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00:00In terms of an outline of what we're going to be talking about, first we will review
00:05a brief history, move into the indications, then we'll be talking about TEVA basics and
00:13recommendations, and finally we'll round out the presentation talking about some advantages,
00:19disadvantages, and practical tips of TEVA.
00:25In terms of a brief history, in 1874, chloral hydrate was used in the intravenous form to facilitate
00:34surgical procedures.
00:37If we fast forward to 1934, sodium thiopental was invented and intravenous anesthesia became
00:46more popular at this time.
00:49Subsequently, propofol and remifentanyl come to market in 1980 and 1993, respectively.
01:00And then in 1981, Schweldin performed an anesthetic with targeted controlled infusion or TCI.
01:12And this is something we're going to touch on a little bit later on in the presentation.
01:18In terms of TEVA basics, total intravenous anesthesia, or TEVA, employs a sedative hypnotic anesthetic,
01:26typically propofol, and an analgesic component, typically an opioid agent.
01:34And these medications are used for both the induction and the maintenance of anesthesia.
01:39Now, it's important to recognize that the blood, and therefore the brain concentration
01:44of propofol required for anesthesia varies between individuals and cannot be predicted
01:50in advance.
01:51However, there are some patterns that are evident, namely older patients, on average, will
01:57acquire a lower propofol concentration than younger patients, while adding opioids or other
02:04medications may reduce the overall propofol requirement for the surgery.
02:11In 2019, a TEVA guideline was published in the UK by Dr. Nimmo and his colleagues on the
02:20safe practice of TEVA anesthetics, and it stated that all anesthetists should be trained
02:26and competent in the delivery of TEVA, and that schools of anesthesia and training bodies
02:32should provide teaching, training, and practical experience of TEVA to all anesthetic and intensive
02:38care medical trainees, and that we should be able to competently and safely deliver TEVA anesthetics.
02:52And we're going to revisit this guideline by Nimmo et al. a little later on in the presentation.
02:57A discussion about TEVA requires a little review about our pharmacology and physiology.
03:09Namely, I'll start off just talking a little bit about pharmacokinetics.
03:13So, as we know, this phase takes into account the changes the drug experiences in the body
03:19through absorption, distribution, metabolism, and elimination.
03:23And the goal is to maintain a constant, accurate, and predictable concentration within a therapeutic
03:30window that ensures a desired effect.
03:34Now, for TEVA anesthetic, a three-compartment model has been proposed for drug administration,
03:45and we're going to review this a little later on in the presentation.
03:49And as we know, pharmacodynamics is a study of the relationship between the concentration of a drug at
03:57the site of action and the biochemical and physiological effect.
04:02And the simultaneous administration of anesthetic agents can give rise to different interactions
04:07that can be additive in nature or inhibitory in nature.
04:14In terms of the indications for TEVA anesthetics, TEVA is applicable to nearly all types of surgery,
04:22but has particular value in clinical scenarios where we really want to stress-free extubation,
04:29free of laryngospasm.
04:31Some specific indications for TEVA can include malignant hyperthermia risk, of course, a history
04:38of severe post-operative nausea and vomiting, any sort of two-less surgery in ENT, specific
04:46to neurosurgery, perhaps to limit intracranial volume, or surgery requiring neuroendocrine
04:52neurophysiological monitoring.
04:58In terms of the agents used for TEVA anesthetic, in theory, any IV hypnotic or plus or minus
05:06an opioid can be used.
05:09In recent years, the combination of probophol as a hypnotication and remifentanyl as an analgesic
05:18seems to have emerged as the most popular TEVA technique, according to literature.
05:24Both drugs are supplied as a continuous infusion, and ideally the probophol may be titrated against
05:31an electroencephalogram, EEG-based monitor such as a BIS monitor, and kept at a consistent
05:38level to ensure that there's appropriate anesthesia provided, and that you can also use a targeted
05:51controlled infusion approach, which we're going to touch on in a little bit.
