2.8: Intravenous Induction Agents

Intravenous induction of anaesthesia is a safe, reliable, pleasant method of inducing anaesthesia. However, intravenous induction can be very dangerous in some patients.

Most intravenous induction agents will cause apnoea and relaxation of airway muscles resulting in airway obstruction. Intravenous induction agents should be used with extreme caution for patients whose airway may be difficult to manage. For these patients inhalation induction, awake intubation or ketamine may be safer. Intravenous induction agents must not be given by individuals who are not skilled in airway control. Ketamine will mildly depress respiratory rate and tidal volume. It has a minimal effect on responsiveness to hypercarbia and will maintain protective laryngeal reflexes longer than with other intravenous induction agents. Muscle tone is usually well maintained. However, even with ketamine a safe airway is not guaranteed as airway obstruction can still occur and there is still a danger of aspiration of gastric contents.

Most intravenous induction agents except ketamine will cause a fall in blood pressure. The healthy patient will compensate by vasoconstriction and an increase in their heart rate. However, some patients cannot compensate (hypovolaemia, high spinal) and intravenous induction agents can cause severe hypotension. Hypovolaemia should be treated before anaesthesia.

Common intravenous induction agents include thiopentone, methohexitone, propofol and ketamine. Propanidid and Althesin are not available now because of the high rate of allergy to these drugs. Benzodiazepines and opioids could be used as intravenous induction agents but have a very long duration of action.

THIOPENTONE (thiopental or pentothal)

Duration of Action

Barbiturate induction agents include thiopentone, thiamylal and methohexitone. These drugs are very similar. All are ultra-short acting, causing unconsciousness (by a complex reaction with GABA receptors) within 1 to 2 minutes. They have a short duration of action (5 to 8 minutes) because they rapidly leave the brain due to redistribution to other body organs (fat, muscle). Metabolism is very slow (only 10 to 20% metabolized by the liver each hour). Patients given repeated doses or an infusion of thiopentone would be unconscious for a prolonged period of time (several hours todays). Repeated doses of thiopentone should not be given to prolong anaesthesia.

Dosage

Thiopentone is prepared by dissolving a yellowish powder in sterile water to provide a2.5% solution. This should be used within 24 hours. Thiopentone should not be mixed with other drugs, as it may form a cloudy solution.The usual dose of thiopentone is 3 to 5 mg/kg in adults (methohexitone comes as a 1%solution and the average dose is 1 mg/kg). The dose of thiopentone should be reduced with age greater than 65 years (2 to 3 mg/kg). Pregnancy, renal failure and liver failure have no significant affect on the induction dose of thiopentone. Opioid premedication can reduce the amount of thiopentone needed by 50%. The loss of the eyelash reflex is a good guide to loss of consciousness.

To avoid severe cardiac and respiratory depression in patients who are hypovolaemic, the dose and speed of administration of thiopentone must be greatly reduced. Ideally the anesthetist should give 50 mg to 100 mg (2 to 4 ml of 2.5% thiopentone) doses till the patient is asleep. The anesthetist should check the patient’s blood pressure, pulse and conscious state between each dose.

Placental Transfer

Thiopentone freely crosses the placenta. Maximal foetal blood thiopentone levels occur within 3 minutes of administering thiopentone to the mother.

Central Nervous System

Thiopentone will cause sleep and unconsciousness. (Methohexitone may also cause in voluntary movements and hiccoughs). It is a very poor analgesic and in sub-anaesthetic doses will cause painful stimuli to be more painful (hyperalgesia). Cerebral metabolic rate is decreased by 50%. Cerebral blood flow is reduced by 50% and intracranial pressure is reduced. Cerebral perfusion is not compromised because intracranial pressure decreases more than mean arterial pressure. Thiopentone is an appropriate induction agent for neurosurgical patients.

