Thiopental

Thiopental (thiopentone) was introduced into veterinary practice in the 1930s and over the next 60 years became the most widely used agent for induction of anaesthesia. Thiopental was originally licensed at a dose of up to 30 mg/kg, now considered a massive overdose, but which gave prolonged hypnosis. Previous editions of this book review the veterinary studies. Thiopental’s primary use in human and in veterinary anaesthesia is for the induction of anaesthesia. However, all barbiturates are neuroprotective, are excellent antiepileptics and infusions of thiopental still have place for prolonged sedation, for example in poisoning cases causing fits and, in humans, in cases of head injury (Majdan et al., 2013).

Thiopental sodium is presented as a yellow solid, to be dissolved in water before use, the concentration to be made being as low as practicable in relation to volume required. Thus, 1.25% or less is recommended for cats and small dogs, 2.5% for larger dogs and up to 10 % for horses and cattle. The preparation contains anhydrous sodium carbonate to prevent precipitation of the insoluble free acid by atmospheric CO₂. Aqueous solutions are strongly alkaline and are incompatible to mix with many analgesics and sedative drugs, but do seem compatible with propofol (Chilvers et al., 1999; Ko et al., 1999). Depending on concentration, the solution is highly irritant. It can only be used IV and even 1.25% causes skin sloughs if accidentally injected extravascularly; 10% solutions can result in major damage to surrounding tissues. Solutions of thiopental may be kept for several days; bacterial growth does not easily occur (Strachan et al., 2008).

The pharmacokinetics of thiopental are typical of a cumulative agent. Following a single IV injection, blood and brain levels rise then fall rapidly as the drug is redistributed into other tissues, in particular fat. From a single ‘induction’ dose of thiopental, recovery of consciousness is as rapid as for propofol as both are very lipophilic and have a large volume of distribution. However, for thiopental, metabolism by the liver is slow, so if larger or multiple doses are given, it accumulates in the tissues; recovery now depends on metabolism and can be very prolonged. With only an induction dose of thiopental, there is residual sedation following recovery. In animals with little fat, or in which liver enzymes may not be fully functional (e.g. greyhounds; neonates), recovery is even slower (Sams et al., 1985; Robinson et al., 1986). In mixed-breed dogs, the half-lives of elimination have been reported as from approximately 2.5 to 7 hours and plasma clearances as from 1.5 to 97 mL/kg/minute (Brandon & Baggot, 1981; Ilkiw et al., 1991). It has always been claimed (and is the author’s experience) that barbiturates are shorter acting in herbivores than in cats and dogs but, with the range of reported values from different laboratories, it is not possible to find evidence to prove this (Ilkiw et al., 1991; Abass et al., 1994). Thiopental is highly protein bound (more than 75%); it is the non-bound fraction that is active, so animals with hypoproteinaemia (including anaemia) are very sensitive to its effects. The drug also is partially ionized and acts as a weak organic acid; the dissociation constant is such that a small change in pH will markedly affect the degree of ionization, and this in turn can alter distribution.

When thiopental is injected IV, it results in a smooth induction of anaesthesia within a circulation time: in the unpremedicated animal, this is very rapid (with fast injection, it can be as little as 20 seconds in a horse). If premedication reduces cardiac output (as do the α₂-agonists), then speed of induction will be slowed. The induction dose of thiopental required for endotracheal intubation in an unpremeditated animal (most domestic species) can be over 15 mg/kg; after acepromazine premedication with rapid injection in dogs, the dose is 7–10 mg/kg and, after α₂-agonists, the dose reduces further depending on the sedation achieved (Young et al., 1990; England & Hammond, 1997). Doses used to induce anaesthesia in horses premedicated with acepromazine are 11 mg/kg, while after moderate α₂-premedication, 7 mg/kg suffices (Clarke & Gerring, 1990). Previously, the recommendation (for humans and dogs) was to give thiopental very rapidly, but current advice for small animals is that the drug should be injected more slowly, over around one minute, in order to reduce the initial cardiorespiratory depression. A major reason for fast administration was to avoid an excitement phase at induction; effective sedative premedication negates this problem.