05:58Typically, the probophol can be infused at 70 to 150 mics per kilo per minute, with of course
06:06titration based on individual requirements, the degree of surgical stimulation, and the
06:12co-administration of other anesthetic agents.
06:15Remifentanyl delivery may be adjusted frequently based on the degree of surgical stimulation, and
06:24nociceptive input.
06:28In terms of other agents that you could add on to your TEVA technique, these include things
06:32like dexmedetomidine, ketamine, and lidocaine.
06:37I just included this table here to highlight some of the opioids that can be used during
06:47a TEVA anesthetic, and from what they were talking about in Miller's anesthesia, that the
06:57optimal propofol concentration is less as you move from fentanyl to remifentanyl.
07:05So perhaps this is why, or maybe part of the reason why, propofol plus remifentanyl has emerged
07:11as one of the favorites for a TEVA technique.
07:19Now when providing a TEVA anesthetic, it can be done by a manual infusion.
07:26So in this example, you want to achieve a blood or therefore brain concentration of between
07:341.5 and 6 micrograms per mil of propofol.
07:40Now Roberts et al. in 1998, sorry, 1988 described a manual infusion scheme for targeting a propofol
07:47concentration of 3 micrograms per mil.
07:51And in their approach, they used a loading dose of 1 milligram per kilogram.
07:57After this, they ran 10 milligrams per kilogram per hour for 10 minutes, and then 8 milligrams
08:05per kilogram per hour for the next 10 minutes.
08:07And finally, after that, it was six milligrams per kilogram per hour.
08:11And overall, a mean blood propofol concentration of 3.67 micrograms per mil was achieved within two
08:20minutes and maintained stable for the duration of surgery they were looking at here, I believe
08:25it was 80 to 90 minutes of surgery.
08:31Now, in contrast to a manual infusion, there is also a target controlled infusion or TCI.
08:39The first available target controlled infusion system was introduced in 1996.
08:46In terms of what a targeted control infusion is, essentially a TCI pump contains a microprocessor
08:56that is programmed with the pharmacokinetic models for relevant drugs that may be used in Ativa
09:01anesthetic.
09:02And the user selects the drug and the model by which they want the pump to administer the drug.
09:09And they can input patient characteristics such as body weight and age,
09:13and the desired effect site concentration.
09:19And after this, the pump will determine the initial bolus and the subsequent infusion
09:24weights that are required.
09:28Now, two propofol models have emerged as favorites in the adult population.
09:33And these are the Marsh and Schneider models that are most commonly used.
09:39Now, in terms of those guidelines that I mentioned earlier by Dr. Nimmo and his colleagues,
09:47these emerged out of the UK, and they were titled the guidelines for the safe practice of total
09:54intravenous anesthesia.
09:57And they make clear that there's four key principles they wanted to highlight in their guidelines that
10:04anesthetists should be aware of when delivering Ativa anesthetic.
10:09Number one, principles behind achieving and maintaining appropriate plasma and brain concentration.
10:15Number two, factors determining appropriate target drug concentration.
10:20Number three, practical aspects to ensure intended dose of drug is delivered.
10:26And number four, monitoring of the patient.
10:29We'll now go through each one of these points in a little bit more detail.
10:34In terms of understanding the drug concentration being delivered to the patient,
10:44knowing the pharmacokinetic principles underpinning Ativa needs to be highlighted in order to maintain
10:52an appropriate concentration of an IV anesthetic or analgesic drug in the patient's plasma and brain.
10:59Now, the drug, I'm just going to walk this diagram here, is administered into the central compartment,
11:08or V1, which represents the initial volume of distribution.
11:13The second, V2, and third, V3 compartments are mathematical constructs that explain rapid and slow
11:24redistribution of a drug from V1 into highly perfused and less well perfused issues.