Respiratory System

Barbiturate induction drugs cause central nervous system and respiratory depression.The extent of the respiratory depression depends on the dose, rate of injection and type of barbiturate and is potentiated by opioids. Patients given an anaesthetic dose of thiopentone usually take 2 or 3 big breaths, and then become apneic. There is rarely bronchospasm or laryngospasm after barbiturate induction of anaesthesia however unless very large doses of barbiturates are used, laryngeal and tracheal reflexes remain intact. If the patient is only lightly anesthetized and the airway is stimulated (e.g.oropharyngeal airway, suctioning, laryngeal mask or endotracheal tube) the patient may develop laryngospasm. Because propofol causes a greater depression of laryngeal reflexes, laryngospasm is less common with propofol than thiopentone. Thiopentone is safe to use in treated asthmatic patients.

Cardiovascular System

The main cardiovascular effect of barbiturate induction is dilation of veins(venodilation) causing pooling of the blood in the periphery. Normally patients compensate for the venodilation by increased sympathetic nervous system activity with an increase in heart rate and vasoconstriction. In healthy patients, 5 mg/kg of thiopentone will cause a transient drop in blood pressure of 10 to 20 mmHg compensated for by a rise in heart rate of 15 to 20 beats per minute. The baro receptor reflex is only slightly depressed by barbiturate induction drugs. Barbiturate induction agents must be used with extreme care in patients who cannot compensate by increasing their sympathetic nervous system activity (high spinal, severe hypovolaemia) or in whom an increased heart rate or pooling of blood (decreased preload) would be dangerous.

Thiopentone has no significant effect on the liver or kidneys and is safe to use in renal and liver failure. It has no effect on the neuromuscular junction.

Contraindications

Thiopentone must not be used if the patient is allergic (1:30,000) or has porphyria. It must be avoided or used with extreme care if the patient has an obstructed airway, uncompensated heart disease (mitral stenosis, aortic stenosis, constrictive pericarditis,cardiac tamponade) or severe shock.

Complications

Intravenous administration of thiopentone is painless (methohexitone may cause mild pain). If the patient complains of pain on injection, the needle is probably not in a vein and injection should be immediately stopped. Subcutaneous injection of thiopentone or methohexitone will cause pain and redness. The area should be infiltrated with lignocaine. Intra-arterial injection of thiopentone or methohexitone will cause severe pain, spasm of peripheral arteries and can cause gangrene and loss of fingers or hand. If intra-arterial injection is suspected (severe pain, blanching of the extremity followed by cyanosis) the anesthetist must immediately stop injecting, leave the needle in the artery and inject normal saline to dilute the thiopentone. Give lignocaine/procaine to treat the pain, a vasodilator (papaverine 40 mg, tolazoline 40 mg, phentolamine 2 to 5 mg) to reduce arterial spasm and heparin to reduce thrombosis. Brachial plexus block and stellate ganglion block (before giving heparin) have been used to help vasodilatation.

PROPOFOL

Propofol is an intravenous induction agent very similar to thiopentone but has some important advantages, however it is more expensive.It is a white solution. The usual dose is 2 to 2.5 mg/kg. This should be reduced in the elderly and hypovolaemic patient. Unfortunately pain on injection of propofol is common. Mixing propofol with 1 ml of lignocaine and injecting into a large vein reduces the incidence of pain. Intra-arterial injection does not cause intense pain andvasospasm.Allergy to propofol has been reported but it is much less common (1 in 60,000) than allergy to thiopentone.Like thiopentone, propofol will cause a fall in blood pressure, respiratory depression,and reduces intracranial pressure.Propofol causes a greater depression of laryngeal reflexes than thiopentone.Laryngospasm is less common.Propofol has the same onset time as thiopentone but has a quicker recovery time (4 to 8 minutes) and does not rely on redistribution for recovery. Propofol can be given as repeated doses or as an infusion.

Total Intravenous Anaesthesia

Propofol may be used as part of total intravenous anaesthesia (TIVA) where all drugs are administered as infusions by electronic syringe pumps. These syringe pumps are“target controlled.” The patient’s weight and the desired blood concentration (propofol induction 4 to 8 micrograms/ml, maintenance 3 to 6 micrograms/ml) of the drug are entered into the syringe pump and the pump automatically delivers the correct infusion rate. An alternative to target controlled pumps is to follow an “infusion recipe”. One such recipe is to administer propofol (along with 66% nitrous oxide) at 10 mg/kg/h for 10 minutes, then at 8 mg/kg/h for 10 minutes then at 6 mg/kg/h. These rates should be adjusted according to clinical signs (blood pressure, heart rate).

