Intravenous Anesthesia – TIVA – TCI

Intravenous Anesthesia

Author: Calle Öhman ÖL SÄS

Intravenous anesthesia (TIVA/TCI) refers to a complete form of anesthesia managed solely with intravenous drugs, without inhalation anesthetics. This anesthesia form is typically controlled entirely by infusion pumps, but dosing can be supplemented with manually administered doses of intravenous drugs as needed. The technique is described in detail below. The drugs used induce sleep, hypnosis, and analgesia, which together provide adequate anesthesia. In intravenous anesthesia, drug administration is usually divided into two phases: induction dose and maintenance dose. The drugs are administered intravenously with high precision using infusion pumps set for TIVA technique or TCI according to pre-programmed protocols. A combination of propofol and remifentanil is often used, but several different variants are available.

Intravenous anesthesia provides controllable and well-balanced anesthesia that allows the patient to wake up quickly with minimal postoperative effects and rapid recovery. The method can also be combined with inhalation anesthesia, but with significantly lower doses of inhalation anesthetics than usual. Respiration and airway tone recover faster compared to after inhalation anesthesia, and the patient becomes alert and clear earlier afterward. The method is also environmentally friendly, as no anesthetic gases are released in the operating room or in the postoperative department. The anesthesia form is adapted and controlled according to the surgery/procedure, considering the patient’s medical condition and general health. This anesthesia form requires good knowledge of the pharmacology and pharmacodynamics of the drugs used, as well as familiarity with the medical equipment. The method presupposes secure venous access throughout the procedure and good monitoring of the patient’s consciousness, respiration, airway, hemodynamics, infusions, and venous access (PVK/CVK).

The drugs commonly used should ideally have as short a half-life as possible, as well as a favorable “Context Sensitive Halftime.” This term expresses the time it takes for a drug to equilibrate between the blood compartment and the CNS compartment. This applies to drugs used for premedication, anesthesia, and postoperative pain relief. The aim is, among other things, to reduce the risk of POCD (“Postoperative Cognitive Dysfunction”) and the risk of postoperative nausea (PONV).

Effect Site Target or Plasma Target Mode

In anesthesia, drug delivery is usually divided into two phases: induction dose and maintenance dose. When using TCI, the pump is pre-programmed with either “Plasma Target” or “Effect Site Target,” which controls the speed of the induction dose in TCI. Effect Site Target provides an initial “Overshoot” of the drug during induction, which Plasma Target does not. Effect Site Target induces faster, making it more suitable for young, essentially healthy patients (ASA 1-2), while Plasma Target induces somewhat slower, making it more suitable for older and frail patients (ASA 3-4). The mode set is usually pre-programmed by medical technology but can be changed by the responsible anesthesia nurse or anesthesiologist. It is essential to know which mode is set before each anesthesia.

Most syringe pumps with functions for TIVA/TCI operate according to pharmacokinetic models developed by Marsh (propofol) and Minto (remifentanil), which take into account the drugs’ pharmacokinetics, the patient’s age, lean body mass, and gender. The pump adjusts the infusion to achieve the set target concentration in plasma and thereby also in the target organ, the CNS, after equilibrium is reached as quickly as possible and is maintained until the setting is changed. Note that Marsh’s algorithm regarding propofol does not take age into account, even though it is set on the pump. Using the TCI technique minimizes the time it takes for the desired target concentration in the target organ CNS (Ce) to be reached. On some syringe pumps’ displays, ml/hour and μg/kg/min or mg/kg/hour are also displayed for the current drug in TCI, but what is displayed and how it looks varies between different syringe pump brands. To initially get a better feel for the TCI setting, you should monitor both the TCI value and the infusion rate (text display).

Advantages of the TCI technique

• The desired target concentration is quickly achieved and closely related to the desired pharmacological effect.
• No need to calculate an infusion rate.
• Adjusts the amount of drug delivered relative to weight for propofol and age, gender, and lean body mass for remifentanil.
• No manual bolus doses are given.
• Reduced total doses.
• You can monitor Ce values and thereby know the doses applicable to the current patient. This reduces the risk of awareness and also reduces the risk of overdosing.
• Takes infusion time into account, see Context Sensitive Halftime.

Intravenous drugs for induction, hypnosis (sleep), analgesia, and muscle block

A balanced combination of remifentanil and propofol is usually used for both induction and maintenance, but several different combinations are possible. See different protocol cards below. Several different drugs are available for intravenous anesthesia, e.g.:

• Induction agents: Propofol, Remifentanil, Pentothal, Ketamine
• Hypnosis (sleep): Propofol, Remifentanil
• Analgesia: Remifentanil, Alfentanil, Ketamine (+ possibly block)
• Muscle block: Celocurin, Rocuronium, Atracurium (patients with liver-kidney failure)

When dosing the drugs, you must consider the current patient’s age, weight, diseases, ASA class, general condition, and whether simultaneous regional block with local anesthetics is used. With increasing age, high ASA class, and possibly simultaneous block, the doses for the drugs included in the anesthesia should be reduced. The infusion pumps (syringe pumps) used must be of such quality that they can operate safely with the various infusion techniques used in TIVA or TCI mode.

Anesthesia Technique

The different infusion techniques commonly used in intravenous anesthesia are TCI (Target Controlled Infusion) or TIVA technique (total intravenous anesthesia with weight-based dosing – TIVA mode), i.e., the pump delivers induction dose and maintenance dose based on body weight, as well as the third method and now rarely used method with a fixed volume per time unit (x number of ml/hour with volume pump).

Anticholinergic initiation

It is common for an anticholinergic to precede anesthesias involving Rapifen (alfentanil) and Ultiva (remifentanil) to counteract mucus secretion in the airways and bradycardia/hypotension. The drugs mainly used are Robinul and Atropine, preferably Robinul. This is because the preparation does not cause tachycardia, which we want to avoid, partly to not shorten the diastolic phase, and partly because the bradycardia that often occurs when using remifentanil is an indirect sign of anesthetic depth.

Anesthesia-induced Hypotension

Hypotension can be seen in intravenous anesthesia as well as in other anesthesia methods, especially after the induction dose. In the first instance, hypotension should be prevented by keeping the patients normovolemic and in an optimally cardiac condition.

The methods commonly used for hypotension associated with anesthesia induction are fluid administration in the form of crystalloids and/or colloids and/or fast-acting inotropic drugs such as ephedrine and phenylephrine. The crystalloid usually used is Ringer’s acetate, and as colloids, albumin, Venofundin, or Macrodex are often used. If the patient has elevated creatinine or is at risk of kidney impairment during the surgery, Venofundin or other products with hydroxyethyl starch should not be used.

Further pharmacological treatment can be used for hypotension. Common drugs are ephedrine and phenylephrine for short-term blood pressure drops. If the heart rate is over 80 beats/min or the patient has arrhythmias (atrial fibrillation), ephedrine should not be used, but phenylephrine should be. In difficult-to-treat hypotension, continuous phenylephrine infusion (0.1 mg/ml or 0.2 mg/ml) or alternatively noradrenaline (0.04 mg/ml/0.1 mg/ml) or dopamine infusion can be used. In the operating room, ephedrine and phenylephrine should be prepared, and equipment for phenylephrine infusion should be available

. In bowel surgery and major vascular surgery, fluids should be used sparingly, and phenylephrine or ephedrine should be used to regulate blood pressure. If the patient is beta-blocked, ephedrine can be used.

