Intravenous Anesthesia – Pharmacology and Drugs

Medicines for Total Intravenous Anesthesia

Below is a brief summary of common medicines for intravenous anesthesia. The medicines are then presented again in detailed format.

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

Propofol is a hypnotic used both as an induction agent and maintenance agent for intravenous anesthesia. As described above, there are different techniques to administer propofol, such as Target Controlled Infusion (TCI), total intravenous anesthesia (TIVA), and simple volume-controlled infusion (ml/hr). For intravenous anesthesia, propofol is usually used at a strength of 10 mg/ml, but for children, the strength of 5 mg/ml is commonly used. The anesthesia nurse prepares the medicine in syringes before each procedure. One disadvantage of propofol is that it affects circulation, mainly through hemodynamic instability with the risk of hypotension. Hypotension is most pronounced in elderly, stressed, and hypovolemic patients. This may be due to a decreased sensitivity to endogenous norepinephrine.

Remifentanil (Remifentanil®, Ultiva®)

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

Alfentanil (Rapifen®)

Alfentanil is a relatively short-acting opioid with a triphasic elimination. Alfentanil can be administered intermittently (bolus doses) or as a continuous infusion. The following dosages provide guidance depending on whether a laryngeal mask or intubation is used.

Short procedures (less than 30 min): 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 given before starting the propofol infusion. Half or the entire dose can be repeated if necessary after about 15-20 min.

Long procedures (over 30 min): Alfentanil is then appropriately 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 given before starting the propofol infusion. When the initial dose is given, the infusion is started. The size of this depends, as mentioned earlier, on age, ASA class, type of procedure, etc. A guideline is 30 μg/kg/hr. It should be noted that after about two hours of infusion, alfentanil’s context-sensitive half-time is about one hour.

The maintenance dose must be adjusted downwards for long operations. The rate is reduced by 5 μg/kg/hr after about 2 hours and by an additional 5-10 μg/kg/hr after 3 hours. The infusion is usually stopped when 15 min remains of the procedure. This obviously depends on how long the infusion has been running 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 its rapid action, the maximum analgesic and respiratory depressive effect is not achieved until a few minutes after administration. Typically, the analgesic effect of an intravenous injection of 100 micrograms of fentanyl lasts about 30 minutes. Pharmacodynamically, fentanyl resembles morphine but has more potent analgesic and respiratory depressive effects. Even in large bolus doses, fentanyl has often been used to induce anesthesia 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 bound to plasma cells, and plasma protein binding is minimally affected by pH. Fentanyl is metabolized in the liver to inactive metabolites.

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

Remifentanil (Remifentanil®/Ultiva®)

Intravenous ultra-short-acting anesthetic. Remifentanil is a selective and potent opioid.

Solution 50 μg/ml. The recommended dilution for general anesthesia is 50 μg/ml for adults and 20 μg/ml for children ≥ 1 year.

Remifentanil is a selective μ-opioid agonist with rapid onset and very short duration of action. Remifentanil is an esterase-metabolized opioid, metabolized by non-specific blood and tissue esterases.

Indication

Used as an analgesic during induction and/or maintenance of general anesthesia during assisted ventilation in surgical procedures, including anesthesia for cardiac surgery. For pain relief and sedation in intensive care for mechanically ventilated patients aged 18 years and older.

Dosage

Intubation dose TIVA 0.25-0.5 μg/kg/min, TCI 6-8 ng/ml. 0.5 μg/kg/min can be given as an induction dose in TIVA up to 100-150 μg.

• Single dose induction 1 μg/kg, induction without muscle relaxants 2-3 μg/kg (90 sec to effect)
• Maintenance superficial surgery TIVA 0.15-0.25 μg/kg/min, TCI 4-6 ng/ml
• Maintenance deep surgery TIVA 0.2-0.5 μg/kg/min, TCI 5-10 ng/ml

After administration of the recommended doses of remifentanil, the effective half-life is 3-10 minutes. The average clearance of remifentanil in healthy young adults is 40 ml/min/kg, the central distribution volume is 100 ml/kg, and the steady-state distribution volume is 350 ml/kg.

Remifentanil reduces the need for hypnotics necessary to maintain anesthesia, so the dose of hypnotics should be reduced. Since adverse hemodynamic effects of remifentanil are more pronounced and frequent in patients with ASA III-IV than with more long-acting opiates, great caution should be exercised when administering Ultiva to this patient group.