Thiopental is very respiratory depressant. Rapid IV injection of the drug causes apnoea and a fall in blood pressure, even in normovolaemic animals, through a decrease in systemic vascular resistance. In hypovolaemic animals, rapid injection of thiopental can be fatal. After the initial fall, in normovolaemic animals, the blood pressure returns to about the normal level but there is a persistent tachycardia. The drug has a dose-dependent direct depressant effect on the myocardium but, at normal induction doses, cardiac output is maintained by the increase in heart rate. Thiopental is a poor analgesic; very deep levels of anaesthesia are necessary to prevent response to noxious stimulation so, if used other than as an induction agent, additional analgesia, such as fentanyl, is required. Muscle relaxation is poor, possibly partly the effect of increased PaCO₂ through respiratory depression. Shivering is common in all species of animal in the recovery period and may be due to persistent cutaneous vasodilation in a cold environment.

The only absolute contraindication to the use of thiopental as an induction agent is porphyria, a disease characterized by progressive acute demyelination of nerves, that is well documented in humans. Porphyria is very rare but has been diagnosed in cattle, pigs and cats (Tobias, 1964). Partial contraindications for thiopental include neonates, caesarean section with a live fetus, very thin animals, uraemia, untreated hypovolaemia and hypoproteinaemia. In small animals, there are several agents available which are preferable to thiopental for longer periods of anaesthesia, although the drug can be useful for this purpose in small ruminants.

Thiopental’s current limited availability relates to its replacement in human anaesthesia by propofol (see below) but, where available, it remains a useful agent in veterinary anaesthesia.

Methohexital

Methohexital sodium is a racemic mixture of the α-d and a-l isomers of sodium 5-allyl-1-methyl-5-(1-methyl-2-pentynyl) barbiturate, and differs from thiopental in having no sulphur in the molecule. It is supplied as a colourless solid and, when dissolved in water, forms a colourless solution which is stable for at least six weeks kept at room temperature.

Methohexital is approximately twice as potent as thiopental, and it is less irritant if accidentally given outside the vein. As for thiopental, when given by rapid IV injection, it rapidly crosses the blood–brain barrier and causes anaesthesia in a circulation time. As for thiopental, initial lowering of plasma levels and awakening is due to redistribution, but it differs from thiopental in that metabolism is much faster, is relatively non-cumulative and complete recovery is rapid, seldom exceeding 30 minutes even after prolonged infusion. Hepatic metabolism breaks methohexital down to non-active metabolites which are rapidly excreted. Cardiorespiratory actions and lack of analgesia are similar to those of thiopental. Sedative premedication avoids muscle tremors during the induction of and recovery from anaesthesia. Suitable doses will be discussed in the relevant species chapters.

Methohexital has been superseded by propofol for most indications but, where it is still available, it can prove a useful agent both for anaesthetic induction and for the maintenance of hypnosis.

Pentobarbital sodium

Pentobarbital sodium in the form of a racemic mixture of sodium 5-ethyl-5-(1-methylbutyl) barbiturate is marketed as a sterile 6.5% solution containing propylene glycol. Pentobarbital has been, and in some areas still is, used to provide total injectable anaesthesia. It is relatively non-irritant and, although the best results are obtained with IV administration, it has been used by intraperitoneal injection in laboratory animals. In humans, it can be used for sedation by the oral or rectal routes. When given IV, it is slow to cross the blood–brain barrier, so anaesthetic induction is slow. The usual mode of administration is to give two-thirds the calculated dose rapidly, so that there is not an excitement phase on induction (one of its isomers has an excitatory effect). Following induction, the anaesthetist must wait some time (a minute or more) to ensure full effect before giving the next increment, or overdose may occur. Doses in unpremedicated dogs and cats to give anaesthesia long enough for 30 minutes of surgery (with additional analgesia) are up to 30 mg/kg IV. Full recovery is accompanied by excitement and, in dogs, vocalization, and takes up to 24 hours. Premedication reduces the dose needed, reduces the chance of excitement at induction or recovery, and speeds recovery. Use of the intraperitoneal route, which is not recommended, often results in a major excitement reaction during the induction period.

