186

Special Article : an update on the first twenty-five years of clinical

David L. Reich MD, George Silvay MD PhO experience

Contents Ketamine is a dissociative anaesthetic agent that has Pharmacology acquired an unique place in clinical practice. Since the - Pharmacokinetics first published report of its clinical use ~an understanding - Pharmacodynamics of its anaesthetic, analgesic, and amnestic qualities has - Mechanism of action - N-methyl-aspartate receptor theory grown from extensive clinical and laboratory research. - receptor theory The initial experience with ketamine as a sole anaesthetic - Miscellaneous receptor theory agent led to the recognition of unpleasant emergence Central nervous system effects reactions and cardiovascular stimulant properties, which - Eleetroencephalographic effects limited its usefulness. However, supplementation with - lntracranial pressure other drugs such as the benzodiazepines have reduced - Emergence phenomena Cardiovascular effects these side effects. Previous reviewersz'J have detailed the

- Mechanism early work on the pharmacology and clinical uses of - Effects on rhythm ketamine. This review encompasses the more recent - Prevention of cardiovascular stimulation research on ketamine, and emphasizes human data. - lschaemic heart disease Ketamine's role in clinical anaesthesia is changing as a - Cardiovascular effects in children and neona~s Respiratory effects result of the evolving concepts of its mechanism of action

- Respiratory pattem and the advantages of alternative routes of administration. - Hypoxic pulmonary vasoconstriction

- Bronchodilation - Airway maintenance Optical isomers Pharmacology Other pharmacologic effects Ketamine [KETALAR~, KETAJECT| is chemically - Neuromuscular blockade related to (PCP) and cyclohexamine, it - Endocrine/metabolic response has a molecular weight of 238 and a pKa of 7.5. Although Effects on intraocular pressure ketamine hydrochloride is water soluble, ketamine's lipid - Effects on coagulation Clinical uses solubility is ten times that of thiopentone. The molecular

- Epidural and intrathecal ketamine structure (2-(O-chloropheny l)-2-methylamino cyclohex-

- Oral and rectal ketamine anone) contains a chiral centre at the C-2 carbon of the - Obstetrics cyclohexanone ring so that two enantiomers of the Paediatrie radiation therapy and burn patients ketamine molecule exist: s(+)ketamine and r(-)keta- - Outpatient anaesthesia mine. Commercially available racemic ketamine prep- - Critically ill patients - Cardiac surgery arations contain equal concentrations of the two enan-

- Miscellaneous topics tiomers. These enantiomers differ in anaesthetic potency, Summary in the responses of the electroencephalograph (EEG), in Key words effects on catecholamine reuptake, and possibly in the incidence of emergence reactions. ANAESTHETICS,INTRAVENOUS: ketamine.

From the Department of Anacsthcsiology, Box 1010, Mount Pharmacokinetics Sinai Medical Center, One Gustavc L. Levy Place, New Ketamine has a high bioavailability following intravenous York, New York 10029 U.S.A. or intramuscular administration. First-pass metabolism Address correspondence to: Dr. D. L. Reich. and lower absorption necessitate higher dosages when