Airway Management

The airway is secured in intravenous anesthesia in the usual way with a laryngeal mask or alternatively endotracheal intubation. In the case of intubation or placement of a laryngeal mask, it is not always necessary to administer muscle relaxants, especially if remifentanil is used. Muscle relaxants are not given during thyroid or parathyroid surgeries where a nerve detector (“Neurosign”) is used.

Routinely, patients are mechanically ventilated with positive pressure ventilation during anesthesia, regardless of whether they have a laryngeal mask or are intubated. This is done to avoid hypoventilation, hypoxia, and to counteract atelectasis formation. An auto-PEEP is normally set on the ventilators, but if the patient is overweight or during laparoscopic procedures, the PEEP level should be increased. Patients with a laryngeal mask or tracheal tube and remifentanil should be ventilated. This is because remifentanil can quickly cause apnea.

If alfentanil is used in infusion, the patient can breathe in the ventilator with pressure-supported ventilation. This method is less suitable for remifentanil, where controlled ventilation is preferred. In intubation with alfentanil in continuous infusion, a bolus should be given before intubation, and the dosage should be significantly higher compared to laryngeal mask anesthesia.

Things to Consider

If intravenous anesthesia is used together with regional blockade, e.g., epidural, and the doses are relatively reduced, resulting in a light anesthesia depth, a tube, arterial line in the radial artery, or venipuncture in the upper extremity cannot be inserted without deepening the anesthesia. The patient may wake up from such stimuli. This also applies to neuromuscular function measurement like TOF, (“Train of Four”), on the upper extremity. Neuromuscular function measurement is not routinely used (TOF) in intravenous anesthesia, only on indication. If a repeat dose of muscle-blocking agents is given with the above anesthesia technique, one must ensure that the patient has adequate anesthesia depth to avoid “awareness” (shallow anesthesia/unplanned awakening). Patients must wear hearing protection during surgeries. This can be with or without music.

Anesthesia for the Elderly (> 80 years)

Intraoperative complications related to administered anesthetic drugs, primarily hemodynamic instability (hypotension), are often due to an overdose of the administered drugs. Therefore, it is crucial to be aware of the changes that aging brings. Remifentanil infusion protocols according to Minto take age into account. Propofol infusion protocols according to Marsh do not take age into account, so this must be considered in dosing.

Changes in Body Composition

Body composition in the elderly changes so that lean body mass and total body water decrease, while there is a relative increase in fat tissue.

Pharmacokinetic Changes

In the elderly, the effect of intravenous drugs is increased. This means that the distribution volume for fat-soluble drugs increases, e.g., propofol. This results in a relatively lower plasma concentration and delayed elimination. Furthermore, the distribution volume for drugs that are less fat-soluble, e.g., remifentanil, decreases, leading to faster, higher plasma concentration and quicker elimination. This is partly due to decreased plasma volume and increased sensitivity to administered drugs. In the elderly, there is also slower distribution from plasma to effector organs.

Doses for the elderly must be reduced. Regarding propofol administered with TCI technique according to Marsh’s algorithm, which does not take age into account, the anesthesiologist must make this dose reduction. Remifentanil given according to Minto’s algorithm does take age into account. Despite this, a dose reduction should also be made here.

Anesthesia for Obese Patients

The most significant change in body composition is, of course, the increased amount of adipose tissue in obese individuals. This means that drugs with high fat solubility, particularly propofol, have an increased volume of distribution, while drugs with low fat solubility do not have a correspondingly increased distribution volume. Drug doses are calculated based on the ideal body weight plus approximately 10%. (Ideal body weight can be simply calculated as body length in cm minus 105 for women and minus 100 for men.)

It is of great value to use drugs with a short half-life in this patient group so that they can regain adequate spontaneous breathing as quickly as possible postoperatively.

Regarding propofol and obese patients, dosing can be managed in two ways:

1. The induction dose is given according to the ideal weight. Since the volume of distribution is high, the maintenance dose is increased to almost match the absolute weight. This prevents underdosing of the maintenance dose. However, this leads to a relatively large amount of propofol accumulating in the adipose tissue, which may result in a prolonged awakening time.
2. An induction dose corresponding to the ideal weight is given, and the maintenance dose is also based on this. This may lead to underdosing of propofol, but this is compensated by increasing the dose of remifentanil, which offsets any potential underdosing of propofol. This ensures that the awakening time is not prolonged.

For remifentanil, the TCI setting can be calculated after ideal weight plus 10%, which has proven to work well in clinical practice.

To avoid the risk of awareness in severely obese patients where muscle relaxants are used, it is recommended to routinely use some form of monitoring of anesthesia depth (BIS/Entropy).

If opioids are used for postoperative pain relief at the end of anesthesia, such as morphine, the dose should be based on ideal body weight, as morphine does not have high fat solubility.

Anesthesia for Patients with Ischemic Heart Disease and Intravenous Anesthesia

These patients should be kept as hemodynamically stable as possible. It is important to avoid hypotension, hypoxia, and tachycardia. It is therefore often indicated to use a continuous infusion of a vasopressor from the start of anesthesia, such as phenylephrine in infusion (0.2 mg/ml or 0.1 mg/ml) or norepinephrine in infusion (0.04 mg/ml/0.1 mg/ml). Sevoflurane probably has a cardioprotective effect in patients with ischemic heart disease. During anesthesia for this patient group, sevoflurane can be added to propofol as a hypnotic for intubated patients. After intubation and verification of tube placement, sevoflurane is added (recommended MAC value of 0.2-0.3-0.6). The propofol infusion is reduced accordingly. If the patient has a peanut allergy, propofol is not recommended for induction, and anesthesia should be induced with Pentothal and maintained with Sevorane.

Anesthesia with TCI Technique, Target Controlled Infusion

The various infusion techniques commonly used in intravenous anesthesia are TCI (Target Controlled Infusion) or TIVA technique (total intravenous anesthesia with weight-based dosing). The pump delivers an induction dose and a maintenance dose based on body weight, as well as the third and now rarely used method of simple volume-controlled infusion (ml/hour – with volume pump). Infusion pumps deliver induction dose and maintenance dose according to pre-programmed protocol with a display showing either TCI or TIVA technique. Some pump brands, but not all, can display both TCI values and dose based on body weight (TIVA) simultaneously. Not all syringe pumps can provide TCI, only those with this built-in function. For children, TIVA technique is mainly used and not TCI. We do not recommend TCI for children under 16 years.

Procedure for Anesthesia with TCI Technique, Target Controlled Infusion

TCI mode should be the first choice in intravenous anesthesia. The method can be used for induction and maintenance of anesthesia in adults. The technique is based on setting a desired target concentration of selected drugs (propofol/remifentanil/alfentanil) in plasma (Cpt = concentration plasma target) and thereby indirectly in the effector organ, CNS (Ce). Cp and Ce are calculated values that can be compared to MAC in inhalation anesthesia. Furthermore, age and body weight are entered in the pump for propofol, and age, body weight, height, and gender are entered for the remifentanil infusion. For significantly obese patients, an estimated ideal weight is used. The conventional administration technique, TIVA (specific amount of drug/time unit), results in a slower change in plasma concentration and thereby concentration in the target organ, CNS.

Some Practical Advice

When using anesthesia with the TCI technique, the following procedure is usually followed: An anticholinergic drug (Atropine/Robinul) is initially administered. The pumps are set so that the so-called text display is shown, where the Ce value is clearly visible. Preoxygenation is started. Then the propofol infusion is initiated. The person inducing anesthesia continuously speaks calmly to the patient with the oxygen mask over the airway.

Typically, the patient is relatively quiet initially. As the effect of propofol takes hold, some patients begin to talk as they relax. Ce values are noted for the changes in consciousness that the patient undergoes.