Remifentanil and Hyperalgesia

Hyperalgesia is defined as an increased pain intensity at a constant pain stimulus. This hyperalgesia may be due to two mechanisms: opioid-induced hyperalgesia and the induction of acute opioid tolerance. Studies show that there is an increased postoperative morphine consumption after anesthesia where large doses of remifentanil were given, and no blocks were placed. This is compared to equivalent operations where other anesthesia techniques were used. This hyperalgesia can be partially counteracted by using gabapentin in premedication or administering ketamine intraoperatively in a low dose. A disadvantage of gabapentin is that patients can become very tired.

The patient groups most relevant to administering Ketalar are those who have received high doses of Ultiva, patients with ulcerative colitis/Crohn’s disease, and those who preoperatively have known pain problems with significant opioid consumption.

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 takes the patient’s age into account.

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

Since there is a higher sensitivity to the drug in older patients, spontaneous breathing does not start until the concentration is 1 ng/ml, and it takes about 4 more minutes.

The advantages of using remifentanil are several:

• A unique pharmacokinetic profile with rapid onset and offset without accumulation
• Very good intraoperative analgesia
• Easy to titrate the appropriate dose
• Doses do not need to be adjusted for renal or liver failure
• You adjust doses of concomitant hypnotics relative to the Ultiva dose
• Fast and predictable recovery after analgesia is discontinued

Disadvantages:

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

Remifentanil is currently not routinely used in patients <12 years, but the drug is registered for use down to 1 year of age. Ultiva is supplied in dry ampoules of 1, 2, or 5 mg, which are then diluted before anesthesia. It is common to mix remifentanil to a strength of 50 μg/ml with sodium chloride. Remifentanil should always be given as an infusion via a syringe pump. Ultiva is intended for intravenous administration only and should not be given as an epidural or intrathecal injection. Ultiva is compatible with 5% glucose solution or 0.9% sodium chloride. If remifentanil is used as the sole intraoperative analgesic, postoperative pain relief must be carefully planned and started in time. 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 the operation, morphine is given IV or both IV and SC. A suitable dose is 0.2-0.3 mg/kg. Parecoxib (Dynastat) can also be given at this time if there are no contraindications, and the surgeon is informed before the drug is administered.

If the operation lasts less than 30 minutes, morphine is given in connection with anesthesia induction. For certain types of scopes, such as esophagoscopy, which do not cause significant postoperative pain, morphine can be omitted. Consider also infiltration of a local anesthetic in the surgical wound or a regional block at the end of the operation (activate epidural). In orthopedic procedures in large joints, ropivacaine (Narop) 7.5 mg/ml can be advantageously instilled in the joint by the surgeon.

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

Propofol is a substituted phenol that, when administered intravenously, provides general anesthesia. Here is basic pharmacological information about this drug.

Propofol is a short-acting intravenous anesthetic for induction and maintenance of general anesthesia in adults and children over 1 month. Propofol is also used for sedation during diagnostic and surgical procedures in adults and children over 1 month. Propofol is used for the sedation of ventilated patients over 16 years old in the intensive care unit.

Propofol (2,6-diisopropylphenol) is a substituted phenol that, when administered intravenously, induces anesthesia. The mechanism of action of propofol is not entirely known, but it likely exerts its effect via a non-specific membrane binding of the substance in arousal-regulating neurons in the brain, primarily in the thalamus. Intravenous administration of propofol induces rapid anesthesia within approximately 30 seconds, and the effect lasts about 5-10 minutes. Awakening is relatively quick.

Concentration: 5 mg/ml, 10 mg/ml, or 20 mg/ml. For anesthesia in adults, 10 mg/ml is usually used. For sedation in ICU, 20 mg/ml is often used. For children, 5 mg/ml is recommended for induction by hand.

Dosage: The normal dose for the induction of anesthesia is 1.5-2.5 mg/kg intravenously at a rate of 40 mg/10 sec until anesthesia occurs. In patients with complicated conditions (ASA 3 and 4), anesthesia should be induced more slowly, at 20 mg/10 sec. Patients over 55 years old may require a lower induction dose. The total dose can be reduced if the induction dose is administered at a slower rate (20-50 mg/min). Depending on the injection rate, the time to induction of anesthesia is between 30 and 40 seconds. After a bolus injection, the effect is short-lived due to the rapid metabolism and excretion (4-6 min).

TIVA Dosage

• Intubation dose: 10-14 mg/kg/h.
• Maintenance dose for superficial surgery: 6-12 mg/kg/h.
• Maintenance dose for deep surgery: 14-16 mg/kg/h.
• Induction 1-2-3 mg/kg over 45 sec.