The active ingredient of propofol, 2,6 di-isopropylphenol (Fig 6.1), exists as an oil at room temperatures. Propofol is presented for anaesthetic use as a free flowing oil-in-water milk-coloured macro-emulsion, the original format (Diprivan®) containing 1% w/v soya bean oil, 1.2% w/v purified egg phosphatide and 2.25% w/v glycerol (see ‘Formulation’ above). Contamination of syringes of propofol was implicated in a high incidence of postoperative infection (Bennett et al., 1995) and so some preparations now contain preservatives. The first clinical trials of propofol were reported for humans in 1977, for dogs in 1984 (Hall, 1984) and 1987 (Watkins et al., 1987) and for cats in 1988 (Brearley et al., 1988). Since this time, propofol has become the IV induction agent most widely used in human anaesthesia, as well as being used for TIVA and for sedation in intensive care.

Propofol is licensed for IV use as an anaesthetic agent in humans, cats and dogs. There is occasionally pain on injection. Although propofol is non-irritant, it can only be used IV as its elimination is too rapid for use by other routes. A number of generic versions of propofol are available. Currently (2012) in the USA and in Europe, there are two formats with veterinary licences. Propoflo® is similar to the original, and vials are for single use only. Propofol™ Plus (PropoFlo™28) contains benzyl alcohol as preservative, and its multidose bottles may be used for up to 28 days after the vial is first broached. PropoClear™ was a formulation as a micelle but, unfortunately, in clinical use, it proved painful on injection (Michou et al., 2012) and possibly caused local tissue damage and has been withdrawn.

Following IV injection of propofol, hypnosis is induced in a circulation time with anaesthetic depth reaching maximal after around 90 seconds (Reves et al., 2012). Recovery is extremely rapid and complete. The initial recovery from a bolus injection is through redistribution, as is thiopental. Also, as for thiopental, propofol is highly protein bound. The difference between the two agents is that the clearance of propofol as it is released from these tissues is very rapid (see Table 6.1), so residual sedation is not seen. Propofol is highly lipophilic and rapidly metabolized primarily to inactive glucuronide conjugates, involving cytochrome P450 systems, the metabolites being excreted in the urine. However, clearance can be greater than liver blood flow, and extrahepatic mechanisms (e.g. lung and kidney) are thought to contribute.

Pharmacokinetic studies in animals have shown species, breed and individual variations, and also variations depending on other anaesthetic and sedative agents given, in speed of elimination of propofol. In dogs, half-life of elimination, depending on other drugs administered, has been reported as between 75 and 486 minutes, volume of distribution as from 3.7 to 6.5 L/kg and clearance as between 34 and 58 mL/kg/minute (Nolan et al., 1993; Reid & Nolan, 1993, 1996; Zoran et al., 1993; Hall et al., 1994; Hughes & Nolan, 1999); the values of clearance and volume of distribution being considerably higher than the human values (see Table 6.1). Zoran et al. (1993) compared the pharmacokinetics of propofol in greyhounds with mixed breed dogs; half-life of elimination was longer (175 minutes cf 122 minutes) and clearance less (54 cf 115 mL/kg/minute) in greyhounds. In vitro studies have shown breed and gender differences in metabolic utilization of propofol (Hay Kraus et al., 2000) and also suggest that the canine kidney (in contrast to humans) does not metabolize the drug (Soars et al., 2001). In the goat, half-life of elimination is very rapid (15 minutes) and clearance very high (275 mL/kg/minute) (Rigby-Jones et al., 2002).

The cat, however, because of its inability to conjugate phenols, metabolizes both propofol and the lipid solvent more slowly than other carnivores. Table 6.2 gives data from the original developmental work (JB Glen, personal communication to LWH), and demonstrates that the utilization of propofol is very slow in cats. Very recent, as yet unpublished (2012) work has investigated the pharmacokinetics of a single dose of 8 mg/kg propofol in the cat. Early analysis of the results (a one compartmental model) suggests that the volume of distribution is 14 ± 6 L/kg; the half-life of elimination 5.9 ± 3.6 hours, and the clearance 115 ± 45 mL/kg/minute (Khursheed Mama, also on behalf of colleagues, personal communication to KC, October 2012).

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