Intravenous anaesthetic agents and sedatives

Intravenous anaesthetic drugs

Intravenous induction of anaesthesia is smooth and rapid compared with inhalational induction with most volatile anaesthetics. Combinations of i.v. drugs (e.g. propofol, midazolam, opioids) are often used together for coinduction of anaesthesia because their actions are synergistic, allowing reduced dosages for a given clinical end-point and potentially fewer adverse effects. Intravenous agents may also be used for maintenance of anaesthesia if administered as repeated boluses or by continuous i.v. infusion (either as a sole agent or in combination with opioids and/or nitrous oxide). Other uses include sedation during endoscopic procedures, regional anaesthesia, for patients in ICU and in the treatment of status epilepticus. The compounds used as i.v. anaesthetics (with the exception of propofol) are chiral molecules (see Chapter 1 ). Thiopental and ketamine are administered as racemic mixtures, etomidate as a pure R-enantiomer ( Fig. 4.5 ), dexmedetomidine as a pure S-enantiomer ( Fig. 4.13 ) and a formulation of S-ketamine ( Fig.4.4 ) is available in Europe. Therapeutic activity resides mainly in one of the enantiomers, whilst the other can have undesirable properties, different therapeutic activities, be pharmacologically inert or have a different rate of metabolism.

Mechanism of action

Intravenous anaesthetics exert their action at γ-aminobutyric acid A (GABA _A ) or N -methyl- d -aspartic acid (NMDA) receptors, which are both ligand-gated ion channels. The GABA _A receptor is a large pentameric protein with separate allosteric binding sites for propofol, benzodiazepines, barbiturates and ethanol ( Fig. 4.1 ). Binding of an agonist enhances the affinity of the GABA _A receptor for its endogenous ligand, which increases the frequency of channel opening and intracellular chloride ion conductance. Hyperpolarisation of the postsynaptic membrane results, and this inhibits synaptic transmission. The GABA _A receptors with specific β subunits appear to mediate sedative (β2) and anaesthetic (β3) activity. Benzodiazepines bind to the GABA _A receptor at the α/γ subunit interface. The binding of other compounds to the benzodiazepine site explains their synergistic activity and the development of cross-tolerance. Propofol and barbiturates also potentiate the effects of glycine at glycine receptors (chloride influx and inhibition of synaptic transmission) both in the brain and spinal cord. Propofol has further inhibitory actions on voltage-gated sodium channels and activity at 5HT ₃ receptors; the latter may explain its antiemetic effects.

Ketamine (in common with nitrous oxide and xenon) acts predominantly at tetrameric excitatory NMDA receptors that usually bind glycine and glutamate (see Fig. 4.1 ). Binding of ketamine to the NMDA receptor is non-competitive and reduces synaptic transmission by inhibiting conductance of positively charged ions. Ketamine appears to have no effect at GABA _A or glycine receptors but may partially exert clinical action via cholinergic receptors and at voltage-gated ion channels for sodium, potassium and calcium.

Pharmacokinetics

Bolus administration of an i.v. anaesthetic causes a rapid increase in plasma concentration followed by an exponential decline ( Fig. 4.2 ) (see Chapter 1 ). Hypnosis results from diffusion of drug along a concentration gradient between arterial blood and the brain. The initial rate of transfer into the brain and onset of effect are regulated by factors outlined next. In general, factors increasing the plasma concentration of free drug also increase the intensity of adverse effects.

