Rapid onset – this is achieved by an agent which is mainly un-ionized at blood pH and which is highly soluble in lipid; these properties permit penetration of the blood–brain barrier

 Rapid recovery – early recovery of consciousness is usually produced by rapid redistribution of the drug from the brain into other well-perfused tissues, particularly muscle. The plasma concentration of the drug decreases, and the drug diffuses out of the brain along a concentration gradient. The quality of the later recovery period is related more to the rate of metabolism of the drug; drugs with slow metabolism are associated with a more prolonged ‘hangover’ effect and accumulate if used in repeated doses or by infusion for maintenance of anaesthesia

 Analgesia at subanaesthetic concentrations

 Minimal cardiovascular and respiratory depression

 No emetic effects

 No excitatory phenomena (e.g. coughing, hiccup, involuntary movement) on induction

 No emergence phenomena (e.g. nightmares)

 No interaction with neuromuscular blocking drugs

 No pain on injection

 No venous sequelae

 Safe if injected inadvertently into an artery

 No toxic effects on other organs

 No release of histamine

 No hypersensitivity reactions

 Water-soluble formulation

 Long shelf-life

 No stimulation of porphyria.

Distribution to Other Tissues

The anaesthetic effect of all i.v. anaesthetic drugs in current use is terminated predominantly by distribution to other tissues. Figure 3.1 shows this distribution for thiopental. The percentage of the injected dose in each of four body compartments as time elapses is shown after i.v. injection. A large proportion of the drug is distributed initially into well-perfused organs (termed the vessel-rich group, or viscera – predominantly brain, liver and kidneys). Distribution into muscle (lean) is slower because of its low lipid content, but it is quantitatively important because of its relatively good blood supply and large mass. Despite their high lipid solubility, i.v. anaesthetic drugs distribute slowly to adipose tissue (fat) because of its poor blood supply. Fat contributes little to the initial redistribution or termination of action of i.v. anaesthetic agents, but fat depots contain a large proportion of the injected dose of thiopental at 90 min, and 65–75% of the total remaining in the body at 24 h. There is also a small amount of redistribution to areas with a very poor blood supply, e.g. bone. Table 3.3 indicates some of the properties of the body compartments in respect of the distribution of i.v. anaesthetic agents.

After a single i.v. dose, the concentration of drug in blood decreases as distribution occurs into viscera, and particularly muscle. Drug diffuses from the brain into blood along the changing concentration gradient, and recovery of consciousness occurs. Metabolism of most i.v. anaesthetic drugs occurs predominantly in the liver. If metabolism is rapid (indicated by a short elimination half-life), it may contribute to some extent to the recovery of consciousness. However, because of the large distribution volume of i.v. anaesthetic drugs, total elimination takes many hours, or, in some instances, days. A small proportion of drug may be excreted unchanged in the urine; the amount depends on the degree of ionization and the pH of urine.

Chemical Structure

Sodium 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate.

Physical Properties and Presentation

Thiopental sodium, the sulphur analogue of pentobarbital, is a yellowish powder with a bitter taste and a faint smell of garlic. It is stored in nitrogen to prevent chemical reaction with atmospheric carbon dioxide, and mixed with 6% anhydrous sodium carbonate to increase its solubility in water. It is available in single-dose ampoules of 500 mg and is dissolved in distilled water to produce 2.5% (25 mg ml^–1) solution with a pH of 10.8; this solution is slightly hypotonic. Freshly prepared solution may be kept for 24 h. The oil/water partition coefficient of thiopental is 4.7, and the pKa 7.6.

Pharmacokinetics

Blood concentrations of thiopental increase rapidly after i.v. administration. Between 75 and 85% of the drug is bound to protein, mostly albumin; thus, more free drug is available if plasma protein concentrations are reduced by malnutrition or disease. Protein binding is affected by pH and is decreased by alkalaemia; thus the concentration of free drug is increased during hyperventilation. Some drugs, e.g. phenylbutazone, occupy the same binding sites, and protein binding of thiopental may be reduced in their presence.