TCI Dosage

• Intubation dose: 4-6 μg/ml.
• Maintenance dose for superficial surgery: 2-4 μg/ml.
• Maintenance dose for deep surgery: 4-6 μg/ml.

ICU Dosage

Propofol 20 mg/ml IV

• Maintenance for sedation: 0.1-1.4 mg/kg/h, only for patients > 16 years.

Propofol is widely distributed and rapidly eliminated from the body (total body clearance: 1.5–2 liters/minute). Elimination occurs through metabolic processes, mainly in the liver where it is blood flow-dependent, forming inactive conjugates of propofol and the corresponding quinol, which are excreted in the urine.

Propofol 20 mg/ml is not recommended for general anesthesia in children under 3 years old because it is difficult to adjust the correct dose of the 20 mg/ml strength since treatment of small children requires extremely small volumes. For children between 1 month and 3 years, when a dose lower than 100 mg/hour is needed, Propofol 10 mg/ml is recommended.

Administration of Propofol with a TCI system (Target Controlled Infusion) is not recommended for use in children < 16 years.

Warning: A few reports have been received of adult patients suffering from metabolic acidosis, rhabdomyolysis, hyperkalemia, and/or rapidly progressing heart failure (in some cases fatal) after being sedated for more than 58 hours with doses exceeding 5 mg/kg/hour.

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 its rapid action, the maximum analgesic and respiratory depressive effect is not achieved until a few minutes after administration. Typically, the analgesic effect of an intravenous injection of 100 micrograms of fentanyl lasts about 30 minutes. Pharmacodynamically, fentanyl resembles morphine but has more potent analgesic and respiratory depressive effects. Even in large bolus doses, fentanyl has often been used to induce anesthesia 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 bound to plasma cells, and plasma protein binding is minimally affected by pH. Fentanyl is metabolized in the liver to inactive metabolites.

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

Dosage

During 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 in cases of reduced lung capacity, alcohol abuse, liver or kidney insufficiency. Tolerance and abuse can 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 IV (70 kg = 70-600 μg = 2-12 ml).
• For children 2 – 12 years old, 1-3 μg/kg is given in combination with inhalation anesthesia.

TIVA Dosage

Fentanyl can be given 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.

For ventilated patients, a loading dose of fentanyl can be given as a rapid infusion of approximately 1 μg/kg/minute during the first 10 minutes, followed by an infusion of approximately 0.1 μg/kg/minute. Alternatively, the loading dose of fentanyl can be given as a bolus dose. The infusion rate should be titrated based on individual patient response; lower infusion rates may be sufficient.

TCI Dosage (insufficient data)

Fentanyl is not normally administered in TCI mode but rather in TIVA mode or in intermittent boluses. The target maintenance 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) is given over 10 seconds.

Concentration

Solution 50 μg/ml.

Strength

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

Side Effects

Can cause respiratory failure and respiratory depression. Can cause muscle rigidity, especially at high doses, and difficulty in manually ventilating the patient. It can cause drowsiness and increased fatigue. Can cause bradycardia and hypotension. Muscle rigidity has been observed with increased frequency at high doses and with rapid administration of fentanyl. Bradycardia and possibly asystole may occur if the patient receives an insufficient dose of anticholinergics 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. Since the adverse hemodynamic effects of fentanyl are more pronounced and frequent in patients with ASA IV than with long-acting opiates, great caution should be exercised when administering fentanyl to this patient population.

Alfentanil (Alfentanil®, Rapifen®)

Intravenous anesthetic and analgesic. Ultra-short-acting potent opioid. Alfentanil is intended for use in pain relief during short and medium-length surgical procedures. Alfentanil is a selective μ-opioid agonist with rapid onset and very short duration of action. Alfentanil maintains spontaneous breathing better relative to anesthesia depth compared to remifentanil. Alfentanil works well in continuous infusion with spontaneous breathing via a laryngeal mask.

The maximum effect is achieved within 90 seconds with an effect duration of 5-10 minutes. Alfentanil is chemically related to fentanyl. Pharmacodynamically, alfentanil resembles morphine but has a more potent analgesic and respiratory depressive effect.

