Abstract
Total intravenous anaesthesia (TIVA) is the delivery of general anaesthesia entirely via the intravenous route. This can be achieved through a variety of drugs. The most common combination used is propofol and a short-acting opiate, such as remifentanil. Different target- controlled infusion (TCI) models are used, depending on the age of the child.
TIVA use in paediatric anaesthesia offers certain benefits over volatile anaesthesia. Advantages for the patient include reduced postoperative nausea and vomiting (PONV), delirium, time in recovery and less airway reactivity. It provides a safe method of anaesthesia for children with certain conditions who cannot have volatile anaesthesia. There are also environmental benefits to using TIVA instead of volatile anaesthesia and surgical benefits, for example in cases requiring somatosensory monitoring.
TIVA use in paediatrics is increasing and this article will provide an overview of use in the paediatric population as well as some of the barriers and disadvantages.
After reading this article you should be able to:
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understand the benefits of using total intravenous anaesthesia (TIVA) in paediatric anaesthesia
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be aware of the target controlled infusion models that can be used in the paediatric population
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discuss the environmental advantages and disadvantages of using TIVA
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outline the contraindications to using TIVA in paediatric anaesthesia
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understand rational for depth of anaesthesia monitoring in the paediatric population
Introduction
Total intravenous anaesthesia (TIVA) is the induction and maintenance of general anaesthesia using a combination of intravenous agents without any given by the inhalational route (including nitrous oxide). In a recent survey of 290 UK paediatric anaesthetists over half reported using TIVA at least weekly, although one-third use it rarely or never. This represents an increase in usage in paediatrics; in 2008 a national survey reported that only 10% of paediatric anaesthetists were using TIVA at least weekly. This increase in use reflects the perceived advantages in paediatrics including surgical, patient and environmental factors. However, significant barriers to its use still exist; lack of equipment and familiarity with technique, depth of anaesthesia monitoring and concerns about the safety of prolonged propofol infusion.
Compartments
When a drug is administered into a central compartment (plasma/blood), it undergoes redistribution, metabolism and elimination. This can be modelled using compartmental models; in the case of propofol using three compartments ( Figure 1 ). Whilst these compartments are, in reality, merely mathematical constructs it is illustrative to think of these in biological terms. Compartment one is the plasma, and compartment two is highly vascular tissue (e.g. muscle). Compartment three is poorly vascularized tissue (e.g. adipose). In addition, there is a diffusion from the central compartment to the effector site (brain). Distribution constants describe movement of the drug between these compartments. For example K 12 is the distribution constant from the central compartment to compartment two, and K 21 is the distribution constant from compartment two back to the central compartment. In addition, drug is eliminated from the central compartment, and this is given the constant K 10 .
Pharmacokinetics and pharmacodynamics: propofol and remifentanil
Following a bolus of an intravenous drug, the plasma level will rapidly peak, followed by a rapid decline due to redistribution, metabolism and elimination. In order to reach a steady state plasma concentration, a continuous infusion is required at a rate which is matched by the rate of redistribution to peripheral compartments and the rate of elimination from the central compartment. Whilst this is possible to achieve with a continuous infusion only, it would be slow, and therefore an initial bolus followed by a continuous infusion is used in practice. Once equilibrium is achieved, it is theoretically possible to maintain with an infusion rate which matches the rate of elimination. However, longer infusion duration is associated with increased distribution to the third compartment, and a subsequent redistribution back to the central compartment on cessation of the infusion. The time taken for the plasma concentration of a drug to reduce by half following a steady-state infusion is referred to as the context-sensitive half-time (CSHT). Drugs with a shorter CSHT offer a more predictable “off”, and are advantageous to use during surgical procedures. Figure 2 shows the CSHT for some commonly-used anaesthetic infusions. This demonstrates the rationale for the most frequently-used combination of propofol and remifentanil for TIVA.
Remifentanil provides analgesia and anaesthesia resulting in reduced blood pressure and heart rate. At high doses this can manifest as hypotension, bradycardia and apnoea. Remifentanil is associated with postoperative hyperalgesia. It is recommended to give longer acting analgesia around 30 minutes before stopping remifentanil for adequate analgesia. Like all opiates remifentanil can cause nausea and vomiting, pruritis and postoperative shivering.
Paediatric target-controlled infusion (TCI) models
Dedicated pharmacokinetic pumps utilize software which, according to their modelling, control the effector and/or plasma concentrations of propofol and remifentanil using mathematical processing. These allow for rapid changes to targets in response to surgical requirements. Cognitive load and potential for error are reduced compared to manual adjustments.