Thiopental diffuses readily into the CNS because of its lipid solubility and predominantly un-ionized state (61%) at body pH. Consciousness returns when the brain concentration decreases to a threshold value, dependent on the individual patient, the dose of drug and its rate of administration, but at this time nearly all of the injected dose is still present in the body.

Metabolism of thiopental occurs predominantly in the liver, and the metabolites are excreted by the kidneys; a small proportion is excreted unchanged in the urine. The terminal elimination half-life is approximately 11.5 h. Metabolism is a zero-order process; 10–15% of the remaining drug is metabolized each hour. Thus, up to 30% of the original dose may remain in the body at 24 h. Consequently, a ‘hangover’ effect is common; in addition, further doses of thiopental administered within 1–2 days may result in cumulation. Elimination is impaired in the elderly. In obese patients, dosage should be based on an estimate of lean body mass, as distribution to fat is slow. However, elimination may be delayed in obese patients because of increased retention of the drug by adipose tissue.

Dosage and Administration

Thiopental is administered i.v. as a 2.5% solution; the use of a 5% solution increases the likelihood of serious complications and is not recommended. A small volume, e.g. 1–2 mL in adults, should be administered initially; the patient should be asked if any pain is experienced in case of inadvertent intra-arterial injection (see below) before the remainder of the induction dose is given.

The dose required to produce anaesthesia varies, and the response of each patient must be assessed carefully; cardiovascular depression is exaggerated if excessive doses are given. In healthy adults, an initial dose of 4 mg kg^–1 should be administered over 15–20 s; if loss of the eyelash reflex does not occur within 30 s, supplementary doses of 50–100 mg should be given slowly until consciousness is lost. In young children, a dose of 6 mg kg^–1 is usually necessary. Elderly patients often require smaller doses (e.g. 2.5–3 mg kg^–1) than young adults.

Induction is usually smooth and may be preceded by a taste of garlic. Adverse effects are related to peak blood concentrations, and in patients in whom cardiovascular depression may occur the drug should be administered more slowly; in very frail patients, as little as 50 mg may be sufficient to induce sleep.

No other drug should be mixed with thiopental. Neuromuscular blocking drugs should not be given until it is certain that anaesthesia has been induced. The i.v. cannula should be flushed with saline before vecuronium or atracurium is administered, to obviate precipitation.

Supplementary doses of 25–100 mg may be given to augment nitrous oxide/oxygen anaesthesia during short surgical procedures. However, recovery may be prolonged considerably if large total doses are used (> 10 mg kg^–1).

Adverse Effects

Hypotension. The risk is increased if excessive doses are used, or if thiopental is administered to hypovolaemic, shocked or previously hypertensive patients. Hypotension is minimized by administering the drug slowly. Thiopental should not be administered to patients in the sitting position.

Respiratory depression. The risk is increased if excessive doses are used, or if opioid drugs have also been administered. Facilities must be available to provide artificial ventilation.

Tissue necrosis. Local necrosis may follow perivenous injection. Median nerve damage may occur after extravasation in the antecubital fossa, and this site is not recommended. If perivenous injection occurs, the needle should be left in place and hyaluronidase injected.

Intra-arterial injection. This is usually the result of inadvertent injection into the brachial artery or an aberrant ulnar artery in the antecubital fossa but has occurred occasionally into aberrant arteries at the wrist. The patient usually complains of intense, burning pain, and drug injection should be stopped immediately. The forearm and hand may become blanched and blisters may appear distally. Intra-arterial thiopental causes profound constriction of the artery accompanied by local release of norepinephrine. In addition, crystals of thiopental form in arterioles. Thrombosis caused by endarteritis, adenosine triphosphate release from damaged red cells and aggregation of platelets result in emboli and may cause ischaemia or gangrene in parts of the forearm, hand or fingers.

The needle should be left in the artery and a vasodilator (e.g. papaverine 20 mg) administered. Stellate ganglion or brachial plexus block may reduce arterial spasm. Heparin should be given i.v. and oral anticoagulants should be prescribed after operation.

The risk of ischaemic damage after intra-arterial injection is much greater if a 5% solution of thiopental is used.

Laryngeal spasm. The causes have been discussed above.