• Maximum effect within 90 seconds after injection – short duration 5-10 min. Can cause muscle rigidity, especially at high doses.
• Dose for short painful procedures: 0.25-0.5 mg – repeat as needed.
• Optimal intubation dose: 20 μg/kg IV (70 kg = 1.5 mg = 3 ml)
• TIVA (μg/kg/min) – Intubation 0.4-0.5, Maintenance 0.2-0.7 μg/kg/min
• TCI (ng/ml) – Intubation 40-50 ng/ml, Maintenance 40-80 ng/ml

The distribution volume is 0.4-1.0 l/kg. Plasma protein binding is 92%. Alfentanil is not bound to plasma cells, 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 IV – repeat as needed. Optimal intubation dose: 20-40 μg/kg IV (70 kg = 1.5-3 mg = 3-6 ml). Estimated operation time 10-30 minutes: 20-40 μg/kg, intravenous total dose up to 3-6 ml/70 kg. Estimated operation time 30-60 minutes: 40-80 μg/kg, intravenous total dose up to 4-7 ml/70 kg.

TIVA Dosage

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

TCI Dosage

• Maintenance dose surgical anesthesia: 40-70 ng/ml
• Default concentration 50 ng/ml (Cpt)
• Induction: 109 µg (0.218 ml) is given over 10 seconds.

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

Strength: Approximately 25 times morphine’s potency (1 ml Rapifen ≈ 12.5 mg morphine).

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

Warning: Can cause muscle rigidity and difficulty ventilating the patient, especially at high doses. Can cause bradycardia and hypotension. Muscle rigidity has been observed with increased frequency at high doses and with rapid administration of Rapifen. Bradycardia and possibly asystole may occur if the patient receives an insufficient dose of anticholinergics 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. Since adverse hemodynamic effects of alfentanil are more pronounced and frequent in patients with ASA III-IV than with more long-acting opiates, great caution should be exercised when administering Rapifen to this patient group.

Dosage of Rapifen (alfentanil) in TIVA and TCI

Below 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 Dosage

• Maintenance dose 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 is given over 30 sec (70-kg man)
• During the first 2 min, 560 µg is given
• During the first 5 min, 635 µg is given
• To give 500 µg takes: 29 sec
• To give 1000 µg takes: 19 min 54 sec

TCI Dosage

• Maintenance dose surgical anesthesia: 40-70 ng/ml, default concentration 50 ng/ml (Cpt).
• Induction: 109 µg (0.218 ml) is given over 10 sec.
• During the first 2 min, 263 µg (0.26 mg) is given
• During the first 5 min, 433 µg (0.43 mg) is given
• To give 500 µg takes: 6.35 min
• To give 1000 µg takes: 28.18 min
• Cp 50 ng/ml is reached after 20 seconds

Thiopentone (Pentocur®/Pentothal®) “Pento”

Ultra-short-acting intravenous anesthetic that is a barbituric acid derivative. Thiopentone induces sleep quickly when given intravenously. It induces hypnosis and anesthesia but not analgesia. Primarily used for the induction of anesthesia for surgery but also for short medical procedures where short-term sleep is desired. Usually given by manual injection with a syringe (25 mg/ml) where speed and dose are adjusted according to the patient’s condition and the nature of the procedure. Thiopentone can be given as a continuous infusion in the treatment of status epilepticus and increased intracranial pressure in brain edema. Thiopentone was the standard drug for anesthesia induction for several decades but has recently been replaced by propofol and other anesthetics. It provides a dose-dependent depression of respiration and circulation. Thiopentone is only a hypnotic and not an actual analgesic, but pain relief may follow to some extent with anesthesia depth. Therefore, for surgical anesthesia, thiopentone is usually complemented with strong opioids such as fentanyl in balanced anesthesia. Compared to propofol, thiopental does not provide the same relaxation in the upper airways, which may result in some rigidity and difficulties in manual ventilation. A small dose of thiopental can be given to prevent or treat laryngospasm.

Concentration: 25 mg/ml.

Thiopentone is supplied and stored as a dry substance and is usually diluted to a fresh daily concentration of 25 mg/ml. Diluted solution has a shelf life of only 24 hours and should be stored in a refrigerator.

Dosage

• Anesthesia induction: 4-6 mg/kg.
• The normal dose for a 70 kg patient is approximately 14 ml (± 4 ml) = 350 mg.

Use in neurological patients with increased intracranial pressure.

Intermittent bolus injection of 1.5 – 3 mg/kg body weight can be given to reduce the increase in intracranial pressure during controlled ventilation. In continuous infusion 2-4 mg/kg/hour. A maximum dose of 5 mg/kg/hour should not be exceeded.