CAN J ANAESTH 1989 ! 36:2 / pp 186-97 Reich and Silvay: KETAMINE, TWENTY-FIVE YEARS CLINICAL EXPERIENCE 187 ketamine is administered by the oral or rectal routes (vide high concentrations of ketamine for intravenous regional infra). Biotransformation takes place in the liver, and anaesthesia and subarachnoid block, m,~ multiple metabolites have been described. The most important pathway involves N-demethylation by cyto- Mechanism of action chrome P4so to , an active metabolite with The anaesthetic state produced by ketamine was original- an anaesthetic potency one third that of ketamine. Nor- ly described as a functional and electrophysiological ketamine (originally termed metabolite I in the earlier dissociation between the thalamoneocortical and limbic literature) is then hydroxylated and conjugated to water systems. Ketamine as the sole anaesthetic produces a soluble compounds that are excreted in the urine. The cataleptic state with nystagmus and intact corneal and cyclohexanone ring also undergoes oxidative metabo- light reflexes. Hypertonus, purposeful movements and lism. Earlier literature listed dehydronorketamine (meta- vocalization may occur. bolite I1) as an important breakdown product of ketamine, Ketamine is a potent analgesic at subanaesthetie plasma but this compound is most likely an artifact of the concentrations, and its analgesic and anaesthetic effects chromatographic analysis, and not an important meta- may be mediated by different mechanisms. The analgesia bolite in vivo. 4 may be due to an interaction between ketamine and central Ketamine pharmacokinetics follow a three-term or spinal opiate receptors. ~: exponential decline. In unpremedicated patients, distribu- tion half-life (h12~') was 24.1 seconds, redistribution half-life (h/2a) was 4.68 minutes, and elimination half- N-METHYL-ASPARTATE RECEPTOR THEORY life (h~213) was 2.17 hours. 5 Pharmacokinetics were sim- N-methyl-aspartate (NMA) is an excitatory amine, and its ilar in children, except that absorption was more rapid receptors in mammalian brain are blocked by PCP and following intramuscular administration, and higher con- ketamine, t3'~4 The NMA receptors may represent a centrations of norketamine were present. 6 Diazepam subgroup of the sigma opiate receptors ("the PCP site") seems to inhibit the hepatic metabolism of ketamine, but that block spinal nociceptive reflexes. IS Ketamlne also etomidate does not. 7 blocks NMA-induced seizures at high doses, and NMA- induced behavioural changes at lower doses in the rat model. Js Metaphit, a recently synthesized piperidine derivative, Pharmacodynamics The pharmacodynamic effect of ketamine in humans is blocks the action of NMA by acetylating the receptors. It apparently due to the CNS activity of the parent com- was hoped that metaphit might displace ketamine from pound. As CNS levels of ketaminc decline by redistribu- NMA receptors and reverse ketamine anaesthesia. How- tion to the peripheral compartment, the CNS effects ever, metaphit acts as an agonist/antagonist at the recep- subside, although not as rapidly as would be predicted tors, and does not reverse dissociative anaesthesia in fl~e rat model. ~7 from its high lipid solubility,s Decreased renal fnnction, and the presence of active metabolites, do not prolong the drug's action. Tolerance and hepatic enzyme induction OPIATE RECEPTOR THEORY have been reported following chronic administration. Ketamine's affinity for opiate receptors is controversial, Both halothane and diazepam prolong the clinical but this provides an attractive theory for its analgesic anaesthetic effect of ketamine. However, it is not clear activity at central and spinal sites. Smith et al. showed whether this is due to the synergistic effects of CNS that racemic ketamine displaced tritiated from depressant drugs, decreased ketamine clearance, or a rat brain opiate receptors in vitro, and that (+)ketamine combination of these factors. Diazepam causes an in- was about twice as potent as (-)ketamine for this crease in plasma ketamine levels, but also a prolongation purpose. 18 Finck and Ngai not only confirmed the above of tu2a and tlt213 in humans. study, but also found similar stereospecific opiate recep- Analgesia from ketamine is associated with a plasma tor binding by (+)ketamine in guinea pig ileum in vitro, t9 concentration of 0.15 ~g. ml-t following intramuscular Cross-tolerance between the and ketamine would administration, and 0.04 v,g" ml-J following oral admin- also be expected if there is a common receptor. This has istration. The difference in the analgesic plasma concen- now been shown in two independent animal studies. 