Bronchospasm. This is unusual, but may be precipitated in asthmatic patients.

Allergic reactions. These range from cutaneous rashes to severe or fatal anaphylactic or anaphylactoid reactions with cardiovascular collapse. Severe reactions are rare (approximately 1 in 14 000–20 000). Hypersensitivity reactions to drugs administered during anaesthesia are discussed on pages 54–55.

Thrombophlebitis. This is uncommon (Table 3.5) when the 2.5% solution is used.

Indications

Absolute Contraindications

Precautions

Special care is needed when thiopental is administered in the following circumstances:

Cardiovascular disease. Patients with hypovolaemia, myocardial disease, cardiac valvular stenosis or constrictive pericarditis are particularly sensitive to the hypotensive effects of thiopental. However, if the drug is administered with extreme caution, it is probably no more hazardous than other i.v. anaesthetic agents. Myocardial depression may be severe in patients with right-to-left intracardiac shunt because of high coronary artery concentrations of thiopental.

Severe hepatic disease. Reduced protein binding results in higher concentrations of free drug. Metabolism may be impaired, but this has little effect on early recovery. A normal dose may be administered, but very slowly.

Renal disease. In chronic renal failure, protein binding is reduced, but elimination is unaltered. A normal dose may be administered, but very slowly.

Muscle disease. Respiratory depression is exaggerated in patients with myasthenia gravis or dystrophia myotonica.

Reduced metabolic rate. Patients with myxoedema are exquisitely sensitive to the effects of thiopental.

Obstetrics. An adequate dose must be given to ensure that the mother is anaesthetized. However, excessive doses may result in respiratory or cardiovascular depression in the fetus, particularly if the interval between induction and delivery is short.

Outpatient anaesthesia. Early recovery is slow in comparison with other agents. This is seldom important unless rapid return of airway reflexes is essential, e.g. after oral or dental surgery. However, slow elimination of thiopental may result in persistent drowsiness for 24–36 h, and this impairs the ability to drive or use machinery. There is also potentiation of the effect of alcohol or sedative drugs ingested during that period. It is preferable to use a drug with more rapid elimination for patients who are ambulant within a few hours.

Adrenocortical insufficiency.

Extremes of age.

Asthma.

Chemical Structure

Sodium α-dl-5-allyl-1-methyl-5-(1-methyl-2-pentynyl) barbiturate.

Physical Properties and Presentation

Although no longer available in the United Kingdom, methohexital is still used in a number of other countries. The drug has two asymmetrical carbon atoms, and therefore four isomers. The α-dl isomers are clinically useful. The drug is presented as a white powder mixed with 6% anhydrous sodium carbonate and is readily soluble in distilled water. The resulting 1% (10 mg mL^–1) solution has a pH of 11.1 and pKa of 7.9. Single-dose vials of 100 mg and multidose bottles containing 500 mg or 2.5 g are available in some countries. Although the solution is chemically stable for up to 6 weeks, the manufacturers recommend that it should not be stored for longer than 24 h because it does not contain antibacterial preservative.

Pharmacology

Pharmacokinetics

A greater proportion of methohexital than thiopental is in the un-ionized state at body pH (approximately 75%), although the drug is less lipid-soluble than the thiobarbiturate. Binding to plasma protein occurs to a similar degree. Clearance from plasma is higher than that of thiopental, and the elimination half-life is considerably shorter (approximately 4 h). Thus, cumulation is less likely to occur after repeated doses.

Dosage and Administration

Methohexital is administered i.v. in a dose of 1–1.5 mg kg^–1 to induce anaesthesia in healthy young adult patients; smaller doses are required in the elderly and infirm.

Adverse Effects

Cardiovascular and respiratory depression. This is probably less than that associated with thiopental.

Excitatory phenomena during induction, including dyskinetic muscle movements, coughing and hiccups. Muscle movements are reduced by administration of an opioid; the incidence of cough and hiccups is reduced by premedication with an anticholinergic agent. The incidence of excitatory effects is dose-related.

Epileptiform activity on EEG in epileptic subjects.

Pain on injection (Table 3.5).

Tissue damage after perivenous injection is rare with 1% solution.