Offset of hypnotic effect

The clinical action of the i.v. anaesthetics (see Table 4.1 ) is terminated by redistribution away from the brain. The plasma concentration decreases exponentially and causes diffusion away from the brain along a reversed concentration gradient. Fig. 4.2 shows how the percentage of an injected propofol bolus changes with time in four groups of body tissues. Well-perfused vital organs (e.g. brain, heart, liver and kidneys) receive a high percentage of the dose initially. Uptake into muscle is slower because of lower lipid content but becomes quantitatively important because of the relatively large tissue mass and good blood supply. Despite high lipid solubility, i.v. anaesthetics distribute more slowly into fatty tissue because of lower blood flows. Fat contributes little to the termination of action of a single bolus of agent, but fat depots ultimately contain a large proportion of the injected drug (see Fig. 4.2 ). Drug is released back to the plasma slowly over time but fails to achieve an anaesthetic brain concentration because of high clearance from the plasma by the liver. This dynamic alters when these agents are used to maintain anaesthesia for some hours by continuous infusion. In this situation the drug concentration in organs with high or medium blood flow is in equilibrium with the plasma. When the infusion stops, distribution to fatty tissue and hepatic clearance of drug from the plasma become more important in reducing brain concentration. As a consequence, plasma concentration declines more slowly than after a single bolus (context-sensitive half-time (CSHT)) and time to consciousness increases. Complete elimination of drug from the body may be delayed in the obese because of retention in the high fat mass. Metabolism of i.v. anaesthetics occurs predominantly in the liver and may contribute to the recovery of consciousness if the process is rapid. However, elimination of a typical i.v. agent takes many hours or days because they have a high volume of distribution. A small proportion of drug may be excreted unchanged in the urine depending on the drug's degree of ionisation and the pH of urine.

Precautions when using i.v. anaesthetics

Special care is required in some circumstances as the drug may be contraindicated or the injected dose and rate of administration may need modification ( Table 4.3 ).

Pharmacology of individual intravenous anaesthetic drugs

Propofol

Propofol, an alkylphenol, became available commercially in 1986.

Chemical structure

The chemical structure of propofol is 2,6-di-isopropylphenol ( Fig. 4.3 ).

Physical properties and presentation

Propofol is extremely lipid soluble but almost insoluble in water, so the drug is presented as a white aqueous emulsion containing soya bean oil and purified egg phosphatide. The triglyceride component varies between manufacturers and may be long chain (12–20 carbon atoms) or medium chain (6–10 carbon atoms), which is claimed to reduce pain on injection. The lipid load of the latter formulation is more readily tolerated and metabolised in humans. Propofol is available in concentrations from 20 to 0.5 mg ml ⁻¹ (2%–0.5%), and the lower concentration is preferred for paediatric practice. Prefilled 50 ml syringes are available for use in target-controlled infusion (TCI) techniques (see later). Dosing schemes are shown in Table 4.4 .

Table 4.4

Dosing schemes and principal indications for i.v. anaesthetic agents

Drug	Use	Dose range		Onset of effect after bolus (s)	Time to peak effect after bolus (s)	Duration of effect after bolus (min)	Principal indications
Propofol	Bolus i.v. dose Sedation Maintenance TCI target Antiemesis	Adult Frail adult 1–12 years 16 years Use TCI With analgesics No analgesics	1.5–2.5 mg kg −1 Reduce by 50% 3–3.5 mg kg −1 Use adult doses 0.5–1.5 µg ml −1 2–4 µg ml −1 4–8 µg ml −1 10–20 mg bolus, then 1–2 mg kg −1 h −1 PRN	30–60	90–120	5–10	Induction of anaesthesia Maintenance of anaesthesia using TCI/TIVA Procedural sedation
Ketamine	Bolus i.v. Bolus i.m. Oral sedation Analgesia	Children	2 mg kg −1 8–10 mg kg −1 6–10 mg kg −1 0.1–0.5 mg kg −1 bolus, then 0.1–0.2 mg kg −1 hr −1 PRN, max 15 mg hr −1	15–45	60	10–20	Induction of anaesthesia in emergency patient Paediatric sedation Analgesia
Etomidate	Bolus Infusion		0.2–0.3 mg kg −1 0.04–0.05 mg kg −1 hr −1	15–45	Unknown	3–12	Induction of anaesthesia ICU sedation (very rarely)
Thiopental	Bolus Infusion		3–6 mg kg −1 1–15 mg kg −1 hr −1	<30	40–60	5–10	Induction of anaesthesia Sedation in neurocritical care or status epilepticus

TCI, Target-controlled infusion.