When the Ce value for propofol reaches 0.2-0.4 μg/ml, the remifentanil infusion is started, if remifentanil is used. If alfentanil is used instead of remifentanil, a bolus dose is given, followed by an infusion before starting the propofol infusion. When the patient feels the effect, usually slight dizziness and drowsiness, the propofol infusion is started with this technique. For alfentanil doses, see below. As the infusions continue, the patient’s speech becomes increasingly slurred until it eventually stops, and respiration becomes impaired. Note the Ce values of the drugs. Also, note when the patient’s spontaneous breathing ceases and the Ce value that remifentanil has reached at that time.

Wait 30-60 seconds and take a firm hold of the airway, attempting to ventilate the patient manually with caution. If the patient reacts with arm or hand movements, facial grimacing, wait another 30-60 seconds, and repeat the maneuver. The doses can be increased or left unchanged.

When the patient does not react, wait about 30 seconds. Check if the jaw feels relaxed. Ventilate through a breathing mask, and if the patient accepts positive pressure ventilation, you can try to gently insert the laryngoscope into the mouth without intubating or alternatively inserting the laryngeal mask. Note the Ce values. If the patient reacts, usually by moving arm/hand, foot, or grimacing as above, wait another moment, about a minute. Make another attempt. When the patient does not react to stimuli, you know that at these Ce values, there is no risk of awareness for this specific patient. There is no need to assume a value; you know what applies to this patient. Ce values have a very large individual variation. The Ce value noted when the patient does not react during airway manipulation should be recorded in the anesthesia record. Muscle relaxants are then administered. If you want to intubate without muscle relaxants, wait another minute before doing so. If necessary, the remifentanil dose can be increased. There is no standard dosage applicable to all patients; the dosage is highly individual, and the dose that applies to the current patient is reflected in the Ce value when the patient does not react to pain stimuli.

During the induction phase of anesthesia, monitor heart rate when remifentanil is used. When remifentanil starts to take effect, the heart rate usually drops, and apnea occurs around the same time, which should be noted on paper. The heart rate decrease is a sign that the patient is sleeping. This is another reason to use Robinul, which does not cause the same tachycardia as Atropine. Atropine can mask this sign of remifentanil’s effect. This technique avoids overdosing the drugs and also avoids the risk of awareness.

When the patient is intubated or has a laryngeal mask inserted, the infusion rate of propofol and remifentanil is adjusted. Any infusion in an epidural catheter for regional block can be started.

Preoperative Sedation via Pump

Another approach is to start both propofol and remifentanil at a low TCI dose of 0.7-1.0 as soon as the patient enters the operating room. Respiration is monitored. The

patient becomes lightly sedated, and the total dose during induction is reduced, resulting in more stable hemodynamics. During the awakening phase, the propofol infusion is usually stopped first (when the last suture is placed), and the remifentanil infusion is stopped during bandaging. To achieve a calmer awakening, a small dose of morphine, e.g., 5 mg, can be given about 30 minutes before the end of anesthesia. The pumps should not be turned off, but the infusion should be stopped with the pumps active. The Ce value is then monitored during awakening. If the patient fell asleep at a specific Ce value, they usually wake up at about the same value (but sometimes lower). This depends on the so-called “hysteresis,” which means a cumulative effect of the drugs used during anesthesia, such as an opioid given shortly before awakening. One cannot expect the patient to wake up at a higher Ce value than they fell asleep to. The same applies to the Ce value for remifentanil. If apnea occurred at a certain Ce value, spontaneous breathing cannot be expected to return until the Ce value has dropped to this level.

As mentioned above, patients using remifentanil at normal doses are ventilated. During the awakening phase, the patient is ventilated until they open their eyes or breathe against the ventilator. Eye opening and the return of spontaneous breathing usually occur relatively quickly and simultaneously. If the pump is turned off or the TCI function is interrupted in another way during ongoing anesthesia, TCI should not be restarted. This is because the pump will then deliver an induction dose again and at a high infusion rate, and the TIVA setting should be restarted instead.

Propofol and TCI

The TCI pumps most commonly used operate according to the Marsh algorithm. Based on the set data (body weight), the pump calculates an induction dose and a maintenance dose. During anesthesia, the pump calculates and adjusts the current maintenance dose based on factors such as Context Sensitive Halftime, the duration of anesthesia, etc. Note that this algorithm does not account for age, which must be considered by the anesthesia staff.

The pump has a default target concentration pre-set by medical technical personnel, usually at 4 μg/ml in Cpt (target value in plasma). Of course, this target concentration can be adjusted as needed. The pump does not take into account the simultaneous administration of opioids or blocks but does consider the patient’s weight, the duration of the infusion, and any pauses in the infusion for syringe changes, etc.

At the start of anesthesia, the person setting the pump must take into account the patient’s age, ASA class, type of procedure, simultaneous administration of opioids, blocks, etc., when setting the desired target concentration. Higher age, increasing ASA class, more severe illness, etc., require lower dosing.

Suitable Propofol Settings for TCI

For patients under 60 years old and ASA class 1-2, a setting between 3-6 μg/ml is recommended, considering the factors mentioned above.

For example, if a relatively high dose of remifentanil is administered, you can start with a lower dose of propofol, and vice versa. You can also start with a relatively low target concentration and gradually increase it by 0.5 μg/ml, after which the pump, after each upward adjustment, delivers a small bolus dose followed by a slightly higher infusion rate. This increase in target concentration can be made during ongoing anesthesia if needed. Of course, the adjustment can also be made in the opposite direction. The pump then pauses and settles at a lower infusion rate. The Ce values for the patient’s current state are continuously noted. When using remifentanil as an analgesic, TCI with propofol is typically started, and when the Ce value for propofol reaches 0.2-0.4 μg/ml, the remifentanil infusion can be started. This is primarily for two reasons:

• The onset time of propofol is slightly slower than that of remifentanil. By starting propofol slightly earlier, the effects of both drugs will occur at approximately the same time.
• If remifentanil is administered rapidly and in a high dose, there is a risk that the patient may develop muscle rigidity, which could threaten ventilation in the worst-case scenario.

It is possible to start remifentanil before the propofol infusion, but at a low dose, around 1-2 nanograms/ml with TCI technique, and ideally when the patient has entered the room, and monitoring has been connected. Respiration is closely monitored.

When induction begins, the propofol infusion is started, and shortly thereafter, the target concentration for remifentanil is increased. After the laryngeal mask is placed, or the patient is intubated, the doses of propofol and the opioid are adjusted. If a simultaneous block that has previously been tested for the intended distribution is used, the doses of both drugs are reduced. With TCI and propofol, you can adjust to the level indicated by the Ce value when the patient did not react during airway manipulation or pain stimuli. Regarding remifentanil, you can adjust to the Ce value indicated during intubation or slightly higher.

You can reduce the propofol level below the Ce value where the patient did not react to the aforementioned stimuli, but then you must increase the remifentanil level. This can often be more beneficial, as remifentanil does not affect circulation as much as propofol. Anesthesia is best managed by making dose adjustments of remifentanil.

The propofol infusion is stopped about 5-15 minutes before the end of the procedure. The exact timing depends entirely on the chosen anesthesia technique, the duration of anesthesia, the patient’s age, simultaneous block, type of procedure, etc.

For patients over 60 years old and/or ASA class >2, an initial setting of 2-5 μg/ml is recommended. For this patient category, it may be more appropriate to use the stepwise method mentioned earlier. The Ce values for the patient’s condition are continuously noted.