A normal induction dose for adults is 4-6 mg/kg body weight, but the individual response is so variable that no fixed dosage can be specified. Usually, between 200 and 400 mg is given as an induction dose (8 – 16 ml at 25 mg/ml), with a normal starting dose of 14 ml. In patients with poor general condition, the dose is usually reduced and carefully titrated. After intravenous administration, unconsciousness occurs within 30 seconds and persists for 20-30 minutes after a single dose. Rapid uptake occurs in most vascular areas of the brain, followed by redistribution to other tissues. It is rarely justified to administer more than 500 mg intravenously. Thiopental has a distribution half-life of 2-4 hours after a single intravenous dose, and for elimination, the half-life is 9-11 hours. Plasma protein binding is 80-90% at therapeutic concentration.

Cave

Porphyria, upper airway obstruction, asthma attack, extravasal and intra-arterial injection. Pentothal is histamine-releasing, and a transient skin flush (usually over the chest and neck) can be seen after intravenous injection.

Caution

Caution in severe obesity, hypovolemia, hypotension, or severe shock.

Brand Names

Pentocur, Thiopental (withdrawn).

Etomidate

A sedative and hypnotic ultrashort-acting hypnotic drug used for induction and maintenance of anaesthesia or sedation. Contains a carboxylate imidazole ring. Acts on GABA-A receptors. Provides a safe cardiovascular profile with little effect on blood gases and ventilation. It is administered only by intravenous route. Duration of action is intermediate between thiopental and methohexital, and recovery from a single dose is rapid with little residual depression. Like the barbiturates and propofol, etomidate is does not induce analgesia.

• Onset 10-65 seconds after injection.
• Duration of action is 6-10 minutes.
• Protein binding 75%.
• Elimination half-life: 2.9-5.3 hrs.
• VD: 2.5-45 L/kg.
• Terminal half-life 15-20 minutes.

Provides water solubility in acidic solutions and lipid solubility at physiological pH.

Etomidate is metabolized by plasma and hepatic esterases.

Dose: Induction 0.2-0.6 mg/kg iv. Standard dosing for the induction of anesthesia is 0.3 mg/kg, after which hypnosis lasts for 5–10 min.

Formulation. Administered as a lipid emulsion of triglycerides, no dilution is required for administration. pH 8.1

Adverse effects: Pain on injection. May trigger myoclonus, adrenal suppression and antiplatelet activity.

Contraindications: Adrenal insufficiency.

Concentration: 2 mg/ml.

Remimazolam (Byfavo®)

Remimazolam is a short-acting sedative benzodiazepine. Remimazolam is indicated for procedural sedation in adults. Remimazolam is a potent sedative intravenous drug that requires careful titration and slow administration. Patient’s physical status, age, and other medications must be considered.

Remimazolam has a rapid onset and the sedation diminishes quickly. The effect sets in about 1-2 minutes after injection. The maximum effect is achieved after 3 – 3.5 minutes. Patients fully awaken 12–14 minutes after the last dose of remimazolam.

The distribution volume at steady state is 0.9 l/kg. Remimazolam is 90% bound to plasma proteins, mainly albumin. In healthy volunteers, the elimination half-life of remimazolam is between 7 and 10 minutes. The half-life and effect are significantly prolonged in severe liver disease.

Indication: Sedation in connection with diagnostic examinations or therapeutic procedures, e.g., catheterizations or endovascular procedures.

Concentration: Solution: 2.5 mg/ml. (20 mg in 8 ml). Usually administered intravenously.

Dosage

Sedation before procedures with opioid in adults < 65 years

Induction: Administer opioid and wait 1–2 minutes.

Start dose: Injection: 5 mg (2 ml) in 1 min. Wait 2 minutes. The remimazolam dose should be individually titrated to the effective dose that provides the desired sedation depth and minimizes side effects. Additional doses can be administered as needed to induce or maintain the desired sedation level. At least 2 minutes should elapse before any additional dose is administered to allow a full assessment of the sedative effect.

Maintenance/titration: Injection: 2.5 mg (1 ml) in 15 sec.

The highest total dose administered in clinical trials was 33 mg.

Sedation before procedures with opioid in adults ≥ 65 years and/or with ASA-PS III–IV and/or body weight < 50 kg

Induction: Administer opioid and wait 1–2 minutes.

Start dose: 2.5–5 mg (1–2 ml) in 1 min. Wait 2 minutes.

Maintenance/titration Injection: 1.25–2.5 mg (0.5–1 ml) in 15 sec.

The highest total dose administered in clinical trials was 17.5 mg.

Sedation before procedures, without opioid in adults < 65 years

Induction injection: 7 mg (2.8 ml) in 1 min. Wait 2 minutes.