A bolus/elimination/transfer (BET) principle is used to derive the constant plasma level of the drug. Once the bolus has filled V 1 , the subsequent infusion allows for the rapid (V 2 ) and slow (V 3 ) distribution, as well as the elimination rate constant K 10 . As mentioned earlier, when a steady state is reached, the infusion rate drops to match the rate of elimination. With propofol, this occurs after approximately 20 hours of continuous infusion.
Paedfusor and Kataria
Both these models use weight as the parameter for scaling the compartments V 1-3 . In the Paedfusor model, the weight is additionally used to calculate the elimination constant K 10 . It is an extrapolation of the Marsh modelling, and scales V1 in a non-linear fashion ( Table 1 ) above the age of 12 years.
| Model | Fixed parameter | Variable parameters | Parameter determined by | Recommended target site (targeting effect site gives a bigger initial bolus with potential increased side effects, e.g. hypotension) |
|---|---|---|---|---|
| Marsh | All rate constants | V 1,2,3 | Weight | Effect or plasma site |
| Schnider | V 1 = 4.7 litres V 3, K 13, K 31 | V 2 K 12, K 21 K 10 | Age Age Age, weight and LBM | Effect site |
| Paedfusor | All rate constants except K 1o | V 1,2,3 K 10 | Weight Weight | Effect or plasma site |
| Kataria | All rate constants | V 1,2,3 | Weight | Effect or plasma site |
| Minto | V3 = 5.42 litres | V 1,2 and rate constants | Age, LBM | Effect or plasma site |
| Eleveld | – | V 1,2,3 | Age, weight | Effect site (most accurate model for predicting effect site) |
Marsh
The Marsh model ignores age (it has a minimum programmable age of 16 years) and uses an initial bolus related to a V 1 which is much larger than other adult models – this leads to a larger initial bolus. It is important to be mindful of this if using TIVA in haemodynamically unstable patients.
Eleveld propofol
The Eleveld model provides the first allometric scaling of infusion dosing; that is, relating the size of the patient to the physical characteristics of their age and physiology. It also incorporates compartment allometry, and a maturation model for clearance (CL) based on post-menstrual age. It is best utilized as an effector-site model. It also assumes a low K e0 (distribution to a theoretical effect site compartment). This results in a prolonged gap with no infusion following the (relative to other models, large) initial bolus. The model has a maturation model, relating to the reduced clearance of propofol in the neonatal population (though this may not be fully implemented in commercially available pumps). The Eleveld model assumes a rapid maturation, which is 95% complete by 5 months of age. The Eleveld model is also unique in adjusting its pharmacokinetics with concomitant opioid use.
Minto remifentanil
The Minto model is a three-compartment model that can be programmed to target effect site (cet) or plasma site (cpt). Age, weight (kg), height (cm) and sex are used to calculate lean body mass (LBM) which determines the fixed (V3) and variable (V1, V2 and rate constants) parameters. It has an age cut off of 12 years and a minimum weight of 30 kg. Targeting cet uses higher plasma concentrations of remifentanil (3–4× bolus size compared to cpt) and has an increased risk of chest wall rigidity, apnoea and non-vagal mediated bradycardia. It is recommended to use an incremental dosing approach to desired cet to reduce this risk. ,
Eleveld remifentanil: the Eleveld remifentanil model is similar to the adult Minto model. It too uses allometric scaling, but pharmacodynamic data is extrapolated from that in adults, and therefore is probably best used cautiously in children living with obesity.
Remifentanil infusion
Remifentanil can be run as an infusion (micrograms/kg/minute). The disadvantage of this is that it uses only actual body weight (ABW) to predict the pharmacokinetics of remifentanil in an individual patient. LBM is a more accurate variable.
Use of remifentanil for general anaesthesia usually requires a cet of 3–10 ng/ml or an infusion of 0.1–0.3 micrograms/kg/minute. This can be titrated according to response. ,
Additional medications
Opioids are the most common drug used alongside propofol as part of a TIVA regimen. Other drugs that act synergistically to reduce the required brain propofol concentration, improve haemodynamic stability and provide analgesia are ketamine, α-2 agonists, nitrous oxide, magnesium and benzodiazepines. Dexmedetomidine is an α-2 agonist that provides analgesia, sedation and anxiolysis. Typically it is given as an IV loading dose of 1 microgram/kg followed by an infusion of 0.2–0.7 micrograms/kg/hour. Its sedative effects can prolong recovery and so it is recommended to stop the infusion around 30 minutes before the end of anaesthesia. Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has a synergistic sedative effect when combined with propofol. It can be given as an IV loading dose of 0.1–1 mg/kg followed by an infusion of 0.1–0.2 mg/kg/hour. It has strong analgesic effects and can reduced the hyperalgesia seen with other agents. The cardiovascular effects of increased heart rate and blood pressure can be a useful contrast to help offset the depressor effects seen with other agents. Side effects of ketamine include nausea, hallucinations and increased secretions. To minimize dissociative anaesthesia in recovery ketamine should be stopped 30 minutes before the end of anaesthesia.