Intra-arterial injection may cause gangrene, but the risk with 1% solution is considerably less than with 2.5% thiopental.

Allergic reactions occur, but are uncommon.

Thrombophlebitis is a rare complication.

Indications

Induction of anaesthesia, particularly when a rapid recovery is desirable. Methohexital was used commonly as the anaesthetic agent for electroconvulsive therapy (ECT) and for induction of anaesthesia for outpatient dental and other minor procedures.

Absolute Contraindications

These are the same as for thiopental.

Precautions

These are similar to the precautions listed for thiopental. However, methohexital is a suitable agent for outpatients. It should not be used to induce anaesthesia in patients who are known to be epileptic.

Chemical Structure

2,6-Di-isopropylphenol (Fig. 3.3).

Physical Properties and Presentation

Propofol is extremely lipid-soluble, but almost insoluble in water. The drug was formulated initially in Cremophor EL. However, several other drugs formulated in this solubilizing agent were associated with release of histamine and an unacceptably high incidence of anaphylactoid reactions, and similar reactions occurred with this formulation of propofol. Consequently, the drug was reformulated in a white, aqueous emulsion containing soyabean oil and purified egg phosphatide. Ampoules of the drug contain 200 mg of propofol in 20 mL (10 mg mL^–1), and 50 mL bottles containing 1% (10 mg mL^–1) or 2% (20 mg mL^–1) solution, and 100 mL bottles containing 1% solution, are available for infusion. In addition, 50 mL prefilled syringes of 1 and 2% solution are available and are designed for use in target-controlled infusion techniques (see below). Recently, a 0.5% solution has been made available (5 mg mL^− 1 in 20 mL). This produces less pain on injection, and is intended primarily for use in children.

Pharmacology

Pharmacokinetics

In common with other i.v. anaesthetic drugs, propofol is distributed rapidly, and blood concentrations decline exponentially. Clearance of the drug from plasma is greater than would be expected if the drug was metabolized only in the liver, and it is believed that extrahepatic sites of metabolism exist. The kidneys excrete the metabolites of propofol (mainly glucuronides); only 0.3% of the administered dose of propofol is excreted unchanged. The terminal elimination half-life of propofol is 3–4.8 h, although its effective half-life is much shorter (30–60 min). The distribution and clearance of propofol are altered by concomitant administration of fentanyl. Elimination of propofol remains relatively constant even after infusions lasting for several days.

Dosage and Administration

In healthy, unpremedicated adults, a dose of 1.5–2.5 mg kg^–1 is required to induce anaesthesia. The dose should be reduced in the elderly; an initial dose of 1.25 mg kg^–1 is appropriate, with subsequent additional doses of 10 mg until consciousness is lost. In children, a dose of 3–3.5 mg kg^–1 is usually required; the drug is not recommended for use in children less than 1 month of age. Cardiovascular side-effects are reduced if the drug is injected slowly. Lower doses are required for induction in premedicated patients. Sedation during regional analgesia or endoscopy may be achieved with infusion rates of 1.5–4.5 mg kg^–1 h^–1. Infusion rates of up to 15 mg kg^–1 h^–1 are required to supplement nitrous oxide/oxygen for surgical anaesthesia, although these may be reduced substantially if an opioid drug is administered. The average infusion rate is approximately 2 mg kg^–1 h ^–1 in conjunction with a slow infusion of morphine (2 mg h^–1) for sedation of patients in ICU.

Adverse Effects

Cardiovascular depression. Unless the drug is given very slowly, cardiovascular depression following a bolus dose of propofol is greater than that associated with a bolus dose of a barbiturate and is likely to cause profound hypotension in hypovolaemic or untreated hypertensive patients and in those with cardiac disease. Cardiovascular depression is modest if the drug is administered slowly or by infusion.

Respiratory depression. Apnoea is more common and of longer duration than after barbiturate administration.

Excitatory phenomena. These are more frequent on induction than with thiopental, but less than with methohexital. There have been occasional reports of convulsions and myoclonus during recovery from anaesthesia in which propofol has been used. Some of these reactions are delayed.

