]

Remifentanil undergoes rapid equilibration and has been extensively used in paediatric TIVA. Adequate analgesia is achieved with remifentanil in a dose of 0.1 μg/kg/min. For surgeries with higher stimulus, the doses can be increased to 0.5 μg/kg/min. Fentanyl, alfentanil, midazolam, and alpha-2 agonists, can be used but may cause delay in recovery times. Ketamine, though used, holds a controversial place due to its ability to cause neuroapoptosis when given as an infusion, especially in younger children.[28] Nonetheless, the successful use of ‘ketodex’(ketamine and dexmedetomidine combination) has been reported for magnetic resonance imaging (MRI) in syndromic children.[29]

Total intravenous anaesthesia in geriatrics

Considering the hypothetical three compartment model of drug distribution, since the central compartment has a lower volume (reduction by 25%) and decrease in drug clearance by 20%, the elderly require a lower loading dose.[30] Pharmacodynamically, the sensitivity of receptors to propofol also increases, thus further decreasing the requirement. Similarly, the doses of opioids also should be reduced. Currently, none of the TCI models available make elderly-specific adjustments. The closest that we can get to is the Schnider model, which keeps the loading constant, but decreases the maintenance and clearance.[31] In a study comparing the Schnider and Marsh models in patients aged 69–100 years, no differences were found in the propofol dose requirements, decreases in mean blood pressure, and requirement for vasopressors.[32] Other models like the White and Schütler model also underestimate the changes in the pharmacology of drugs in the elderly. In summary, the effect-site concentrations must be cut down so as to not overdose, and as a thumb rule, one should slowly titrate the doses to effect, with the simultaneous use of EEG monitoring.

Total intravenous anaesthesia in pregnancy

TIVA in pregnancy is not very different than it is in non-pregnant patients. Even though there is decrease in maternal albumin, the concentration required to induce loss of consciousness in pregnant patients is not different. Due to lack of studies in pregnant patients, the Marsh model with actual body weight input appears feasible.[33]

CORONAVIRUS DISEASE 2019 AND TOTAL INTRAVENOUS ANAESTHESIA

The merits of TIVA were highlighted during the coronavirus disease 2019 (COVID-19) pandemic, confirming its potential further in the post-COVID clinical practice as well. Prevention of aerosol generation with the use of TIVA was the main advantage and made TIVA popular during the COVID-19 pandemic. It also avoided the deleterious effects of immunosuppression and respiratory irritation that were associated with inhalational agents. Many peripheral surgeries could be done in the spontaneously breathing patient without any airway device. This avoided airway instrumentation and resultant droplet and aerosol generation. During the COVID-19 crisis, obese, hypertensive, and diabetic parturients with COVID-19 infection who required emergency caesarean section were effectively and safely managed with TIVA as an adjuvant to central neuraxial blockade.[34]

TOTAL INTRAVENOUS ANAESTHESIA OUTSIDE THE OPERATING ROOM

TIVA has tremendous potential in NORA practice. It can be adopted for sedation and analgesia in catheterisation labs for monitored anaesthesia care and neuro-interventional and percutaneous device insertion procedures. All hybrid procedures in the operating room, MRI suites, and the intensive care unit have the scope for judicious use of TIVA.[1,35]

TOTAL INTRAVENOUS ANAESTHESIA AND THE ENVIRONMENT

TIVA is devoid of the risks of occupational exposure and negative environmental impact that are associated with volatile anaesthetic gases. It can be used as an alternative to inhalational anaesthetic agents, but it is not entirely devoid of potential negative environmental effects. Nevertheless, one has to take into account the total environmental impact of TIVA and agents such as propofol must be disposed off in an appropriate manner.[36,37] TIVA in the paediatric population has a positive environmental impact by reducing carbon footprint compared to inhalational anaesthesia.[38] The choice of TIVA technique, particularly in the paediatric patient population can thus help to save the environment from the negative effect of anaesthetic gases and thus provide the future generations with a safe environment.[39]

LIMITATIONS OF TOTAL INTRAVENOUS ANAESTHESIA AND SCOPE OF IMPROVEMENT

In spite of its many advantages, TIVA has many limitations. The anaesthesiologist must be aware of the potential drawbacks of TIVA. The most favoured TIVA drugs such as propofol and remifentanil are not devoid of adverse effects. One is likely to face problems such as the propofol infusion syndrome and hyperalgesia. TIVA in morbidly obese patients must be practised with extra precautions for a safe recovery from the accumulation of drugs.[2]

Difficult cannulation can hinder the administration of TIVA, especially in children, the obese, and the elderly. Pain on injection interferes with the use of certain agents in total intravenous sedation techniques. Ciprofol, the new drug being tested in China and Australia, may be the answer to this problem.[14] Bacterial contamination is known to occur with lipid-based emulsions like propofol, especially in prolonged procedures. Strict asepsis needs to be followed and change of the administration sets is recommended in prolonged infusions. Frequent misconnections leading to inefficient drug delivery have been reported in literature, leading to awareness during the procedures. To avoid this, all infusion lines should be visible and continuously monitored and checked every 15 minutes. TCI and depth of anaesthesia equipment are expensive and are not available in many centres. Though these equipment are a one-time investment to reap much greater benefits, the cost of drugs or disposable monitoring electrodes is not enticing.[40] The favourable effect of TIVA in the environment is offset by the wastes generated, such as plastics, which cause additional greenhouse effects.

Awareness during anaesthesia is an appalling complication that makes anaesthesiologists reluctant to use TIVA when adequate monitoring is not available. As there is no ability to monitor drug concentration in real time, uncertainty often exists when a combination of drugs and muscle relaxants are being administered. When it comes to managing haemodynamic instability and patients with opioid and benzodiazepine tolerance using TIVA, the choices are limited. Nonetheless, the chances of neurotoxicity with the prolonged administration of these agents are yet to be evaluated.[41]

The most common contributory factor for awareness under TIVA is inadequate education and training. Training in TIVA with a holistic approach should be a part of core anaesthesia training to ensure competency and safety in TIVA use. The Association of Anaesthetists and the Society for Intravenous Anaesthesia have recommended joint guidelines for the use of TIVA drugs, concentrations, infusion pumps, specific clinical scenarios, precautions, monitoring, and training for clinical practice.[21] Similarly, there should be national or international guidelines for the safe, best, and easy practice of TIVA. The relevant anaesthetic organisations should establish a set of standards and recommendations for the best practice of the use of TIVA, and the scope of TIVA can thus escalate in leaps and bounds. Research studies on TCI by Indian anaesthesiologists are still sparse and they need to gather more momentum so that more local data are generated and our own pharmacokinetic models can be generated based on our population genomics.

SUMMARY

Though the maintenance of general anaesthesia can be done with the administration of inhaled volatile anaesthetics or by TIVA, administering inhalational anaesthesia is difficult in NORA or during patient transfer, is less desirable in COVID-19 cases, and is contraindicated in specific conditions. Therefore, all anaesthesiologists should be able to deliver TIVA, both competently and safely. Use of infographics in TIVA and training workshops can improve the knowledge and appeal of TIVA in routine anaesthesia practice. While advances in TIVA are dependent on newer drug inventions, research is pertinent over optimising and identifying appropriate and available drug combinations. Advancement in digital technology with mobile applications has increased the scope of TIVA in day-to-day use. Limitations can always be resolved by providing good training to the anaesthesiologists, and the formulation and update of guidelines can establish a safe and efficient practice of TIVA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.