Advantages of TIVA
Surgical considerations
TIVA is the anaesthetic technique of choice in children having spinal surgery to allow accurate monitoring with somatosensory and motor evoked potentials. Inhalational agents reduce the amplitude of the evoked potentials and so are not suitable.
TIVA is used in children having neurosurgery to provide haemodynamic stability and maintain cerebral perfusion pressure (CPP), a stress-free awake extubation to allow timely assessment of neurology and reduction in intracranial pressure (ICP) by decreasing cerebral blood flow and metabolic activity.
Neuromuscular disease
TIVA is a necessary safe alternative anaesthetic technique for children with certain types of neuromuscular disease who cannot have inhalational anaesthetic agents due to the risk of malignant hyperthermia and/or rhabdomyolysis. Children may already have a confirmed diagnosis of malignant hyperthermia (previous history or muscle biopsy) or a significant family history or specific predisposing condition (central core disease, King–Denborough syndrome and Evans myopathy). Rhabdomyolysis risk is highest in younger children (<8 years old) with neuromuscular disease.
In addition to using TIVA, at risk of MH, should be done first on the list using a clean vapour free anaesthetic machine to minimize exposure. All children with a neuromuscular or metabolic condition having an elective procedure should have an anaesthetic pre-assessment and be discussed with a specialist metabolic team to make a safe perioperative plan.
Airway surgery and reduced airway reactivity
Up to 3 in 100 children will have a perioperative respiratory adverse event (PRAE) under general anaesthesia. Children with a respiratory co-morbidity, e.g. asthma, household exposure to tobacco smoke, having airway surgery or a those with a recent upper respiratory tract infection (within 2 weeks of anaesthesia) are at a higher risk.
TIVA has a reduced incidence of PRAEs compared to inhalational anaesthesia. The risk of PRAEs is significantly lower when comparing both intravenous induction versus inhalational induction and intravenous maintenance versus inhalational maintenance. A recent study reported children who had an inhalational induction were significantly more likely to have laryngospasm on emergence of anaesthesia, regardless of the type of maintenance of anaesthesia used.
TIVA offers a distinct advantage for airway surgery and shared airway procedures. Reduced airway reactivity results in less laryngospasm, bronchospasm and stridor at extubation. Furthermore, TIVA does not rely on the airway for delivery of anaesthesia and is not affected by any airway obstruction that may occur during the procedure. In the case of a difficult, prolonged or failed intubation TIVA provides a method of delivering anaesthesia that ensures adequate depth during airway management and reduces the risk of awareness 5th national audit project (NAP5). TIVA is titratable to maintain spontaneous ventilation in children where dynamic assessment of the airway during respiration is required.
Reduced postoperative nausea and vomiting
TIVA reduces the incidence of postoperative nausea and vomiting (PONV). This is especially true when propofol is used for both induction and maintenance of anaesthesia. Propofol has anti-emetic effects that last for up to 30 minutes postoperatively.
Children over the age of 3 years old are at increased risk of PONV. Additional patient risk factors for PONV are a previous history, post-pubertal female patients or a history of motion sickness. Surgery type and operation length contribute to PONV risk. Strabismus surgery, tonsillectomy and middle ear surgery, as well as surgery length >30 minutes, all carry a higher risk of PONV. TIVA using propofol as a single agent or in conjunction with short-acting opioids, is recommended in these cases to mitigate the risk. Although a side effect of opioid analgesia is nausea and vomiting, short-acting opioids used as part of a TIVA regimen do not increase the risk.