Remifentanil and TCI

During dosing in TCI with remifentanil, the target concentration is measured in nanograms/ml of blood in the effector organ, the CNS. Due to the pronounced synergy between the drug used for hypnosis, usually propofol, and remifentanil, the dose of the hypnotic drug must be reduced compared to if alfentanil is used. The extent of this reduction depends on the type of procedure and the patient’s age. When lean body mass is calculated according to Minto, it is slightly underestimated for women with a BMI > 35 kg/m² and for male patients with a BMI > 40 kg/m². The target concentration for these patients should be set slightly higher to avoid underdosing. Ideal weight is generally used for dosing remifentanil. The target concentration of remifentanil used to start an operation (used together with a hypnotic drug, either gas or propofol) is usually 4-8 nanograms/ml. The level is adjusted according to the patient’s age and the type of operation, usually around 6 nanograms/ml.

A suitable maintenance dose, the Ce value, is then titrated by following standard parameters for adequate anesthesia depth. For particularly painful procedures, target concentrations of 15 nanograms/ml may be required.

At the end of anesthesia, when the TCI for remifentanil is turned off, the patient typically regains spontaneous breathing at an approximate target concentration of 2 nanograms/ml, sometimes slightly lower. Of course, the current concentration of the hypnotic agent must be considered.

Remifentanil administered with TCI technique at an adequate dose during anesthesia, not sedation (see below), is generally not used for patients with spontaneous breathing, for postoperative analgesia, or for children under 16 years.

Intravenous Anesthesia with Propofol in Combination with Alfentanil (Rapifen)

Setup according to the above guidelines. The anesthesia starts with the administration of an anticholinergic and preoxygenation of the patient. An initial dose of alfentanil is given, which can vary between 5-15 μg/kg. Factors such as age, ASA class, etc., must be considered. After the initial dose is given, the infusion is started. The size of the infusion, as previously mentioned, depends on age, ASA class, type of procedure, etc. A guideline is 30 μg/kg/hour (0.3-0.5 μg/kg/min) or 50-60 ng/ml in TCI mode. For anesthesia with a laryngeal mask, a target value of 50-60 ng/ml in TCI is usually sufficient, while for anesthesia with intubation, significantly higher levels of 90-120 ng/ml for Alfentanil are needed.

The maintenance dose is reduced during a long operation in TIVA mode. After about 2 hours, it is reduced by 5 μg/kg/hour, and another 5 μg/kg/hour after 3 hours. Larger reductions are made as the patient’s age increases. The infusion is usually stopped when there are 15 minutes left of the procedure. This, of course, depends on the duration of the infusion and the type of procedure.

When the patient feels the effect of the initial dose of alfentanil, TCI propofol is started, usually with a setting of Cpt 4.0 μg/ml, but adjusted for age, type of procedure, simultaneous block, etc. The Ce values are monitored during the induction and are noted for the various stages the patient goes through. Speak calmly to the patient. When the patient no longer responds, this Ce value is noted and used as a guideline for the continued anesthesia. At this stage, a muscle relaxant can be administered if necessary.

At the end of the operation, the alfentanil infusion is stopped first, about 15-30 minutes before the end of the operation, and the propofol infusion is stopped about 5 minutes before the end of the operation.

RSI (Rapid Sequence Induction) with TCI

Rapid Sequence Induction, RSI, and TCI

TCI technique can also be used for Rapid Sequence Induction, RSI. In RSI, the goal is rapid induction, and the induction dose is administered based on mg/kg body weight. If propofol is chosen as the induction agent, the doses can vary, ranging from 1 mg/kg for an elderly, severely ill patient to approximately 3 mg/kg for a young, healthy patient.

Induction for RSI can be done in two ways.

Alt. 1: TCI Plus Extra Bolus by Hand

If the propofol pump is set to TCI mode with a target value of 4 μg/ml, it delivers approximately 1 mg/kg as an induction dose, regardless of the set body weight. If you have a patient weighing 80 kg and want to administer an induction dose of 2.5 mg/kg, you can proceed as follows during induction. Draw up a 20 ml syringe with propofol. During induction, the TCI pump, if set to 4 μg/ml, delivers approximately 1 mg/kg = 80 mg, and the remaining amount up to the 2.5 mg/kg dose should be administered manually. In this example, this would be an additional 120 mg given manually with the 20 ml syringe containing propofol. When observing the Ce value, it should be noted that these 120 mg are not included in the pump’s calculated Ce value at the beginning of anesthesia. Start the remifentanil infusion using the TCI technique simultaneously with the induction, with a dosage of 5-8 ng/ml depending on the patient. Muscle relaxants are administered when the blink reflex is absent. If precurarization with 2-3 mg of rocuronium is given during induction, the asymmetric muscle contractions caused by succinylcholine are reduced.

Alt. 2: Induction with Pure TCI

Another method using TCI technique and rapid sequence induction, RSI, is to initially set the propofol pump to a high Cpt value. A suggested setting is a Cpt value of 15 μg/ml. When the pump is started, it delivers a high dose fairly quickly. Monitor the dose given in mg/kg, which can be seen in small numbers just to the right of the Ce value on the syringe pump. When the desired induction dose is achieved, 1-3 mg/kg, the Cpt value is adjusted to the desired level of around 2-5 μg/ml. It is important to continuously monitor the pump during this procedure until the desired induction dose has been administered, at which point the pump is stopped, and the infusion rate is adjusted. When the pump is restarted with the reduced infusion rate, it does not start immediately because the calculated Cp value exceeds the newly set Cpt value. Note that the Ce value is not very high when this induction dose is administered. There is a certain lag in the software’s calculation. Start the remifentanil infusion using the TCI technique simultaneously with the induction. The usual dosage is around 5-8 ng/ml, depending on the patient. Muscle relaxants are administered with this type of induction when the desired propofol dose has been given and the blink reflex is absent. Here too, precurarization with 2-3 mg of rocuronium during induction can reduce the asymmetric muscle contractions caused by succinylcholine. If you choose to administer the entire induction dose of propofol manually with a syringe and then use propofol as the hypnotic agent, TCI technique should not be used, as the patient would receive another induction dose. Instead, choose TIVA technique. Alternative 1 may be preferred for safety reasons because there is a risk of forgetting to stop the pump and reduce the infusion rate when the desired induction dose is given.

If the patient is allergic to propofol or any of its components, or if for other reasons propofol is not to be used as a hypnotic agent, thiopental is used as the induction agent, and Sevorane as the hypnotic agent.

TCI Protocol for Day Surgery

Workflow and Key Steps with TCI in Day Surgery

• Fixed placement of syringe pumps with drugs: remifentanil at the top and propofol at the bottom.
• Back valve for the remifentanil infusion.
• The remifentanil pump is set to TCI with a protocol for remifentanil according to Minto (plasma model).
• Enter age, weight, height, and gender in the pump.
• The induction dose is usually set with “Flash” (small, fast induction dose).
• The propofol pump is set to TCI with a protocol for propofol according to Marsh (plasma model), which adjusts for weight but not age (which is still entered).
• Avoid using a blood pressure cuff on the same arm as the drug infusion.

Remifentanil and propofol are adjusted in relation to Cpt, i.e., the desired plasma concentration, and the syringe pumps calculate the plasma concentration (Cp) and the concentration in the brain (Ce) according to the protocol.

• Cpt: Plasma concentration with target concentration – desired plasma concentration (target concentration)
• Cp: Concentration in plasma – calculated plasma concentration at any given time
• Ce: “Concentration at the effect site” – calculated concentration at the effector site, i.e., in the brain

The concentration in the effector organ (Ce) is passively adjusted by the pump after Cp with a delay of a few minutes.