2~ trations might be explained by a higher norketamine The opiate receptor theory would gain more credence if concentration following oral administration (probably ketamine reversal by naloxone were proven in humans. from first-pass metabolism), which contributes to the Stella et al. reported that none of 68 adult patients analgesia. Awakening from ketamine anaesthesia takes premedicated with naloxone lost consciousness following place at plasma concentrations of 0.64-1.12 p,g- ml- ~.9 the administration of EDso doses of ketamine. 22 Amiot et Both sensory and motor block occur in humans using al. repeated the doses used in the above study, but in 188 CANADIAN JOURNAL OF ANAESTHESIA pregnant patients whose anaesthetic requirements may and found no further increase in ICP with 0.5 or 2.0 have been lower, and without a control group. They found mg.kg-~ of IV ketamine. 36 It was also hypothesized in no evidence of naloxone reversal of ketamine at a similar earlier studies, thai ketamine increased ICP due to a direct dosagefl 3 cerebral vasodilatory action. However, Schwedler et al. injected ketamine directly into cerebral vessels, and found MISCELLANEOUS RECEPTOR THEORY no effects on the vasculature. 37 Anterior fontanelle pres- Other neuronal systems may be involved in the antinoci- sure, an indirect monitor of ICP, declined by I 0 per cent ceptive action of ketamine, since blockade of noradrena- in mechanically ventilated preterm neonates following line and serotonin receptors attenuates the analgesic 2 mg "kg-~ of IV ketamine. 3s action of ketamine in animals. 2a Interaction of kctamine with sigma opiate receptors might be a plausible theory to EMERGENCE PHENOMENA explain dysphoric emergence reactions. 2s The psychic emergence phenomena of ketamine have bccn Ketamine also interacts with muscarinic cholincrgic described as floating sensations, vivid dreams (pleasant or receptors in the CNS. 26 Ketamine decreased the average unpleasant), hallucinations, and delirium. The phenome- lifetime of single-channel currents activated by acetylcho- na are more common in patients over the age of 16 years, line in an in vitro model, z7 This might help to explain in females, in shorter operative procedures, in those ketamine's potentiation of neuromuscular blockade as receiving larger doses and with more rapid administra- well as its central effects. tion. 2 In a comparison of ketamine with thiopentone, in Thus, centrally-acting anticholinesterase agents might healthy unpremedicated volunteers, ketamine resulted in be expected to reverse ketamine anaesthesia. However, more abnormalities of mental status immediately after the experimental data are contradictory fiB.z9 There is pre- anaesthesia. However, these changes were not present by liminary evidence that 4-aminopyridine might reverse the the following day. 39 effects of both ketamine and the benzodiazepines. 3~ The Benzodiazepines have proven the most effective agents combination of 4-aminopyridine and physostigmine was for the prevention of these phenomena.4~ Carlwright and also reported to reverse ketamine anaesthesia. 3t Also, Pingel found that midazolam significantly ['educed the 4-aminopyridine releases acetytcholine at central and incidence of unpleasant dreams compared with diaze- peripheral sites and it enhances neuromuscular transmis- pare. 41 Toil and Romer compared ketamine-midazolam sion. The effects of 4-aminopyridine on NMA transmis- with ketamine-diazepam infusions, and found that sion are worthy of study. ketamine-midazolam resulted in fewer emergence reactions and a shorter time to complete recovery. 42 Central nervous .Lvstem efJects Cardiovascular effects ELECTROENCEPHALOORAI'HICEFEECTS A major feature that distinguishes ketamine from other Ketamine induces consistent changes in the EEG. There is intravenous anaesthetics is stimulation of the cardio- a reduction in alpha wave activity, while beta, delta and vascular system. Numerous investigators have reported thcta wave activity are increased. 32 These changes were increases in heart rate, systemic arterial pressure, system- not significantly altered by diazepam. 33 Further discus- ic vascular resistance, pulmonary arterial pressure, and sion of EEG phenomena is included in the section on pulmonary vascular resistance (PVR). ~3 However, many optical isomers of ketamine. of the earlier haemodynamic studies of ketamine were It is hard to draw objective conclusions regarding the conducted on subjects spontaneously breathing room air, anti-convulsant properties of ketamine. Although keta- and were not controlled for the effects of respiratory n'dne produces epileptiform EEG patterns in human depression or partial airway obstruction. In contrast, limbic and thalamic regions, there is neither evidence that Balfors et al. assisted ventilation with an FIO2 of 0.25 and this affects cortical regions, nor that clinical seizures are found no significant change in PVR during ketamine likely to occur. 