Total intravenous anesthesia (TIVA) refers to the
intravenous administration of
anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using
chloral hydrate,[1] and the common anesthetic agent
propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of
general anesthesia in order to improve post-operative recovery.
In the mid-19th century, specific equipment was developed to enable intravenous anesthesia. Francis Rynd developed the hollow needle in 1845,[1] and Charles Gabriel Pravaz developed the
syringe in 1853,[1] which allowed drugs to be administered intravenously.
Using this new mode of delivery, many chemical compounds were tested as intravenous anesthetics. This was pioneered by Pierre-Cyprien Oré in 1872, who reported using
chloral hydrate as an intravenous anesthetic.[1] However, these early trials were associated with high mortality.[1]Hedonal was later developed in 1909 for general anesthesia, although with limited success due to its long duration of effect.[3] These insufficiencies encouraged the development of
paraldehyde by Noel & Souttar,[4]magnesium sulfate by Peck & Meltzer[5] as well as
ethanol by Nakagawa[6] as intravenous anesthetic agents.
Propofol (di-isopropyl phenol) was synthesized by Glen and colleagues in the early 1970s,[7] but its first formulations were temporarily withdrawn due to a number of adverse reactions during clinical studies.[1] In 1983, a lipid emulsion formulation of propofol was available, which carried great potential during clinical trials.[8] It was licensed for use in Europe in 1986 and received
FDA approval in the US in 1989.[1] Propofol is now used worldwide with a well-defined pharmacological profile for a variety of medical uses.
Medical uses
TIVA is used to induce
general anesthesia while avoiding the
disadvantages of volatile anesthesia (and traditional inhalation agents).[9] Intravenous anesthetic agents are titrated at safe doses to maintain
stage III surgical anesthesia (unconsciousness, amnesia, immobility, and absence of response to noxious stimulation).[10] The use of TIVA is advantageous in cases where volatile anesthesia is of high risk or is impossible, such as cases involving
morbidly obese patients.[11][12] TIVA has also been used for anesthetic delivery at sites of trauma such as serious accidents, disasters and wars.[1]
Rapid emergence out of the effects of infused drugs as soon as the
infusion is terminated.
Propofol-based TIVA significantly improves post-operative recovery profile and comfort, minimizes
nausea and
vomiting, facilitates rapid recovery, greater
hemodynamic stability, preservation of
hypoxic pulmonary vasoconstriction, reduction in intracerebral pressure, and reduces the risk of organ toxicity.[14] Despite these advantages, it accounts for a small proportion of general anesthetics due to the relatively expensive cost of preparation and maintenance.[15]
The drug interactions between sedative-hypnotic agents and adjuvant agents suggest that dosing regimens cannot be fixed.[19] Instead, dosing should be based on adjusted body weight or estimated lean body weight, especially for obese patients. It is recommended that drug doses be titrated in brief intervals (around 20 to 60 seconds).[22]
Smart pumps are commonly used to administer potent anesthetics and various vasoactive drugs such as
vasopressors,
inotropes,
vasodilators, which need to be continuously titrated in the operating room.[24] Smart pumps are advantageous since they administer safe doses with a programmed infusion rate within pre-existing limits based on the institutional standardized medication library.[25]
Syringe pumps are smaller infusion pumps that allow the administration of small amounts of induction agents at a precise rate.[26] The accuracy of syringe pumps is dependent on the selection of syringes during pump programming. Most pumps are able to identify the size of the syringe automatically when the syringe manufacturer's name is input correctly.[27]
Target-controlled infusion (TCI) systems are assisted by computer systems that make use of
pharmacokinetic and
pharmacodynamic modelling to maintain a target concentration of anesthetic in the brain.[28][29] TCI requires clinicians to input a target concentration for an anesthetic or other agents, from which the computer calculates the amount of agent required for the input concentration, then the infusion pump delivers the calculated
bolus dose.[30] Subsequently, the computer continuously recalculates how much drug is in the system and influences the amount of drug required to maintain the desired concentration at the effect site.[31]
Maintenance
During TIVA, the continuous assessment of
heart rate,
blood pressure, and
state of consciousness is essential when titrating anesthetic agents.[20][23] Processed
electroencephalogram (EEG) monitoring is used to assess anesthetic depth.[32] However, there is 30 seconds of lag time between the subject's state of consciousness and the processed EEG signal. This limits its usefulness during the induction of anesthesia.[20][21]
Intravenous agents
Propofol,
etomidate and
ketamine are common
intravenoussedative-hypnotic agents for the induction of TIVA.[19] Their highly lipophilic nature allows the rapid onset of anesthesia upon intravenous injection.[17] It also enables penetration through the
blood–brain barrier and effective
perfusion to the brain. However, the rapid
redistribution of these agents from the brain to other muscle and fat tissues causes it to have a short duration of action.