Delirium
Emergence delirium (ED) is characterized by a range of psychomotor disturbances in children immediately following general anaesthesia, including irritation, irrational behaviour, inconsolability, restlessness and delusions. It is a diagnosis of exclusion, and other contributing factors (pain, hypoglycaemia, hypokalaemia, hypotension and ischaemia, for example) should always be considered. The incidence cited is hugely variable, but 20% is generally accepted as a reasonable estimate and it is most common in those aged 2–6 years. Several studies have compared inhalational and intravenous anaesthetics using emergence delirium as the primary outcome. A systematic review and metanalysis demonstrated that, in 14 trials pertaining to paediatrics, the incidence of ED was lower with propofol anaesthesia than sevoflurane. One theory is that a rapid emergence is a cause of ED; desflurane (a volatile agent with lower solubility) is associated with a more rapid offset time than sevoflurane and also a higher incidence of ED. However, other factors are likely to play a significant part in ED, such as surgical type, delayed onset of adequate postoperative analgesia and preoperative anxiety.
Disadvantages and barriers to use
TIVA use in paediatrics has risen by over twenty percent in recent years. Main barriers to TIVA use are:
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Concerns about propofol-related infusion syndrome (PRIS)
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Risk of awareness
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Unfamiliarity with the technique
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Lack of equipment (TCI pumps and/or depth of awareness monitoring)
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Case length and reduced efficiency for high turnover lists
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Licensing in children.
A recent survey reported the biggest barriers were lack of equipment in departments, perceptions of reduced theatre efficiency and less experience using TIVA in paediatric practice. ,
PRIS
Propofol interferes with mitochondrial energy production through inhibition of multiple complexes of the electron transport chain and transport of free fatty acids (FFA) across the mitochondrial membranes. In rare cases this can result in propofol-related infusion syndrome (PRIS). PRIS causes rhabdomyolysis, acidosis and multi-organ failure. Children are at higher risk for PRIS as a result of lower glycogen stores and greater dependence on fat metabolism. PRIS is more likely with prolonged propofol infusions (>48 hours) at high doses (>4 mg/kg/hour) and in children who are critically ill and on steroids and/or catecholamines. The risk is considerably lower in the context of TIVA for general anaesthesia.
Children with metabolic disease are at increased risk of developing PRIS. Examples of these conditions are mitochondrial disease, fatty acid oxidation disorders and co-enzyme Q deficiency. Anaesthetic technique should aim to minimize the risk of metabolic decompensation and encephalopathy. Propofol infusions should be avoided in patients at risk. Propofol boluses are considered relatively safe in children without severe metabolic disease who are currently well. However, it is not the anaesthetic technique of choice. Perioperative care should be planned in conjunction with specialist metabolic team involvement who have knowledge in the underlying condition and its management.
Practicalities for TIVA
Staff should be educated and trained to use TIVA in the paediatric population. Systems should be in place to prevent errors occurring during TIVA administration. The 5 th National Audit Project on accidental awareness during general anaesthesia found TIVA used with a neuromuscular blocking drug increased the incidence of awareness twofold compared to volatile anaesthesia. Awareness during TIVA is higher risk when switching from an inhalational technique to TIVA, e.g. post-induction or on transfer to a different hospital area such as intensive care. Technical problems that result in a failure of adequate drug delivery can lead to awareness if not recognized. Technical failure can occur at any point in the drug delivery system from the cannula to the pump. The Association of Anaesthetists (AOA) 2018 recommendations can help reduce the risk of technical failure and ensure good clinical practice when using TIVA. This is summarized below:
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Prepare adequately for intravenous access with early patient discussion, distraction techniques and topical local anaesthesia
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Use local anaesthesia with lidocaine to reduce the pain of propofol on injection
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Where possible two cannula should be sited
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Ensure the cannula used for TIVA is attached firmly to the skin. Additional tape is useful to help secure the TIVA set, especially in smaller children
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Make sure the skin is dry before attaching the cannula dressing. Opsite transparent film dressing spray is useful, especially when topical local anaesthetic cream has been applied to numb the skin prior to cannulation.
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The cannula being used for TIVA should be easily accessible and visible throughout the case. The dressing covering the administration site should be transparent.
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The cannula site should be checked during the case to ensure there are no problems with drug delivery and that the cannula is still working
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Specific TCI pumps should be used
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The pumps should be programmed once the syringe is inserted to ensure the set-up is correct for the intended drug
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Dedicated TIVA administration sets should be used that incorporate luer-lock connections at each end, anti-syphon valves on drug delivery lines and anti-reflux valves on the fluid administration line
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Ensure the pumps have sufficient battery and plug the pumps in
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Make sure the patient details (age, gender, weight etc) are entered correctly into the pump
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The high and low pressure infusion alarms should be set (to warn of a ‘tissued’ cannula or disconnection respectively)
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Ensure the cannula is flushed once the TIVA set is disconnected at the end of the case
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Depth of anaesthesia (DOA) monitoring should be used when neuromuscular blocking drugs are administered in children >1 year old
Depth of anaesthesia monitoring
It is recommended that DOA monitors are used when TIVA is the sole anaesthetic technique and a neuromuscular blocking drug has been used. This is to reduce the risk of accidental awareness. There are two different types of electroencephalogram (EEG)-based systems; processed EEG and density spectral array (DSA).