34 Animal data are particularly difficult to administration in 16 adult patients. ~ interpret, because of inter-species variations. MECHANISM INTRACRANIAL PRESSURE The mechanism of ketamine's cardiovascular effects is Many of the early studies of ketamine's effect on not well understood. A direct negative inotropic effect intracranial pressure (ICP) were conducted on spontane- is usually overshadowed by central sympathetic stimu- ously breathing subjects and were not controlled for lation. In an isolated dog heart preparation, Saegusa changes in ICP due to hypercarbia. 35 Pfenninger et al. et al. demonstrated that high plasma concentrations of studied mechanically ventilated pigs with increased ICP, ketamine depressed contractile, but not pacemaker func- Reich and Silvay: KETAMINE , TWENTY-FIVE YEARS CLINICAL EXPERIENCE 189 tion. ':5 Circulating catecholamine levels are increased at CARDIOVASCULAR EFFECTS IN CHILDREN AND NEONATES least partially by an inhibition of reuptake. 46 Central Ketamine is frequently used in children with congenital inhibition of catecholamine reuptake may also contribute heart disease. The acute haemodynamic effects of keta- to ketamine cardiovascular stimulation. mine in children undergoing cardiac catheterization were studied by Morray et al. 62 Two minutes following EFFECTS ON RHYTHM 2 mg.kg -~ of IV ketamine, there were minor haemody- The effect of ketamine on cardiac rhythm is also contro- namic changes, not associated with any difference in versial. There are animal data (in cats) that suggest intracardiac shunting, PaCO2 or PaO2. Following IV ketamine sensitizes the myocardium to the dysrhyth- ketamine, 2 mg. kg-~, Hickey et al. found no change in mogenic effects of adrenaline. 47 However, ketamine pulmonary vascular resistance index, systemic vascular reversed digitalis-induced dysrhythmias in dogs. 48 Cab- resistance index, or cardiac index in 14 intubated infants babe and Behbahani reported two cases of serious who were ventilated mechanically. 63 There was no dysrhythmias in plastic surgery patients who received 0.5 difference between infants with preexisting elevations in mg' kg- ~of IV ketamine for sedation during infiltration of PVR, and those with normal PVR. lidocaine solutions that contained adrenaline. 49 Greeley el al. compared the effects of anaesthetic induction with IM ketamine, 6 mg .kg -~ , with halothane/ PREVENTION OF CARDIOVASCULARSTIMULATION nitrous oxide (70 per cent) on arterial oxygen saturation Numerous drugs have been shown to block the ketamine- measured by digital pulse oxlmetry. 64 They studied induced cardiovascular stimulation, including a- and children who were prone to hypercyanotic episodes. Both [B-blocking agents, and verapamil. 5~ Gold et al. demon- induction techniques were associated with increased arter- strated a dose-response relationship, using esmolol infu- ial oxygen saturation. Laishley et al. similarly found sions to block the responses to ketamine and endotracheal ketamine to be a safe induction agent in patients with intubation 51 Mayumi el al. showed that cervical epidura] cyanotic congenital heart disease, although ketamine was blockade blunted increases in HR and systolic blood associated with increased HR. 65 pressure, probably secondary to a chemical cardiac Anaesthetic induction in the preterm neonate is fre- sympathectomy. 52 quently complicated by hypotension. In a comparison The benzodiazepines are the most efficacious agents of IV and inhalational induction techniques, ketamine, for attenuating the cardiovascular effects of ketamine. 2 mg.kg -I, resulted in a significantly lower incidence Diazepam, midazolam, and flunitrazepam are all effec- of hypotension than , 20 txg'kg-~, halothane tive for this purpose, s3 Midazolam is water-soluble, very 0.5 per cent, or isoflurane 0.75 per cent. 66 While keta- similar to ketamine in its pharmacokinetic behaviour, and mine resulted in an average 16 per cent decrease in systolic has become a common adjunct to ketamine anaesthesia.54 arterial pressure, this returned to preinduction values after The interaction with other anaesthetic agents, including skin incision in both the ketamine and fentanyl groups. the potent volatile agents, either diminishes or abolishes In a haemodynamic study of spontaneously breathing ketamine's cardiovascular stimulant effects. Dobson neonatal lambs, Burrows et al. found no significant showed that the combination of ketamine and thiopentone cardiovascular changes with IV ketamine, 1 mg. kg -~ or greatly reduced ketamine-induced cardiovascular stimu- 2 rag. kg- 1.67 lation, s~ Respiratory effects ISCHAEMIC HEART DISEASE Ketamine is a mild respiratory depressant. Bourke et al. In the patient with ischaemie heart disease, the cardio- found dose-related respiratory depression with incremen- vascular stimulant effects of ketamine might precipitate tal doses of kctamine. 