Pharmacology

Central nervous system

Diffusion from the blood is relatively slow compared with agents such as thiopental. Loss of verbal contact is a useful marker of anaesthetic onset, and loss of response to vigorous jaw thrusting indicates sufficient depth for insertion of a supraglottic airway device (SAD). The EEG frequency decreases and amplitude increases with a dominant slow wave α/δ pattern; this is accompanied by reductions in cerebral metabolic requirement for oxygen (CMR o ₂ ), CBF and intracranial pressure. Non-epileptic myotonia may be evidenced by irregular muscular activity. Propofol reduces the duration of seizures induced by electroconvulsive therapy (ECT) in humans, but there are reports of convulsions after its use. Propofol has been used successfully in the management of status epilepticus, and epilepsy is not a contraindication. Recovery of consciousness is rapid, and there is a minimal hangover effect even in the immediate postanaesthetic period. Propofol is the preferred agent for volunteer studies on the neurophysiological mechanisms that underlie sedation and general anaesthesia.

Cardiovascular system

Arterial pressure decreases to a greater degree than with thiopental. This results principally from the vasodilatation caused by reduced sympathetic neural activity, but there is also a dose-dependent negative inotropic effect. Decreases greater than 40% may occur in elderly and frail patients. Hypotension is mitigated partially by slower administration (more than 30–60 s) and by allowing sufficient time for diffusion into the brain before additional bolus dosing. The pressor response to tracheal intubation is attenuated to a greater degree by propofol than thiopental. Heart rate may increase slightly after induction of anaesthesia, but there have been occasional reports of severe bradycardia or asystole after administration of propofol. Caution is needed in patients with a pre-existing bradycardia or if propofol is given with other vagomimetic drugs (e.g. remifentanil), and a vagolytic agent (e.g. glycopyrronium bromide or atropine) may be required.

Respiratory system

Apnoea occurs more commonly and for longer than with thiopental. During an infusion of propofol, tidal volume is lower and respiratory rate higher compared with the conscious state, with a depressed ventilatory response to carbon dioxide. These effects are more marked if opioid coinduction is used. Propofol has no effect on bronchial muscle tone, and laryngospasm is particularly uncommon. Laryngeal reflexes are suppressed to a greater extent than by thiopental, and there is a lower incidence of coughing or laryngospasm on insertion of a SAD provided that an adequate depth of anaesthesia is achieved.

Skeletal muscle

Tone is reduced, but movements may occur in response to surgical stimulation as the spinal cord action of propofol is limited compared with volatile agents. Coadministration of an opioid, nitrous oxide or a neuromuscular blocking agent is necessary to prevent such responses.

Gastrointestinal system

Propofol has no effect on gastrointestinal motility in animals and reduces the incidence of postoperative nausea and vomiting. The lipid load imposed by a continuous propofol infusion has been cited as a rare cause of pancreatitis in critically ill patients.

Uterus and placenta

Propofol has been used extensively in patients undergoing gynaecological surgery and does not appear to have any clinically significant effect on uterine tone. Propofol crosses the placenta, but its safety in the neonate has not been formally established.

Hepatic/renal

There is a transient decrease in renal and hepatic perfusion secondary to reductions in arterial pressure and cardiac output. Liver function tests are not deranged after infusion of propofol for 24 h.

Endocrine

Plasma concentrations of cortisol are decreased after administration of propofol, but a normal response occurs to the administration of adrenocorticotrophic hormone (Synacthen test).

Pharmacokinetics

The distribution of propofol after a single i.v. bolus is rapid (see Fig. 4.2 ). Clearance of drug from the plasma is greater than expected if it were metabolised only in the liver, and extrahepatic sites (e.g. lungs) are proposed. The kidneys excrete the metabolites of propofol (mainly glucuronides), and only 0.3% of the administered dose is excreted unchanged. The terminal elimination half-life of propofol is 3–4.8 h, although the duration of clinical effects is much shorter because of redistribution to other tissues (see Chapter 1 ). The distribution and clearance of propofol are altered by concomitant administration of drugs that alter cardiac output. Constant infusions lasting many hours do increase CSHT but less so than with other agents. This causes little effect on the offset of effect after termination of an infusion, and propofol is particularly suited to maintenance of intravenous anaesthesia.