The choice of target concentration depends on several factors: use of a tube/laryngeal mask, simultaneous use of fentanyl, type of surgery, use of local anesthetics, gender, age, and weight. The pharmacokinetic model for remifentanil (Minto) takes into account weight, height, gender, and age, while the propofol model (Marsh) only considers weight.

Remifentanil is mixed to a concentration of 50 micrograms/ml: 2 mg of remifentanil is dissolved in 40 ml of 0.9% NaCl.

Propofol is administered at a concentration of 10 mg/ml for adults and 5 mg/ml for children.

Key Points with TCI

• Not used in anesthesia for children under 16 years of age.
• If a syringe pump needs to be restarted during ongoing anesthesia, TCI should not be continued, but should switch to TIVA without TCI.
• The drug concentration values on the syringe pumps are calculated from a pharmacokinetic model. Individual patient conditions may cause actual plasma concentrations and effector concentrations to differ from those indicated on the pumps.
• Press the “Menu” button (Fresenius Agilia pump) and then the battery capacity to see the rate in ml/h.
• Press “Menu” (Fresenius Agilia pump) and then the arrow buttons until you get “ml?” on the left side of the display to see the volume/amount of drug actually administered.

Patients with ASA 1 and 2, under 60 years old with BMI <35

Introduction

Before starting the medications, sedative doses of propofol and remifentanil can be given at the beginning. This calms the patient and simultaneously provides insight into how well the patient tolerates the medication.

Sedation Doses

• The target concentration (Cpt) for propofol is set at 0.5 – 1 micrograms/ml.
• The target concentration (Cpt) for remifentanil is set at 0.5 – 1.0 ng/ml.

In some cases, 50 – 100 micrograms of fentanyl may be given at the start, especially if the patient is to be intubated.

Preoxygenation should be provided with 80% oxygen.

Anesthesia Induction

• The target concentration (Cpt) for propofol is set at 4 – 6 micrograms/ml.
• The target concentration (Cpt) for remifentanil is set at 5 – 6 ng/ml when using a laryngeal mask and 10 – 12 ng/ml during intubation without muscle relaxation (>8 ng/ml if muscle relaxation is used).

The patient is ventilated manually with a face mask and breathing bag until the patient is ready for insertion of the laryngeal mask/intubation (assessed clinically after Ce for remifentanil has reached the target concentration).

Intubation

• Minimize the use of muscle relaxants.
• Administer remifentanil until Ce > 8 ng/ml before intubation.
• Note: Do not intubate when the vocal cords are centered! This can damage the vocal cords.

Maintenance

The target concentration (Cpt) for propofol is set to 1.8 – 2.5 micrograms/ml.

The target concentration (Cpt) for remifentanil is set to:

• 5 – 6 ng/ml until the surgery begins.
• 7 – 8 ng/ml at the start of medium-sized surgery.
• 9 – 10 ng/ml at the start of major surgery.
• 12 – 16 ng/ml for particularly extensive surgery (e.g., scoliosis surgery, spinal surgery).
• 9 – 10 ng/ml for surgeries where it is crucial that the patient remains still (e.g., myringoplasty, ENT, plastic surgery).

Doses are adjusted according to the clinical situation. Optional doses of fentanyl 50 – 100 micrograms IV can be given additionally.

Conclusion

About 5 minutes before the end of the operation, the infusions of propofol and remifentanil are stopped. (The remifentanil infusion can possibly continue until the operation is completely finished.) Consider the pain management issue when stopping remifentanil, and possibly administer fentanyl 50 – 100 micrograms IV or another opioid. The ventilator continues to operate until the patient wakes up, and the laryngeal mask can be removed, or the patient can be extubated.

Patients over 60 years and/or ASA 3

Begin with low target concentrations for both propofol and remifentanil, which are 25% to 50% lower than for healthy patients under 60 years. Induce slowly and increase the target concentrations by 0.5 – 1 micrograms/ml for propofol and 0.5 – 1.0 ng/ml at a time until satisfactory clinical effect is achieved.

Maintenance with propofol should not be lower than 1.8 micrograms/ml due to the risk of excessively shallow anesthesia. The maintenance dose of remifentanil can be kept 25% – 50% lower than for healthy patients under 60 years, but must be adjusted according to the clinical picture.

Anesthesia with TIVA technique (TIVA modus)

This anesthesia technique is usually the second choice after TCI technique. TIVA technique provides total intravenous anesthesia with weight-based dosing, meaning the pump delivers induction and maintenance doses based on body weight with a delivery rate set for each time unit. (e.g., alfentanil can be dosed per hour or per minute, varying between different pumps). When using this form of anesthesia, the same considerations as with TCI technique apply, with lower doses for older patients, higher ASA class, concomitant opioid administration, concurrent blocks, etc. In longer anesthesias, there is a risk of drug accumulation, primarily of propofol and alfentanil, as the technique does not account for context-sensitive halftime.

TIVA pumps are preset to deliver an induction dose of propofol at 1.5 mg/kg over 90 seconds and then start an infusion rate of 10 mg/kg/hr. You set the age and body weight. In severely overweight patients, the pump settings are adjusted based on estimated ideal weight. These settings can be adjusted depending on factors affecting dosing. You determine the appropriate induction dose, the time for the induction dose, and the maintenance dose when setting up the pump. When using propofol and remifentanil in combination, a technique can be employed where no bolus dose of propofol is given. The infusions of both drugs then start simultaneously.

The maintenance dose of propofol should be gradually reduced every ten minutes from normally 10 mg/kg/hr to 8 mg/kg/hr, to eventually settle around 6 mg/kg/hr after approximately 20 minutes. The infusion rate should be lower in older patients and those with a higher ASA class.

The propofol infusion is stopped approximately 5-15 minutes before the end of the procedure. The exact timing depends on the anesthesia technique used, the duration of the anesthesia, the patient’s age, concurrent block, type of procedure, etc.

TIVA technique with propofol and remifentanil

With the TIVA technique, you can start the propofol infusion without an induction dose at 3-6 mg/kg/hr and shortly thereafter start the remifentanil infusion at 0.15-0.5 μg/kg/min. This technique takes a bit longer for the patient to fall asleep, but it results in less pronounced circulatory effects. After intubation or placement of a laryngeal mask, the infusion rates of both drugs can be adjusted. The adjustments depend on the depth of anesthesia, whether a concurrent block is present or not, and, of course, the patient’s age, ASA class, etc.

The propofol infusion is usually stopped 5-10 minutes before the end of the surgery, and the remifentanil infusion is typically stopped when the dressing is applied. In some procedures, the infusions of both propofol and remifentanil can be stopped simultaneously at the end of surgery, such as in various endoscopies and laparoscopies. In these cases, painful stimuli remain until the actual end of the operation. Awakening typically occurs relatively quickly, and the patient usually opens their eyes at the same time they take their first breath. The laryngeal mask or endotracheal tube can then be removed.

TIVA technique with propofol and alfentanil

An anticholinergic is usually given initially, and the patient is preoxygenated. Alfentanil is then administered according to the dosage suggestions below.