Pain on injection. This occurs in up to 40% of patients (Table 3.5). The incidence is greatly reduced if a large vein is used, if a small dose (10 mg) of lidocaine is injected shortly before propofol, or if lidocaine is mixed with propofol in the syringe (10–20 mg, i.e. 1–2 mL of 1% lidocaine per 20 mL of propofol). A preparation of propofol in an emulsion of medium-chain triglycerides and soya (Propofol-Lipuro®) causes a lower incidence of pain, and less severe pain in those who still experience it, than other formulations (which use long-chain triglycerides) and may obviate the need for lidocaine. Propofol 0.5% causes less pain than higher concentrations. Accidental extravasation or intra-arterial injection of propofol does not appear to result in adverse effects.

Allergic reactions. Skin rashes occur occasionally. Anaphylactic reactions have also been reported, but appear to be less common than with thiopental.

Indications

Induction of anaesthesia. Propofol is indicated particularly when rapid early recovery of consciousness is required. Two hours after anaesthesia, there is no difference in psychomotor function between patients who have received propofol and those given thiopental or methohexital, but the former experience less drowsiness in the ensuing 12 h. The rapid recovery characteristics are lost if induction is followed by maintenance with inhalational agents for longer than 10–15 min. The rapid redistribution and metabolism of propofol may increase the risks of awareness during tracheal intubation after the administration of non-depolarizing muscle relaxants, or at the start of surgery, unless the lungs are ventilated with an appropriate mixture of inhaled anaesthetics, or additional doses or an infusion of propofol administered.

Sedation during surgery. Propofol has been used successfully for sedation during regional analgesic techniques and during endoscopy. Control of the airway may be lost at any time, and patients must be supervised continuously by an anaesthetist.

Total i.v. anaesthesia (see below). Propofol is the most suitable of the agents currently available. Recovery time is increased after infusion of propofol compared with that after a single bolus dose, but cumulation is significantly less than with the barbiturates.

Sedation in ICU. Propofol has been used successfully by infusion to sedate adult patients for up to several days in ICU. The level of sedation is controlled easily, and recovery is rapid (usually < 30 min).

Absolute Contraindications

Airway obstruction and known hypersensitivity to the drug are probably the only absolute contraindications. Propofol appears to be safe in porphyric patients. Propofol infusion syndrome is a rare reaction to prolonged, high-dose infusion of propofol. It is characterized by bradycardia, metabolic acidosis, hyperlipidaemia, fatty liver enlargement, rhabdomyolysis and/or heart failure. It is more common in children or adolescents, is associated with head injury or the use of vasopressors and is often fatal. Therefore, propofol should not be used for long-term sedation of children (under 16 years of age) in ICU.

Precautions

These are similar to those listed for thiopental. The side-effects of propofol make it less suitable than thiopental or etomidate for patients with existing cardiovascular compromise unless it is administered with great care. Propofol is more suitable than thiopental for outpatient anaesthesia, but its use does not obviate the need for an adequate period of recovery before discharge.

Solutions of propofol do not possess any antibacterial properties, and they support the growth of microorganisms. The drug must be drawn aseptically into a syringe and any unused solution should be discarded if not administered promptly. Propofol must not be drawn up or administered via a microbiological filter.

Chemical Structure

D-Ethyl-1-(α-methylbenzyl)-imidazole-5-carboxylate.

Physical Characteristics and Presentation

Etomidate is soluble but unstable in water. It is presented as a clear aqueous solution containing 35% propylene glycol, or in an emulsion preparation with medium-chain triglycerides and soya-bean oil (Etomidate-Lipuro®). Ampoules contain 20 mg of etomidate in 10 mL (2 mg mL^–1). The pH of the propylene glycol solution is 8.1.

Pharmacology

Etomidate is a rapidly acting general anaesthetic agent with a short duration of action (2–3 min) resulting predominantly from redistribution, although it is also eliminated rapidly from the body. In healthy patients, it produces less cardiovascular depression than does thiopental; however, there is little evidence that this benefit is retained if the cardiovascular system is compromised (e.g. by severe hypovolaemia). Large doses may produce tachycardia. Respiratory depression is less than with other agents.