Maintenance/titration: Injection: 2.5 mg (1 ml) in 15 sec.

The highest total dose administered in clinical trials was 33 mg.

Sedation before procedures, without opioid in adults ≥ 65 years and/or with ASA-PS III–IV and/or body weight < 50 kg

Induction injection: 2.5–5 mg (1–2 ml) in 1 min. Wait 2 minutes.

Maintenance/titration: Injection: 1.25–2.5 mg (0.5–1 ml) in 15 sec.

The highest total dose administered in clinical trials was 17.5 mg.

In patients with hypovolemia, vasoconstriction, or hypothermia, the maintenance dose should be reduced. The sedation level should be regularly assessed.

Side Effects: Respiratory failure, bradycardia, hypotension.

Warning: Caution in renal insufficiency, advanced age, muscle weakness, liver failure, and respiratory insufficiency. The effect is enhanced by other centrally acting sedatives. Prolonged half-life is seen in impaired liver function.

Contraindications: Hypersensitivity to the active substance or other benzodiazepines. Unstable myasthenia gravis and other neuromuscular diseases.

Ketamine (Ketalar®)

Anesthetic for intravenous or intramuscular administration for anesthesia induction and maintenance. Provides analgesia and dissociative anesthesia. Can also be administered orally for sedation. Induction and maintenance of anesthesia in diagnostic and surgical procedures, as the only anesthetic or in combination with other anesthetics. Ketamine can be given before or as a complement to regional anesthesia, even in acute fracture surgery. Ketamine or ketanest can be administered as a continuous infusion in the treatment of severe pain alone or in addition to other pain management. Ketamine has been described as having a rapidly acting antidepressant effect and is currently being tested in depression and severe pain conditions. (For this purpose, ketamine can be given in a nasal spray).

• Ketalar = Ketamine in racemic form (50% Ketamine-R + 50% Ketamine-S)
• Ketanest = Ketamine-S = Esketamine. Ketanest is about twice as potent as Ketalar and causes less cognitive impact.

Ketamine is an NMDA receptor blocker and provides so-called dissociative anesthesia with effective pain relief by selectively interrupting association pathways in the brain. The patient easily falls asleep after induction and enters a hypnotic state where pain or perception (other sensory impressions) is no longer experienced normally. The state is dreamlike, and vivid dreams of a hallucinatory nature are often described. The dreams can be both pleasant and unpleasant. The patient has increased sensitivity to sound, so the environment should be calm, quiet, and peaceful. The depth of anesthesia can be difficult to assess since the patient no longer reacts to sound, light, touch, or speech without appearing to be asleep. In subanesthetic doses, ketamine has an analgesic effect, likely due to interaction with biogenic amine and endogenous opiate systems. Ketamine usually does not affect reflexes in the pharynx and larynx, and muscle tone remains normal or increases slightly. Cardiovascular and respiratory stimulating effects allow ketamine to be given to high-risk patients in hypovolemic shock. The analgesic effect can be utilized as a complement to regional anesthesia or in mass casualty situations/disaster settings.

Concentration

10 mg/ml for intravenous use, 50 mg/ml for intramuscular use.

Induction Anesthesia

1-2 mg/kg IV, alternatively (5)-10 mg/kg IM (+ midazolam 1-3 mg). An intravenous dose of 2.0 mg/kg body weight provides surgical anesthesia within one minute after injection, and the anesthetic effect persists for 5-15 minutes. Intramuscular dosing of 10.0 mg/kg body weight provides surgical anesthesia within 3-5 minutes after injection with a duration of 12-25 minutes. To achieve prolonged anesthesia or analgesia, ketamine can be administered in infusion (0.5-4 mg/kg/h) or a syringe pump for even administration, e.g., in anesthesia of a patient in hemorrhagic shock. The onset of anesthesia is followed by temporary tachycardia, increased blood pressure, and cardiac output, which return to baseline within 15 minutes after injection. (Preferably quiet in the room or headphones on the patient). Orally, ketamine provides good sedation after 10-15 minutes and lasts about 30-45 minutes. It can be given diluted in juice in a dose of about 4-5 mg/kg.

Maintenance Dose Anesthesia

• 0.5-4 mg/kg/h IV in decreasing dosage
• Postoperative pain relief: 5-15 mg bolus
• Maintenance infusion for postoperative pain relief: 0.05-0.5 mg/kg/h

Cave

Hypertension (relative contraindication). The dose should be reduced in liver failure. There is a risk of abuse in non-medical use.