Processed EEG monitors convert the raw EEG into waves of different frequencies and combine different variables to create a single bispectral (BIS) index. The indices scale is 0 (complete burst suppression or an isoelectric EEG) to 100 (completely awake). Appropriate anaesthesia depth is delineated between 40 and 60.
Density spectral array is a two-dimensional representation of the EEG frequency and power over time, that provides more information than the derived indices. Colours are used to represent the strength of the different waves at any moment in time.
DOA monitoring allows titration of anaesthesia to prevent either over-sedation or light-anaesthesia and can reduce the time to emergence from anaesthesia and discharge from recovery.
One limitation to DOA monitors in the paediatric population is the age of the child. Processed EEG monitors use data that have been created and validated from adult patients. Paediatric brains are only considered fully mature at 12 years old in terms of myelination and synaptogenesis. Current devices can be safely used in children ≥12 years old, cautiously used in children 1–5 years old and are not accurate or reliable in infants (up to 1 year old) or neonates (up to 1 month old).
The processed EEG should be interpreted with caution in children with underlying neurological disease, either inherited (metabolic or genetic) or acquired (hypoxic encephalopathy or neurodegenerative disease). Atypical EEG patterns and concurrent use of drugs that affect the nervous system (e.g. anti-epileptics) have found lower BIS values in this sub-population when the same anaesthetic dose is used. It is recommended that DOA monitoring is used in this sub-group when adequate DOA is harder to assess as a result of underlying neurological disease and potential communication difficulties.
The anaesthetic drugs used as part of a TIVA regimen can have different effects on the processed EEG. As blood propofol concentration is increased there is a corresponding slowing of the EEG wave and reduction in the BIS. Ketamine causes an increase in BIS value and entropy that equates to a deeper plane of anaesthesia. α-agonists, e.g. dexmedetomidine, used as an adjunct with propofol anaesthesia, decrease the BIS value. There is limited evidence about the impact of opioid drugs on BIS. Neuromuscular blocking drugs reduce BIS probably as a result of a decrease in electromyelogram (EMG) activity.
Environmental considerations
The NHS has pledged to deliver a net-zero health service by 2040. Children born today are vulnerable to the impact of climate change with 90% of the burden of diseases linked to climate change affecting children under 5 years old. The impact of anaesthetic technique on the environment should be minimized where possible.
Life cycle analysis (LCA) can be used to evaluate the impact of an anaesthetic technique on the environment. This captures all drugs and equipment involved from manufacture to disposal (‘cradle to grave’). LCA has shown propofol TIVA to have a carbon footprint four-orders of magnitude lower than volatiles. This is true even considering the single-use plastic utilized, electricity required for the pumps and the drug manufacturing, transportation and waste. A recent survey found one third of anaesthetists use TIVA in the paediatric population because of the environmental benefits. ,
However, TIVA is not completely carbon free. The biggest carbon footprint from TIVA comes from the energy used to supply the pumps. There is also concern about the pharmaceutical contamination of ecosystems and the toxic effects on aquatic life. Propofol is toxic to aquatic species. One percent of propofol is excreted renally unchanged. Unused drugs remaining at the end of the case must be disposed of correctly in order to be incinerated. Incorrect disposal, e.g. flushing down a sink, causes direct water table contamination. ,
The singe use plastic in the syringes utilized for TIVA is commonly polyvinyl chloride (PVC). One kilogram of PVC results in 6 kg of CO 2 emissions in its lifecycle. However, the impact of TIVA can be reduced by avoiding unnecessary drug preparation and considering the length of the case and amount of drug required. A recent modelling study found the environmental impact of TIVA reduced as the length of the case increased. For cases where an inhalational induction occurred TIVA was only better for the environment in longer cases of greater than 1 hour duration compared to sevoflurane.
The environmental benefit of TIVA is most stark compared to nitrous oxide and the inhalational agent desflurane. Low flow anaesthesia with sevoflurane combined with the gas capture technology in the future may become an equitable alternative.
Conclusion
TIVA is a useful anaesthetic technique in the paediatric population. It offers considerable advantages for patients, the environment and staff. All staff should be trained in its safe use and understand both the benefits and contraindications in this patient group.
References
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