Etomidate inhibits the 11β-hydroxylase enzyme involved in adrenal cortisol synthesis, resulting in reduced synthesis of cortisol by the adrenal gland and an impaired response to adrenocorticotrophic hormone. At much higher doses, adrenal 18β-hydroxylase and other enzymes are inhibited, thus reducing aldosterone and other steroid hormone synthesis. Long-term infusions of the drug in the ICU are associated with increased infection and mortality, probably related to reduced immunological competence. Its effects on the adrenal gland occur also after a single bolus, and last for several hours.

Pharmacokinetics

Etomidate redistributes rapidly in the body. Approximately 76% is bound to protein. It is metabolized in the plasma and liver, mainly by esterase hydrolysis, and the metabolites are excreted in the urine; 2% is excreted unchanged. The terminal elimination half-life is 2.4–5 h. There is little cumulation when repeated doses are given. The distribution and clearance of etomidate may be altered by concomitant administration of fentanyl.

Dosage and Administration

An average dose of 0.3 mg kg^–1 i.v. induces anaesthesia. The propylene glycol preparation of the drug should be administered into a large vein to reduce the incidence of pain on injection.

Adverse Effects

Suppression of synthesis of cortisol. See above.

Excitatory phenomena. Moderate or severe involuntary movements occur in up to 40% of patients during induction of anaesthesia. This incidence is reduced in patients premedicated with an opioid. Cough and hiccups occur in up to 10% of patients.

Pain on injection. This occurs in up to 80% of patients if the propylene glycol preparation is injected into a small vein, but in less than 10% when the drug is injected into a large vein in the antecubital fossa (Table 3.5). The incidence is reduced by prior injection of lidocaine 10 mg. The incidence of pain on injection has been reported to be as low as 4% when the emulsion formulation is injected.

Nausea and vomiting. The incidence of nausea and vomiting is approximately 30%. This is very much higher than after propofol.

Emergence phenomena. The incidence of severe restlessness and delirium during recovery is greater with etomidate than barbiturates or propofol.

Venous thrombosis is more common than with other agents if the propylene glycol preparation is used.

Indications

Etomidate is used usually for patients with a compromised cardiovascular system. It is suitable for outpatient anaesthesia. The high incidence of pain on injection of the propylene glycol preparation of etomidate limited its use to patients in whom depression of the cardiovascular system was undesirable, but the preparation as an emulsion with medium-chain triglycerides has greatly reduced the incidence of pain on injection.

Absolute Contraindications

Precautions

These are similar to the precautions listed for thiopental. Etomidate is suitable for outpatient anaesthesia. However, the incidence of excitatory phenomena is unacceptably high unless an opioid is administered; this delays recovery and is unsuitable for most outpatients.

Chemical Structure

2-(o-Chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride.

Physical Characteristics and Presentation

Ketamine is soluble in water and is presented as solutions of 10 mg mL^–1 containing sodium chloride to produce isotonicity and 50 or 100 mg mL^–1 in multidose vials which contain benzethonium chloride 0.1 mg mL^–1 as preservative. The pH of the solutions is 3.5–5.5. The pKa of ketamine is 7.5.

Pharmacology

Pharmacokinetics

Only approximately 12% of ketamine is bound to protein. The initial peak concentration after i.v. injection decreases as the drug is distributed, but this occurs more slowly than with other i.v. anaesthetic agents. Metabolism occurs predominantly in the liver by demethylation and hydroxylation of the cyclohexanone ring; among the metabolites is norketamine, which is pharmacologically active. Approximately 80% of the injected dose is excreted renally as glucuronides; only 2.5% is excreted unchanged. The elimination half-life is approximately 2.5 h. Distribution and elimination are slower if halothane, benzodiazepines or barbiturates are administered concurrently.

After i.m. injection, peak concentrations are achieved after approximately 20 min.

Dosage and Administration

Induction of anaesthesia is achieved with an average dose of 2 mg kg^–1 i.v; larger doses may be required in some patients, and smaller doses in the elderly or shocked patient. In all cases, the drug should be administered slowly. Additional doses of 1–1.5 mg kg^–1 are required every 5–10 min. Between 8 and 10 mg kg^–1 is used i.m. A dose of 0.25–0.5 mg kg^–1 or an infusion of 50 μg kg^–1 min^–1 may be used to produce analgesia without loss of consciousness.