11:32So, for example, highly profuse V2 could be muscle and V3 could be representing fat.
11:41Now, there are rate constants that describe the proportion of drug moving between the compartments.
11:47For example, K12 indicates the proportion of drug moving between V1 and V2.
11:55And likewise, K21 shows the drug moving from the peripheral compartment back into the central compartment.
12:04Now, the metabolic rate constant here, K10, describes the proportion of drug in V1 that is metabolized
12:14or eliminated in any unit of time. And finally, we have a rate constant here that describes the transfer
12:24from the central compartment into the effect site. Now, the KE0 value, the higher that value is,
12:35it equates to a more rapid equilibrium between these two compartments here.
12:40These volumes and rate constants are determined from studies in which the drug is administered to
12:47volunteers or patients by bolus, infusion or both, and following which time blood samples
12:56are taken to determine drug concentrations.
13:00This is essentially the same diagram as the previous slide. This one just shows the drug being distributed
13:14into the muscle, into the fat tissues, our initial volume of distribution or V1, sorry, and into the target
13:24being the brain.
13:31In terms of drug concentration, we did mention that induction and maintenance may be accomplished with
13:38either manual dosing or a TCI pump. Now, it's important to understand that the pharmacokinetic model
13:46that is developed is more likely to be relevant or similar to patients where they have similar characteristics
13:57to the patients in which it was developed. So from what I was reading, most pharmacokinetic models were
14:02developed in young, healthy, non-obese subjects. And additional caution may be required when using these models
14:11in patients who have different characteristics. For example, your ASA three to five patients,
14:16older patients or obese patients. And we did talk about the Marsh and Schneider models being mostly applicable
14:23to healthy adults. There are also models that were developed for TEVA in children.
14:30The mean difference between estimated and measured concentrations is usually less than 25%. But if the
14:41patient differs from the population in which the model was developed greatly, there could be additional
14:48differences.
14:52Now, when we're thinking about appropriate drug concentration, we did mention about
14:59patient differences and we need to calibrate the amount of drug that we're giving to the patient's
15:06response. And we want to make sure we have enough drug concentration to produce loss of consciousness and
15:13prevent movement and response to nauseous stimuli. However, we don't want to give too much drug such that
15:18it's excessive and we can cause marked hypotension or delayed recovery from anesthesia.
15:23And we want to make sure that we have an understanding of the amount of surgical stimulus that the patient is
15:33receiving. Additionally, the administration of other medications such as opioids, benzodiazepines,
15:41ketamine, may result in a reduction in the amount of propofol that is required at the brain.
15:52And these are the models that we spoke about earlier, the Marsh and the Schneider model.
16:05And they have different means whereby they
16:09provide appropriate propofol target concentration for maintenance of anesthesia.
16:19In terms of monitoring patients who are receiving a TEVA anesthetic,
16:29use of processed EEG monitoring or PEG monitoring is recommended, especially when neuromuscular blockade
16:36is used in TEVA. There was another study out of the UK, the NAP5 report. And in that report,
16:46they said that the majority of cases of self-reported awareness were identified in patients who had
16:51received a neuromuscular blocking drug. And that about half the reports of awareness in NAP5 occurred
17:00around the time of induction and of anesthesia or around the time where patients would be transferred
17:08out of the operating room, for example, to the ICU setting. Now, in terms of the processed EEG monitoring,
17:22we also want to put this together with information from our other patient monitors
17:29and use this picture as a whole to ensure we're providing an adequate anesthetic for our patients.
17:38Now, in terms of advantages of TEVA, that one potential advantage is that it ensures
17:51that a continuous delivery of anesthetic is provided from the moment of induction. Now,
17:57we can contrast this to a situation where we have an intravenous induction
18:05followed by the plan for volatile anesthetic maintenance. And this would involve a time where
18:11the concentration of the intravenous agent is declining while the volatile agent is still rising,
18:18but there is a potential for a gap during which inadequate anesthetic is administered.