Adjuvant agents are typically administered in addition to sedative-hypnotic agents to supplement the induction of TIVA.[17]
Sedative-hypnotic agents
Propofol
Propofol is usually the selected sedative-hypnotic agent to maintain general anesthesia through TIVA because of its rapid onset and offset, beneficial properties and few adverse effects.[33] Its rapid onset of action is due to its high
lipid-solubility, rapid redistribution from the brain to other parts of the body, and rapid
clearance (20 to 30 mL/kg/minute).[33] Most propofol is
conjugated in the liver with pharmacologically inactive metabolites.[33] Although it has a long
terminal elimination half-life of 4 to 30 hours,
plasma concentrations remain low after the typical induction dose.[33]
Ketamine is suitable for hypotensive patients, or patients with risks of developing
hypotension (e.g. those who have
hypovolemia,
hemorrhage,
sepsis or severe cardiovascular compromise).[40][41] This is because ketamine is associated with increased blood pressure, heart rate and cardiac output.[42] Its advantages include profound
analgesic properties,
bronchodilation, and the ability to maintain
airway reflexes and
respiratory drive.[43] It could also be induced via the
intramuscular route if TIVA access gets lost. However, its potential adverse effects impact cardiovascular and neurological functions.
Potential adverse effects on cardiovascular activities are listed below:[44]
Increase in myocardial
oxygen demand due to a rise in heart rate, blood pressure and cardiac output
Choice of specific adjuvant agents is dependent upon the patient and procedure-specific factors.[49] Opioid is a commonly administered adjuvant agent as the analgesic component of TIVA. However, when used with propofol, it might exacerbate the adverse hypotensive effects.[48] Other potential adverse effects include respiratory depression,
bradycardia,
delirium and potential for
acute tolerance.[50]
Risks and complications
Accidental awareness during general anesthesia (AAGA)
Patients under TIVA have a higher risk of AAGA. Unlike inhaled anesthetic agents, intravenous agents do not have an indicative
end-tidal anesthetic concentration (ETAC) for the monitoring of administered drugs, so the determination of successful delivery is usually left to the anesthetist's clinical judgment.[2]
The high incidence of AAGA with TIVA can be attributed to several factors. Firstly, the target concentration of anesthetic agents required to maintain unresponsiveness is not well understood.[2] Although there have been studies aiming to establish the target concentration of propofol, there is a high degree of variability with the established dosing range.[51] Secondly, intravenous delivery may be impaired by lax monitoring of the
intravenous catheter and the insertion site.[2] Thirdly, the use of
neuromuscular blockades is a risk factor of AAGA and also hinders communication of distress in the case of
accidental awareness.[2]
Opioid-induced hyperalgesia
TIVA techniques which involve the continued administration of
opioids (e.g.
remifentanil) at high doses can cause
opioid-induced hyperalgesia.[52] This may lead to difficult postoperative pain control, as patients with
hyperalgesia experience increased chronic pain and require more
analgesics following surgery.[51]
Neurotoxicity
Prolonged anesthetic exposure can result in the death of neural cells and defective
synaptogenesis,[53] caused by increased expression of neurologically harmful substances.[2] The resulting neurologic injuries may lead to a persistent subtle decline of cognitive abilities, especially in elderly or very young patients.[2] Animal studies suggest that propofol may have similar neurotoxic properties as it is associated with apoptotic degeneration of
oligodendrocytes.[2]
Special populations
Obese patients
Obese patients present technical and physiological challenges to TIVA. Physical tasks such as
surgical positioning, intravenous insertion and
ventilation are complicated by excess fat.[54] Associated physiological and pharmacological changes include higher susceptibility to
hypoxemia, decrease in
resting metabolic rate and lower
cardiac output per kg body weight.[55] The use of dosing models derived from non-obese patients is therefore unsuitable for obese patients.[56]
Even within the obese population, the large variability between individuals limits the accuracy of pharmacokinetic models in predicting and informing
anesthetic titration.[54]
Pediatrics
Infants differ from adults in the consideration of
pharmacokinetics,
pharmacodynamics and side effects.[57] In terms of pharmacokinetics, protein binding, organ function and body composition are significantly different.[58] Pharmacodynamic effects such as the capacity of target organs to respond to drugs are also changed.[57] Based on this knowledge, doses are adjusted to achieve optimal clinical response and avoid toxicity in pediatric patients.[59] Generally,
clearance (drug elimination from the body) is greater in children due to the nonlinear scaling between body size and function.[57]
Elderly patients
Aging is associated with an increase in fat and a reduction in
lean body mass and
total body water.[60] These factors increase the
volume of distribution of lipid-soluble drugs, lower their
plasma concentration and delay
elimination.[61] Aged patients typically have a higher sensitivity to drug action due to a reduction in the initial drug
clearance, resulting in higher plasma concentration and hence greater initial drug effect.[61]
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