Adverse Effects

Indications

The high-risk patient. Ketamine is useful in the shocked patient. Arterial pressure may decrease if hypovolaemia is present, and the drug must be given cautiously. These patients are usually heavily sedated in the postoperative period, and the risk of nightmares is therefore minimized.

Paediatric anaesthesia. Children undergoing minor surgery, investigations (e.g. cardiac catheterization), ophthalmic examinations or radiotherapy may be managed successfully with ketamine administered either i.m. or i.v.

Difficult locations. Ketamine has been used successfully at the site of accidents, and for analgesia and anaesthesia in casualties of war.

Analgesia and sedation. The analgesic action of ketamine may be used when wound dressings are changed, or while positioning patients with pain before performing regional anaesthesia (e.g. fractured neck of femur). Ketamine has been used to sedate asthmatic patients in the ICU.

Developing countries. Ketamine is used extensively in countries where anaesthetic equipment and trained staff are in short supply.

Absolute Contraindications

Precautions

Cardiovascular disease. Ketamine is unsuitable for patients with pre-existing hypertension, ischaemic heart disease or severe cardiac decompensation.

Repeated administration. Because of the prolonged recovery period, ketamine is not the most suitable drug for frequent procedures, e.g. prolonged courses of radiotherapy, as it disrupts sleep and eating patterns.

Visceral stimulation. Ketamine suppresses poorly the response to visceral stimulation; supplementation, e.g. with an opioid, is indicated if visceral stimulation is anticipated.

Outpatient anaesthesia. The prolonged recovery period and emergence phenomena make ketamine unsuitable for adult outpatients.

Intermittent Injection

Although some anaesthetists are skilled in the delivery of i.v. anaesthetic agents by intermittent bolus injection, the plasma concentrations of drug and the anaesthetic effect fluctuate widely, and the technique is acceptable only for procedures of short duration in unparalysed patients.

Manual Infusion Techniques

The infusion rate required to achieve a predetermined concentration of an i.v. drug can be calculated if the clearance of the drug from plasma is known [infusion rate (μg min^–1) = steady-state plasma concentration (μg mL^–1) × clearance (mL min^–1)]. One of the difficulties is that clearance is variable, and it is possible only to estimate the value by using population kinetics; depending on the patient’s clearance in relation to the population average, the actual plasma concentration achieved may be higher or lower than the intended concentration.

A fixed-rate infusion is inappropriate because the serum concentration of the drug increases only slowly, taking four to five times the elimination half-life of the drug to reach steady state (Fig. 3.4). A bolus injection followed by a continuous infusion results initially in achievement of an excessive concentration (with an increased incidence of side-effects), and this is followed by a prolonged dip below the intended plasma concentration (Fig. 3.5). In order to achieve a reasonably constant plasma concentration (other than in very long procedures), it is necessary to use a multistep infusion regimen, a concept similar to that of overpressure for inhaled agents. A commonly used scheme for propofol is injection of a bolus dose of 1 mg kg^–1 followed by infusion initially at a rate of 10 mg kg^–1 h¹ for 10 min, then 8 mg kg^–1 h¹ for the next 10 min, and a maintenance infusion rate of 6 mg kg^–1 h¹ thereafter. This achieves, on average, a plasma concentration of propofol of 3 μg mL^–1, and this is effective in achieving satisfactory anaesthesia in unparalysed patients who also receive nitrous oxide and fentanyl; higher infusion rates are required if nitrous oxide and fentanyl are not administered. These infusion rates must be regarded only as a guide and must be adjusted as necessary according to clinical signs of anaesthesia.