Adverse effects

Pain on injection

Pain on injection occurs in 40% of patients and is caused by free propofol in the aqueous phase of the preparation. The incidence is greatly reduced if a large vein is cannulated, propofol is injected into a running fluid infusion, a small dose (10 mg) of lidocaine is injected shortly before induction, or lidocaine is mixed into the propofol syringe (10–20 mg per 200 mg). Preparations containing medium-chain triglycerides cause a lower incidence of pain, which is less severe. Accidental extravasation or intra-arterial injection does not cause adverse effects.

Sedation in ICU

Propofol infusion is used for adult patients in ICU. The lipid load administered must be incorporated into calculations of nutritional requirement and may interfere with functioning of blood gas analysers. Propofol-related infusion syndrome (PRIS) is a rare consequence of prolonged high-dose administration and is often fatal. It is characterised by bradycardia, metabolic acidosis, hyperlipidaemia, rhabdomyolysis and/or heart failure and is associated with head injury or the use of vasopressors. The syndrome is more common in children and adolescents, and propofol is not indicated for long-term sedation of critically ill patients younger than 16 years, but is used safely by intravenous infusion including TCI techniques, in the operating theatre.

Awareness during induction of anaesthesia

Propofol is now the drug of choice for i.v. induction of general anaesthesia in most cases. Rapid redistribution and clearance of propofol from the plasma may increase the risk of awareness during difficult tracheal intubation or if there is a delay in administering an adequate concentration of inhaled anaesthesia, especially during neuromuscular blockade (see NAP5 report). This is also true for the other i.v. anaesthetic agents (see Table 4.1 ).

Other adverse effects

Other adverse effects are listed in Table 4.5 .

Table 4.5

Pharmacological properties of i.v. anaesthetic agents

	Propofol	Ketamine	Etomidate	Thiopental
Properties
Water soluble	–	+	+ a	+
Stable in solution	+	+	+	–
pH of solution	7–8	3.5–5.5	6.5–8 (lipid formulation)	10.8
p K a	11	7.5	4.7 (lipid formulation)	7.6
Protein binding	98%	12%–50%	76%	80%
Long shelf-life	+	+	+	–
Pain on i.v. injection	++ b	–	++ b	–
Non-irritant on subcutaneous injection	Yes	No	No	No
Sequelae from intra-arterial injection	No	+++	Not in animal studies	+++
Low incidence of venous thrombosis	Yes	Yes	No	Yes
Accumulation	–	–	–	++
Features at induction
Excitatory effects	+	+	+++	–
Respiratory complications	+	–	–	–
Cardiovascular depression	++	–	+	+
Other features
Analgesia	–	++	–	–
Allergic reactions	Rare; history of soya or egg allergy does not contraindicate propofol administration	Rarely reported	Very rare reports with lipid formulation	Estimated 1 : 30,000
Interaction with relaxants	–	–	–	–
Salivation	−	++ Anticholinergic necessary	–	–
Postoperative vomiting	–	++	+	–
Emergence delirium, nightmares & hallucinations	–	++	–	+
Safe in porphyria	Yes	Yes	No	No

a Aqueous solution not commercially available.

b Pain may be reduced by using emulsion formulation with medium-chain triglycerides.

Precautions

The general precautions for i.v. agents listed in Table 4.3 apply to propofol.

Ketamine hydrochloride

Ketamine hydrochloride is a phencyclidine derivative and was introduced in 1965. It produces dissociative anaesthesia (via non-competitive antagonism at the NMDA receptor) rather than classical generalised depression of the CNS and is a useful adjunctive analgesic. Ketamine has no action at GABA _A receptors.

Chemical structure

The chemical structure of ketamine is 2-( o -chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride ( Fig. 4.4 ).

Physical characteristics and presentation

Ketamine has a single chiral centre and is usually presented as a racemic mixture of its R(−) and S(+) stereoisomers in water solutions at concentrations of 10, 50 and 100 mg ml ⁻¹ . The S(+) enantiomer has more potent analgesic effects (approximately fourfold), allowing lower doses to be used, with fewer adverse effects and a more rapid clinical recovery than the racemic mixture, but its pharmacokinetics are identical. The enantiopure formulation of S(+) ketamine is not currently available in the UK. Dosing schemes are shown in Table 4.4 .