KETAMINE

Ketamine is an unusual intravenous induction agent. It has hypnotic (sleep producing),analgesic and amnesic (short term memory loss) effects. Unlike other intravenous induction agents it causes a trance like anaesthesia (dissociative anaesthesia). The patient’s eyes may remain open and there may be movement of their limbs but the patient will not respond to pain.Ketamine has some important advantages compared to other intravenous induction agents including bronchodilatation, minimal respiratory depression, cardiovascular stimulation and analgesia.

Dosage

Ketamine is available in concentrations of 10 mg/ml, 50 mg/ml and 100 mg/ml.Ketamine may be given intravenously (1 to 2 mg/kg), intramuscularly (5 to 10 mg/kg)or as an intravenous infusion (1 mg/min) for adults. The higher doses of ketamine will cause a lot of salivation and patients may need to be given atropine (10 to 20 micrograms/kg).Sub-anaesthetic dose of 0.2 to 0.5 mg/kg intravenously provides excellent analgesia without significant respiratory or cardiovascular changes. Oral ketamine (6 mg/kg) may be used for children.Intravenous ketamine causes anaesthesia in 2 to 3 minutes and may last for 10 to 20 minutes. Intramuscular ketamine causes anaesthesia in 3 to 5 minutes and provides 15 to 30 minutes of surgical anaesthesia. Repeated doses of ketamine (quarter the intravenous dose or half of the intramuscular dose) can be given to prolong the anaesthesia when the patient shows signs of pain.Patients may require premedication to reduce the incidence of bad dreams and“emergence delirium”. Adults can be given diazepam 0.15 mg/kg orally one hour  preoperatively or intravenous diazepam 0.1 mg/kg or midazolam at induction. Children can be given promethazine 0.5 mg/kg or midazolam 0.3 mg/kg orally one hour before surgery.

Respiratory System

Ketamine usually maintains airway muscle tone and causes only a mild decrease in respiratory rate and tidal volume. (Apnoea can occur if ketamine is given rapidly).Patients usually will breathe adequately without assistance from the anaesthetist.However, ketamine does not guarantee an unobstructed airway or protection from aspiration. All patients given ketamine should be given oxygen. Ketamine is a good bronchodilator and is a useful drug for severe asthmatics. (An infusion of ketamine 0.5to 2.5 mg/kg/h has been used to treat severe asthma). Ketamine will increase salivation.

Cardiovascular System

Ketamine stimulates the sympathetic nervous system causing an increase in heart rate and blood pressure. The systolic pressure usually increases 20 to 40 mmHg over 3 to 5 minutes then returns to normal over the next 10 to 20 minutes. The heart rate may increase by 20%. Occasionally ketamine can cause a marked increase in blood pressure.All patients given ketamine must have their blood pressure checked. Ketamine is a good choice of induction agent for the hypovolaemic patient. Ketamine should be used with caution in patients with severe hypertension or ischemic heart disease. As ketamine increases blood pressure and also increases intracranial pressure, it should not be used in pre-eclampsia.

Central Nervous System

Ketamine will increase intracranial pressure, increase cerebral blood flow by up to 60%and increase cerebral oxygen consumption. It is not a good choice of anaesthesia for neurosurgery. Ketamine increases intraocular pressure and causes nystagmus. It is not a good choice of anaesthesia for ophthalmic surgery.

Ketamine is an oxytocic. It will increase muscle tone and can cause spontaneous movements. Ketamine does not cause histamine release. Ketamine will produce unpleasant dreams (5 to 30%). They are more common in adults, females and with dosages greater than 2 mg/kg. On recovery the patient may be restless and agitated(emergence delirium). Giving benzodiazepines for premedication or during induction can reduce the incidence of unpleasant dreams and emergence delirium. A patient may continue to experience unpleasant dreams for 24 hours after ketamine has been given.