• Short procedures, < 30 min: Alfentanil is given as an intermittent injection. The initial dose varies between 5-15 μg/kg. Factors such as age, ASA class, etc., must be considered. The dose is given before starting the propofol infusion. Half or the entire dose can be repeated if necessary after approximately 15-20 minutes.
• Procedures > 30 min: Alfentanil is then preferably given as an initial dose followed by an infusion. The initial dose varies between 5-15 μg/kg. Factors such as age, ASA class, etc., must be considered. The dose is given before starting the propofol infusion. After the initial dose is given, the alfentanil infusion is started. The dosage of this depends, as mentioned earlier, on age, ASA class, type of procedure, etc. A guideline is 30 μg/kg/hr (can also be dosed in μg/kg/min). It is important to note that alfentanil’s half-life is relatively long, approximately one hour. The maintenance dose must be reduced if the operation is long. The dose is reduced by 5 μg/kg/hr after about 2 hours and by an additional 5-10 μg/kg/hr after 3 hours. An induction dose of propofol, usually 1-2.5 mg/kg, is then given. This depends on age, ASA class, etc. Afterward, an infusion of propofol is also started. The maintenance dose of propofol should be gradually reduced every ten minutes from normally 10 mg/kg/hr to 8 mg/kg/hr, to eventually settle around 6 mg/kg/hr after approximately 20 minutes. Consideration is given to the amount and type of opioid administered simultaneously. The infusion rate should be lower in older patients and those with a higher ASA class. The maintenance dose is reduced if the operation is long. The dose is reduced by 5 μg/kg/hr after about 2 hours and by an additional 5 μg/kg/hr after 3 hours. The infusion is usually stopped 15 minutes before the end of the procedure, depending on the duration of the infusion and the type of procedure. The propofol infusion is stopped approximately 5-10 minutes before the end of the procedure.

Combination of remifentanil and alfentanil

In certain situations, a combination of remifentanil and alfentanil may be indicated. If anesthesia with propofol (or Sevorane) and alfentanil is used, and it is necessary to increase the dose of alfentanil due to a patient reaction related to pain, e.g., after about an hour of bloodless field, the combination of remifentanil and alfentanil may be a good alternative. If an infusion of 30-40 μg/kg/hr of alfentanil has been used, reduce the dose to 10-15 μg/kg/hr and add remifentanil at 5-7 ng/ml in TCI technique. Anesthesia is then controlled with remifentanil, with a background infusion of alfentanil, as part of the perioperative analgesia and as the start of postoperative pain management.

Muscle relaxants

The muscle relaxant most commonly used routinely is rocuronium (Esmeron). For rapid sequence induction (RSI), succinylcholine (Celocurin) is usually used. In the case of liver and/or kidney failure, atracurium is recommended. It is also possible to intubate without using muscle relaxants if the combination of propofol-remifentanil is used. This is particularly applicable in surgical procedures involving the parathyroid or thyroid glands. If non-depolarizing muscle relaxants have only been administered during induction and more than 60 minutes have passed, the blockade is rarely reversed. If the doses have been iterated and a complete TOF response has been obtained, reversal is also unnecessary.

TIVA protocol for day surgery

Procedures for TIVA

• Workflow
• The syringe pump with propofol should be set to mg/kg/hour.
• The syringe pump with remifentanil should be set to micrograms/kg/minute.
• Fixed placement of drugs in syringe pumps: remifentanil at the top and propofol at the bottom.
• Check valve on the remifentanil infusion.
• Avoid blood pressure cuff on the same arm.

Remifentanil is mixed at a concentration of 50 micrograms/ml: 2 mg remifentanil dissolved in 40 ml 0.9% NaCl.

Patients with ASA 1 and 2, under 60 years with BMI <35

Introduction

• Remifentanil: 0.3 micrograms/kg/min until the patient becomes tired.
• Then 1 – 2 mg/kg propofol until the patient is asleep and achieves sufficient anesthesia depth for ventilation/laryngeal mask. Youths are given a higher dose of propofol (1.5 -2 mg/kg), and older individuals are given a lower dose (1 mg/kg).

In some cases, 50 – 100 micrograms of fentanyl may be given at the beginning, especially if the patient is to be intubated.

Preoxygenation with 80% oxygen. The patient is ventilated with a mask and breathing bag until the patient is ready for the insertion of a laryngeal mask/intubation.

Intubation

• Minimize the use of muscle relaxants.
• Remifentanil 4 micrograms/kg usually provides good intubation conditions in combination with propofol.
• Note: Do not intubate when the vocal cords are centered! This can damage the vocal cords.

Maintenance

• Remifentanil 0.3 micrograms/kg/min.
• Propofol 3 mg/kg/h.

The doses are adjusted according to the clinical situation (procedure and the patient’s condition).

In some procedures, it is crucial that the patient remains completely still (e.g., myringoplasty). In such cases, slightly higher doses of remifentanil should be administered, e.g., 0.4 to 0.5 micrograms/kg/min.

Conclusion

For prolonged anesthesias: in the last 15 minutes, reduce the dose of remifentanil to 0.15 micrograms/kg/min.

For major procedures where adequate local/regional anesthesia could not be administered, fentanyl (50 – 100 micrograms) may be given after the procedure for postoperative pain relief.

Approximately 5 minutes before the end of the operation, the propofol and remifentanil infusions are stopped. (The remifentanil infusion can continue until the procedure is fully completed.)

The ventilator should continue until the patient wakes up and can be extubated or the laryngeal mask can be removed.

Patients over 60 years and/or ASA 3

Evaluate reduced starting doses:

• Remifentanil 0.2 micrograms/kg/min
• Propofol 1 mg/kg

Use plenty of time with slow induction for the elderly, possibly increasing the doses until a satisfactory clinical effect is achieved. Maintenance doses for remifentanil should be 25% to 50% lower than for healthy patients under 60 years, but must be adjusted to the clinical situation. Otherwise, follow the procedure for “patients with ASA 1 and 2, under 60 years and with BMI <35”.

Obese Patients

Consider dose reduction by setting the patient’s weight on the syringe pumps lower than their actual weight. The indicated patient weight is a maximum of 100 kg, even if the actual weight is higher.

Local Anesthesia

Good local anesthesia with possible regional blocks should be aimed for in all patients, if possible.

TIVA for pediatric anesthesia

Workflow

• Fixed placement of syringe pumps with drugs: remifentanil at the top and propofol at the bottom.
• The syringe pump with remifentanil should be set to micrograms/kg/minute.
• The syringe pump with propofol should be set to mg/kg/hour.
• Check valve on the remifentanil infusion.
• Avoid blood pressure cuff on the same arm.

Induction Anesthesia

Preoxygenation is provided with 80% oxygen. The patient is ventilated with a breathing mask and breathing bag until the patient is ready for insertion of a laryngeal mask or intubation.

• Bolus propofol 5 mg/ml (“pediatric propofol”) 3 – 6 mg/kg IV.
• Bolus fentanyl 1 – 3 micrograms/kg IV during induction.
• Start the remifentanil infusion at 0.5 micrograms/kg/min once the child has fallen asleep.
• Atropine 0.01 mg/kg IV is given only if indicated.

If anesthesia is started with sevoflurane inhalation (e.g., when no IV line is available), it can be converted to TIVA after the child is asleep. Half of the bolus dose of propofol is then given, along with other medications according to the previous protocol.

Intubation

• Minimize the use of muscle relaxants.
• Remifentanil 4 micrograms/kg usually provides good intubation conditions in combination with
• Propofol 3.5 mg/kg
• Note: Do not intubate when the vocal cords are centered! This can damage the vocal cords.

Maintenance

• Remifentanil 0.5 – 1.0 micrograms/kg/min
• Propofol 8 – 12 mg/kg/hr, which can gradually be reduced to 6 mg/kg/hr.

The doses are adjusted according to the clinical situation.

Conclusion

Propofol and remifentanil infusions are stopped as the end of the surgery approaches.
Remember to give a bolus of fentanyl 1 – 2 micrograms/kg IV for postoperative pain relief.