Pharmacology

Central nervous system

Ketamine is extremely lipid soluble. Amnesia often persists for up to 1 h after recovery of consciousness. It is a potent somatic analgesic at lower doses. Induction of anaesthesia is smooth, but emergence delirium may occur with restlessness, disorientation and agitation. Vivid and unpleasant nightmares or hallucinations may occur during recovery and for up to 24 h. The incidences of emergence phenomena are reduced by avoidance of verbal and tactile stimulation during recovery and by concomitant administration of benzodiazepines and/or opioids. Unpleasant dreams may persist but are reported less commonly by children and elderly patients. The EEG changes caused by ketamine are dissimilar to those seen with other i.v. anaesthetics, and consist of loss of α rhythm and predominant θ activity, which causes processed EEG (pEEG) depth of hypnosis devices to give paradoxical indications of arousal. Traditionally, head injury and neuroanaesthesia were considered contraindications to ketamine because it was thought to increase CMR o ₂ , CBF and intracranial pressure. However, recent studies have found that ketamine has minimal cerebrovascular effects when used in patients who are normocapnic and receiving a hypnotic agent with GABA _A activity. Clinical data indicate that ketamine can contribute usefully to the sedation/analgesia required by neurocritical care patients and reduces inotropic requirements for normal cerebral perfusion. NMDA receptor blockade by ketamine may provide additional neuroprotection by preventing unbalanced activation of these receptors by toxic extracellular concentrations of glutamate. These occur after brain injury and increase Ca ²⁺ flux and cellular injury.

Cardiovascular system

Arterial pressure increases by up to 25% and heart rate by approximately 20%. Cardiac output and myocardial oxygen consumption may increase, and there is increased myocardial sensitivity to adrenaline. The positive inotropic effect may be related to increased Ca ²⁺ influx, mediated by cyclic adenosine monophosphate (cAMP). Sympathetic stimulation of the peripheral circulation is decreased, resulting in vasodilatation in tissues innervated predominantly by α-adrenergic receptors and vasoconstriction in those with β-receptors.

Respiratory system

Transient apnoea may occur after i.v. injection, but ventilation is well maintained thereafter and may increase slightly unless high doses are given. Pharyngeal and laryngeal reflexes and a patent airway are adequately maintained in comparison with other i.v. agents. However, airway patency cannot be guaranteed and normal precautions must be taken to protect the airway and prevent aspiration. Bronchial muscle is dilated and ketamine infusion is a useful adjunct in the ICU management of status asthmaticus.

Skeletal muscle

Muscle tone is usually increased. Spontaneous movements may occur, but reflex movement in response to surgery is uncommon.

Gastrointestinal system

Salivation is increased.

Uterus and placenta

Ketamine crosses the placenta readily. Fetal concentrations are approximately equal to those in the mother.

Eye

Intraocular pressure increases, although this is often transient. Nystagmus, pupillary dilatation and lachrymation occur. Eye movements often persist during surgical anaesthesia.

Pharmacokinetics

Protein binding is lower than other i.v. agents (see Table 4.5 ). Redistribution after i.v. injection occurs more slowly than with other i.v. anaesthetic agents, and the elimination half-life is approximately 2.5 h. Ketamine undergoes extensive hepatic metabolism by demethylation and hydroxylation of the cyclohexanone ring. Metabolites include norketamine, which is pharmacologically active (20%–30% of the activity of ketamine). Approximately 80% of the injected dose is excreted via the kidneys as glucuronides; only 2.5% is excreted unchanged. After i.m. injection, peak concentrations are achieved after approximately 20 min.

Adverse effects

See Table 4.5 .

Specific indications

The high-risk patient

Ketamine is considered useful in the patient with shock because of maintenance of cardiovascular function, but arterial pressure decreases in the presence of hypovolaemia. High-risk patients often receive postoperative sedation in ICU which minimises the risk of emergence phenomena.

Paediatric anaesthesia

Children undergoing minor surgery, invasive investigations (e.g. cardiac catheterisation), ophthalmic examinations or radiotherapy may be managed successfully with ketamine administered orally or by i.m. or i.v. injection.

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