Target-Controlled Infusion (TCI) Techniques

By programming a computer with appropriate pharmacokinetic data and equations, it is possible at frequent intervals (several times a minute) to calculate the appropriate infusion rate required to produce a preset target plasma concentration of drug. The drug is infused by a syringe driver. To produce a step increase in plasma concentration, the syringe driver infuses drug very rapidly (a slow bolus) and then delivers drug at a progressively decreasing infusion rate (Fig. 3.6). To decrease the plasma concentration, the syringe driver stops infusing until the computer calculates that the target concentration has been achieved, and then infuses drug at an appropriate rate to maintain a constant level. The anaesthetist is required only to enter the desired target concentration and to change it when clinically indicated, in the same way as a vaporizer might be manipulated according to clinical signs of anaesthesia.

The potential advantages of such a system are its simplicity, the speed with which plasma concentration can be changed (particularly upwards) and avoidance of the need for the anaesthetist to undertake any calculations (resulting in less potential for error). The actual concentration achieved may be > 50% greater than or less than the predicted concentration, although this is not a major practical disadvantage provided that the anaesthetist adjusts the target concentration according to clinical signs relating to adequacy of anaesthesia, rather than assuming that a specific target concentration always results in the desired effect.

Using a TCI system in female patients, the target concentration of propofol required to prevent movement in response to surgical incision in 50% of subjects (the equivalent of minimum alveolar concentration; MAC) was 6 μg mL^–1 when patients breathed oxygen, and 4.5 μg mL^–1 when 67% nitrous oxide was administered simultaneously.

A TCI system for administration of propofol is available in many countries. The anaesthetist is required to input the weight and age of the patient, and then to select the desired target concentration. These devices can be used only with prefilled syringes, which contain an electronic tag that is recognized by the infusion pump. These TCI systems are currently suitable for use only in patients over the age of 16 years. Target concentrations selected for elderly patients should be lower than those for younger adults, in order to minimize the risk of side-effects.

The TCI infusion pumps assume that the patient is conscious when the infusion is started. Consequently it is inappropriate to connect and start a TCI system in a patient who is already unconscious, as this results in an initial overdose.

In adult patients under 55 years of age, anaesthesia may be induced usually with a target propofol concentration of 4–8 μg mL^–1. An initial target concentration at the lower end of that range is suitable for premedicated patients. Induction time is usually between 1 and 2 min. The brain concentration of propofol increases more slowly than the blood concentration, and following induction it is usually appropriate to reduce the target concentration; target propofol concentrations in the range of 3–6 μg mL^–1 usually maintain satisfactory anaesthesia in patients who are also receiving an analgesic drug.

Later versions of the TCI infusion pumps show the predicted brain concentration, which may be used as a guide to the timing of alterations in the blood target concentration.

Closed-Loop Systems

Target-controlled infusion systems may be used as part of a closed-loop system to control depth of anaesthesia. Because there is no method of measuring blood concentrations of i.v. anaesthetics on-line, it is necessary to use some type of monitor of depth of anaesthesia (such as the auditory evoked response; see Chapter 16) on the input side of the system.

Clinical Features

In a severe hypersensitivity reaction, a flush may develop over the upper part of the body. There is usually hypotension, which may be profound. Cutaneous and glottic oedema may develop and may result in hypovolaemia because of loss of fluid from the circulation. Very severe bronchospasm may also occur, although it is a feature in less than 50% of reactions. Diarrhoea often occurs some hours after the initial reaction.

Predisposing Factors

Age. In general, adverse reactions are less common in children than in adults.

Pregnancy. There is an increased incidence of adverse reactions in pregnancy.

Gender. Anaphylactic reactions are more common in women.

Atopy. There may be an increased incidence of type IV (delayed hypersensitivity) reactions in non-atopic individuals, and a higher incidence of type I reactions in those with a history of extrinsic asthma, hay fever or penicillin allergy.

Previous exposure. Previous exposure to the drug, or to a drug with similar constituents, exerts a much greater influence on the incidence of reactions than does a history of atopy.

Solvents. Cremophor EL, which was used as a solvent for several i.v. anaesthetic agents, was associated with a high incidence of hypersensitivity reactions.

Incidence

The incidences of hypersensitivity reactions associated with i.v. anaesthetic agents are shown in Table 3.6.

Treatment

This is summarized in Table 3.7. Appropriate investigations should be undertaken after recovery to identify the drug responsible for the reaction.