The ventilator continues until the patient wakes up and can be extubated or the laryngeal mask can be removed.

Local Anesthesia

Good local anesthesia/regional anesthesia should be provided to as many patients as possible. During skin closure of surgical wounds, local wound infiltration with bupivacaine 2.5 mg/kg 0.5 ml/kg can be administered.

Drug Mixing

• Remifentanil 50 micrograms/ml: 2 mg remifentanil dissolved in 40 ml 0.9% NaCl.
• Propofol is given at a concentration of 5 mg/ml.

References

1. Solheim A, Raeder J. Remifentanil versus fentanyl for propofol-based anesthesia during ambulatory surgery in children. Ambulatory Surgery. March 2011; 17 – 20.
2. Klemola UM, Hiller A. Tracheal intubation following induction of anesthesia in children with propofol – remifentanil or propofol rocuronium. Can J Anaesth. September 2000, 47 (9): 854 – 9.
3. Procedures from Ahus: “Anesthesia for children – TIVA in patients under 16 years”, version 1.4, date 24.01.2014.

Medications for Total Intravenous Anesthesia

Propofol (Diprivan^®, Propolipid^®, Recofol^®, Propofol^®)

Propofol is a hypnotic used both as an induction agent and a maintenance agent for intravenous anesthesia. As described above, various techniques can be used to administer propofol, such as Target Controlled Infusion (TCI), total intravenous anesthesia (TIVA), and simple volume-controlled infusion (ml/hr). In intravenous anesthesia, propofol is usually used at a concentration of 10 mg/ml, but a concentration of 5 mg/ml is commonly used for children. The anesthesia nurse prepares the medication in syringes before each procedure. A drawback of propofol is that it affects circulation, primarily causing hemodynamic instability with a risk of hypotension. Hypotension is most pronounced in older, stressed, and hypovolemic patients. This may be due to reduced sensitivity to endogenous norepinephrine.

Remifentanil (Ultiva^®)

Remifentanil is an ultra-short-acting opioid with a half-life of 3-10 minutes. It is an esterase-metabolized opioid, metabolized by “non-specific” blood and tissue esterases. Breakdown occurs independently of organ function such as liver and kidney, and remifentanil is broken down into two metabolites, including a carboxylic acid metabolite. Both have negligible activity with a half-life of about 2 hours. 95% of remifentanil is excreted through the kidneys within 7-10 hours. Metabolism is independent of liver function.

Remifentanil and Age

Clearance is lower in older patients, and pharmacodynamic activity increases with age. Therefore, doses must be reduced for older patients, even though the software in the pump accounts for the patient’s age.

• 1 μg/kg in a young, tall, slender woman results in a plasma concentration peak of about 13 ng/ml, and it takes about 4 minutes for the concentration to drop to 2 ng/ml in the CNS, allowing spontaneous breathing to start.
• The same dose in an older, heavy, short woman results in a plasma concentration peak of about 28 ng/ml, and it takes about 10 minutes for the concentration to reach 2 ng/ml in the CNS.

Due to higher sensitivity to the drug in older adults, spontaneous breathing does not start until the concentration is 1 ng/ml, which takes an additional 4 minutes.

The advantages of using remifentanil are several:

• A unique pharmacokinetic profile with rapid onset and offset of effect without accumulation
• Very good intraoperative analgesia
• Easy to titrate the appropriate dose
• Doses do not need to be adjusted for renal or hepatic impairment
• Doses of concurrently administered hypnotics are adjusted relative to the Ultiva dose
• Rapid and predictable recovery after analgesia is stopped

Disadvantages:

• Pronounced muscle rigidity may occur
• Tendency to cause bradycardia
• Pronounced apnea tendency

Currently, remifentanil is not routinely used in patients <12 years old, but the drug is approved for use from the age of one. Ultiva is supplied in dry ampoules of 1, 2, or 5 mg, which are then diluted before anesthesia. It is common to dilute remifentanil to a concentration of 50 μg/ml with sodium chloride. Remifentanil should always be administered as an infusion via a syringe pump. Ultiva is intended for intravenous administration only and should not be administered epidurally or intrathecally. Ultiva is compatible with 5% glucose solution or 0.9% sodium chloride. When remifentanil is used as the sole perioperative analgesic, postoperative pain management must be carefully planned and initiated in a timely manner. Preoperatively, paracetamol, possibly an NSAID or COX-2 inhibitor, and oxycodone (Oxycontin) 5 or 10 mg, depending on the patient’s age, are given. Thirty (30) minutes before the end of surgery, morphine is administered i.v. or both i.v. and s.c. An appropriate dose is 0.2-0.3 mg/kg. Parecoxib (Dynastat) may also be given at this time if there are no contraindications, and the surgeon is informed before administration.

If the surgery lasts less than 30 minutes, morphine is given during anesthesia induction. For certain types of endoscopies, e.g., esophagoscopy, which do not cause significant postoperative pain, morphine may be omitted. Consider infiltration of a local anesthetic in the surgical wound or regional blockade at the end of the procedure (activate epidural). For orthopedic procedures involving large joints, ropivacaine (Narop) 7.5 mg/ml may be advantageously instilled into the joint by the surgeon.

Alfentanil (Rapifen^®)

Alfentanil is a relatively short-acting opioid with triphasic elimination. Alfentanil can be used in intermittent administration (bolus doses) or continuous infusion. The following dosage provides guidance whether using a laryngeal mask or if the patient is intubated.

Short procedures (less than 30 minutes): Alfentanil in intermittent administration (bolus doses). The initial dose varies between 5-15 μg/kg. Factors such as age, ASA class, gender, weight, and condition must be considered. The dose is administered before the propofol infusion is started. Half or the entire dose can be repeated if needed after about 15-20 minutes.

Long procedures (over 30 minutes): Alfentanil is then preferably administered as an initial dose followed by an infusion. The initial dose varies between 5-15 μg/kg. Factors such as age, ASA class, etc., must be considered. The dose is administered before the propofol infusion is started. Once the initial dose is given, the infusion is started. The amount depends, as mentioned earlier, on age, ASA class, type of procedure, etc. A guideline is 30 μg/kg/hr. For longer infusions, note that alfentanil’s context-sensitive half-time is about one hour after about two hours of infusion.

The maintenance dose must be reduced if the operation is long. Then reduce by 5 μg/kg/hr after about 2 hours and another 5-10 μg/kg/hr after 3 hours. The infusion is usually stopped when there are 15 minutes remaining in the procedure. This, of course, depends on the duration of the infusion and the type of procedure.

Fentanyl (Fentanyl^®, Leptanal^®)

Fentanyl is a short-acting intravenous anesthetic and analgesic. Fentanyl is intended for use during anesthesia for surgical procedures and for sedation during painful or stressful medical procedures. Fentanyl is a selective and potent μ-opioid agonist with rapid onset and short duration of action. Despite rapid onset, the maximum analgesic and respiratory depressant effect is achieved only after a few minutes. Normally, the analgesic effect of an intravenous injection of 100 micrograms of fentanyl lasts about 30 minutes. In pharmacodynamic terms, fentanyl is similar to morphine but has more potent analgesic and respiratory depressant effects. Even in large bolus doses, fentanyl has often been used for anesthesia induction in patients with heart disease due to its cardiovascular stability and its ability to blunt hemodynamic responses to intubation.

Plasma protein binding is 80-85%. Fentanyl is not plasma cell-bound, and plasma protein binding is minimally affected by pH. Fentanyl is metabolized in the liver to inactive metabolites.