18:23Now, this could be more likely in a situation where there's a delay in starting the volatile agent,
18:29such as a delay in turning on the vaporizer or a delay in the agent reaching the patient.
18:35So, for example, if there was prolonged airway management, that was required.
18:40And a similar gap may be seen when changing from a volatile
18:46to an intravenous anesthetic when preparing a patient for transfer at the end of surgery.
18:53Additionally, TEVA anesthetics are known to have a better recovery profile
18:58with reduced risk of postoperative nausea and vomiting.
19:05Additionally, traditional inhalational anesthetics have been associated,
19:10at least in animal studies, with direct inhibition of hypoxic pulmonary vasoconstriction or HPV.
19:17As we know that this reflux causes constriction of blood vessels from hypoxic segments of lungs to normal
19:24areas of lungs.
19:27Such as in like thoracic surgery, when you have a patient who is on one lung ventilation,
19:33TEVA could be a potentially good option for this situation,
19:37if you're having any sort of difficulties in oxygenating the patient.
19:42Additionally, TEVA is useful for situations where there may be interoperative monitoring
19:46required such as somatosensory or motor evoked potentials.
19:55In terms of disadvantages of TEVA, in contrast to our inhalational anesthetics,
20:00for which we have our end tidal concentration in real time and we can adjust these medications in real time,
20:05we do have processed or unprocessed EEG and other neuromonitoring techniques,
20:12but we don't exactly know what the concentration is and it's difficult to figure that out in terms
20:22of what the blood concentration of that anesthetic is at that particular point in time.
20:27Now, comparable to volatile agents, they can cause a depression of airway reflexes,
20:34vasodilation and myocardial depression.
20:39Additionally, there is the potential for unrecognized IV that's gone interstitial or become disconnected.
20:46So we must be on very high alert for these sort of situations.
20:54Additionally, we must make sure that we have good familiarity with the pump and the delivery vices
21:00that are being used because it is possible to program the wrong rate, the wrong concentration of a drug
21:06or the wrong medication. And failure to deliver the intended agent could be catastrophic in a TEVA anesthetic.
21:21Now, there's a number of practical tips I'd like to highlight here in terms of things to maybe keep in mind
21:26when you are administering a TEVA anesthetic. The first one being it's helpful if you have standard
21:33medication concentrations that are used at the particular center where you're working at. So this
21:40takes any potential guesswork out of or potential for air if a concentration is mixed up when administering
21:48a drug. Additionally, you want to make sure you have appropriate lure lock connections such that you
21:53reduce the risk of any potential line becoming disconnected. Appropriate pump alarms. So these should
22:01include things like high pressure, stopped infusion, empty syringe disconnected from the main electrical
22:08supply or low battery. Additionally, you want to avoid mixing syringes such as mixing propofol and
22:14remifentanyl in a single syringe because you can't really titrate the hypnotic and analgesic components
22:22individually. So having separate syringes for the medications that you want to use is probably
22:31helpful. Additionally, you want to minimize the dead space in your IV line. So having your lines joined
22:37close together to the patient as possible so that more drug is entering the patient and not just staying
22:43in the IV line. Additionally, you want to make sure you have very good IVs. Ideally,
22:52you'd like to see your IVs during the procedure so you can monitor and make sure that it hasn't gone
22:57interstitial and it's still working appropriately. You also want to see your pumps and make sure you
23:05you're able to keep track of those. And also be careful about flushing lines at the end of the procedure
23:13such that, you know, if you had a patient who had been extubated, you wouldn't want a whole bunch of
23:17medication sitting in their lines and then accidentally flush that at the end of the procedure.
23:25So it's important to make sure that these lines are clear
23:27at the end of the procedure. The references I used for this presentation.
23:40I'd like to thank you all for attending the Neural Rounds today.
23:47And I hope you have a great evening. Bye-bye everyone.
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