The plasma concentration of fentanyl decreases rapidly after an intravenous injection. The elimination of fentanyl is triphasic, with half-lives of about 1 minute, 15 minutes, and 6 hours. The distribution volume in the central compartment is about 15 liters, and the total distribution volume is about 400 liters. Secondary peaks in plasma levels may occur. About 75% of the dose is eliminated within 72 hours.

Dosage

For anesthesia procedures, the usual initial dose of fentanyl for adults is 50-100-200 μg, 1-2-4 ml, slowly injected intravenously. The dose can be repeated 20-30-45 minutes after the initial dose. Secondary respiratory depression has been observed in cases where large doses have accumulated. There is a risk of accumulation with continuous infusion.

Fentanyl should be used with caution in uncompensated hypothyroidism, lung disease, particularly with reduced lung capacity, alcohol abuse, liver or kidney insufficiency. Tolerance and addiction may be induced. Fentanyl reduces the need for hypnotics necessary to maintain anesthesia, so the dose of hypnotics or volatile anesthetics should be reduced.

• Intubation dose for general anesthesia: 1–8 μg/kg i.v. (70 kg = 70-600 μg = 2-12 ml).
• For children 2 – 12 years, 1-3 μg/kg is given in combination with inhalation anesthesia.

TIVA Dose

Fentanyl can be administered as an infusion.

• Maintenance dose for surgical anesthesia: 0.1-0.70 μg/kg/min.
• Standard dose: 0.15 μg/kg/min.
• Intubation dose: 1-2 μg/kg.

In ventilated patients, a loading dose of fentanyl may be administered as a rapid infusion of approximately 1 μg/kg/min for the first 10 minutes, followed by an infusion of approximately 0.1 μg/kg/min. Alternatively, the loading dose of fentanyl may be given as a bolus dose. The infusion rate should be titrated to the individual patient’s response; lower infusion rates may be sufficient.

TCI Dose (Insufficient Data)

Fentanyl is usually not administered in TCI mode but rather in TIVA mode or intermittently as boluses. The maintenance target concentration (TCI) for surgical anesthesia is unknown: (1-4 ng/ml?). The standard concentration is unknown (2 ng/ml?) (Cpt).

Induction: 100 μg (2 ml) administered over 10 seconds.

Concentration

Solution 50 μg/ml.

Potency

Approximately 100 times the potency of morphine. (1 ml fentanyl ~ 10 mg morphine).

Side Effects

May cause respiratory failure and respiratory depression. May cause muscle stiffness, especially at high doses, and difficulty in manually ventilating the patient. It may cause drowsiness and increased fatigue. May cause bradycardia and hypotension. Muscle rigidity has been observed more frequently at high doses and with rapid administration of fentanyl. Bradycardia and possibly asystole may occur if the patient has received an inadequate dose of anticholinergic or if fentanyl is combined with non-vagolytic muscle relaxants. Secondary respiratory depression has been observed.

Warning

Fentanyl reduces the need for hypnotics (inhalation anesthetics) necessary to maintain anesthesia, so the dose of other anesthetics should be reduced. Because the adverse hemodynamic effects of fentanyl are more pronounced and frequent in ASA IV patients than with longer-acting opiates, great caution should be exercised when administering fentanyl to this patient population.

Alfentanil (Rapifen®)

Intravenous anesthetic and analgesic. Alfentanil is intended for use in pain relief during short and medium-length surgical procedures. Alfentanil is a selective μ-opioid agonist with a rapid onset and very short duration of effect.

Maximum effect is achieved within 90 seconds, with an effect duration of 5-10 minutes. Alfentanil is chemically related to fentanyl. In pharmacodynamic terms, alfentanil is similar to morphine but has stronger analgesic and respiratory depressant effects.

The distribution volume is 0.4-1.0 l/kg. Plasma protein binding is 92%. Alfentanil is not plasma cell-bound, and plasma protein binding is minimally affected by pH. Alfentanil is metabolized in the liver to inactive metabolites.

Dosage: For shorter painful procedures: 0.25-0.5 mg i.v. – repeat as needed. Optimal intubation dose: 20-40 μg/kg i.v. (70 kg = 1.5-3 mg = 3-6 ml). Estimated surgery time 10-30 minutes: 20-40 μg/kg, intravenous bolus dose in 3-6 ml/70 kg. Estimated surgery time 30-60 minutes: 40-80 μg/kg, intravenous bolus dose in 6-12 ml/70 kg.

TIVA Dosing

Maintenance dose for surgical anesthesia: 0.20-0.70 μg/kg/min, default dosing 0.35 μg/kg/min. Intubation dose: 0.70 μg/kg/min.

TCI Dosing

Maintenance dose for surgical anesthesia: 40-70 ng/ml, default concentration 50 ng/ml (Cpt). Induction: 109 µg (0.218 ml) administered over 10 seconds.

Concentration: Solution 0.5 mg/ml = 500 µg/ml

Potency: Approximately 25 times the potency of morphine (1 ml Rapifen ≈ 12.5 mg morphine).

Side Effects: May cause respiratory failure and respiratory depression. May cause muscle rigidity, especially at high doses, and difficulty in manually ventilating the patient. It may cause drowsiness and increased fatigue. May cause bradycardia and hypotension at high doses. Muscle rigidity has been observed more frequently at high doses and with rapid administration of alfentanil. Bradycardia and possibly asystole may occur if the patient has received an inadequate dose of anticholinergic or if alfentanil is combined with non-vagolytic muscle relaxants. Secondary respiratory depression has been observed in rare cases.

Warning: May cause muscle rigidity and difficulty in ventilating the patient, especially at high doses. May cause bradycardia and hypotension. Muscle rigidity has been observed more frequently at high doses and with rapid administration of Rapifen. Bradycardia and possibly asystole may occur if the patient has received an inadequate dose of anticholinergic or if alfentanil is combined with non-vagolytic muscle relaxants. Secondary respiratory depression has been observed in rare cases. Alfentanil reduces the need for hypnotics necessary to maintain anesthesia, so the dose of hypnotics should be reduced. Because the adverse hemodynamic effects of alfentanil are more pronounced and frequent in ASA III-IV patients than with longer-acting opiates, great caution should be exercised when administering Rapifen to this patient population.

Dosing of Alfentanil (Rapifen) in TIVA and TCI

Here are examples of doses measured in simulation. Rapifen starts faster in TIVA dosing compared to TCI dosing. After 2 minutes with TIVA, 212% of the dose has been given compared to TCI. After 5 minutes with TIVA, 146% of the dose has been given compared to TCI.

TIVA Dosing

• Maintenance dose for surgical anesthesia: 0.20-0.70 μg/kg/min, default dosing 0.35 μg/kg/min.
• Intubation dose: 0.70 μg/kg/min.
• Induction: 525 µg administered over 30 seconds (70-kg man)
• In the first 2 minutes, 560 µg is administered.
• In the first 5 minutes, 635 µg is administered.
• To administer 500 µg takes: 29 seconds
• To administer 1000 µg takes: 19 minutes 54 seconds

TCI Dosing

• Maintenance dose for surgical anesthesia: 40-70 ng/ml, default concentration 50 ng/ml (Cpt).
• Induction: 109 µg (0.218 ml) administered over 10 seconds.
• In the first 2 minutes, 263 µg (0.26 mg) is administered.
• In the first 5 minutes, 433 µg (0.43 mg) is administered.
• To administer 500 µg takes: 6.35 minutes
• To administer 1000 µg takes: 28.18 minutes
• Cp 50 ng/ml is achieved after 20 seconds