6s They found that ketamine alone myocardial ischaemia. Studies in dogs indicated that caused the CO2-response curve to shift to the right, but kelamine as a sole agent increased coronary blood flow did not change the slope of the curve. The respiratory and myocardial oxygen consumption. 56'57 However, depression caused by ketamine is similar to that caused by clinical studies of ketamine-diazepam anaesthesia for opiates, and dissimilar from most sedative-hypnotics and cardiac surgical patients indicate haemodynamic sta- anaesthetics, because the slope of the CO2-response curve bility. 5s-6~ is not affected. This evidence suggests that opiate The choice of neuromuscular blocking agent is impor- receptors play a role in the respiratory depressant effects tant in the patient with ischaemic heart diease. The of ketamine. vagolytic action of pancuronium resulted in more rapid tachycardia when administered with ketamine, than a RESPIRATORY PATTERN ketamine-vecuronium combination. 6t Three recent studies have examined the effects of keta- 190 CANADIAN JOURNAL OF ANAESTHESIA mine on respiratory pattern and functional residual capac- for (+)ketamine, human research with the ketamine ity. Morel et al. administered IV ketamine, 1 mg.kg -t, enantiomers commenced. (+)Ketamine produced more over five minutes to unpremedicated volunteers. 69 They effective anaesthesia than the racemate or (-)ketamine. reported periods of increased ventilation interspersed with More psychic emergence reactions occurred after (-)ket- periods of apnoea, with no net change in expired CO2. amine than the racemate or (+)ketamine. 84 Mankikian et al. administered IV ketamine, 3 mg- kg-t, In a more recent study, White et al. found that followed by an infusion of 20 ~g.kg-~.min -I to patients (+)ketamine was approximately four times as potent as who breathed spontaneously through endotracheal tubes. 7~ (-)ketamine. (+)Ketamine and the racemate produced They reported maintenance of functional residual capaci- similar EEG changes, but (-)ketamine produced a lesser ty, minute ventilation, and tidal volume, with an increase degree of EEG slowing. The lesser degree of EEG in the contribution of the intercostal (relative to diaphrag- response to (-)ketamine seemed to correlate with its matic) contribution to tidal volume. Functional residual lower hypnotic and analgesic potency, and its lower capacity is also preserved in young children during affinity for opiate receptors. 8s ketamine anaesthesia.7' Other pharmacologic effects HYPOXIC PULMONARY VASOCONSTRICTION There is evidence to suggest that ketamine does not inhibit NEUROMUSCULAR BLOCKADE hypoxic pulmonary vasoconstriction.72 Rees and Gaines Although ketamine alone produces an increase in skeletal found no difference between ketamine and enflurane in muscle tone, it enhances the action of neuromuscnlar terms of oxygenation or shunt fraction in humans during blockers such as succinylcholine and d-tubocurarine. The one-lung anaesthesia. 73 Weinreich et al., and Rees and effect of ketamine on pancuronium neuromuscular block- Howell demonstrated the use of ketamine infusions in ade is controversial, but a recent study in monkeys humans for pulmonary surgery requiring one-lung anaes- showed a dose-related depression of thumb twitch with thesia.74'75 Rogers and Benumof found that halothane and increasing doses of ketamine in the presence of pancuron- isoflurane did not lower PaO2 during one-lung ventilation ium. 86 Cronnelly etal. s7 proposed that ketamine decreas- in ketamine- or methohexitone-anaesthetized patients, es the sensitivity of the motor end plate, while Marwaha ss and there were no significant differences between the reported that kctamine initially potentiates, and then ketamine and methohexitone groups. 76 blocks the twitch response to direct muscle stimulation.

BRONCHODILATION ENDOCRINE/METABOLIC RESPONSE The bronchodilator effects of ketamine have been evident A recent study compared ketamine with thiopentone- since the early clinical studies. Ketamine is as effective as halothane anaesthesia in patients undergoing pelvic sur- halothane or enflurane in preventing bronchoconstriction gery. Prior to the start of surgery, blood glucose, plasma in an experimental canine model. 77 It is likely that eortisol, and heart rate were increased in the ketamine circulating cathecholamines are the cause of ketaminc's group. However, there were no endocrine, metabolic, or bronchodilatory effects, because propranolol will block haemodynamic differences between the two groups after the protective effects of ketamine in the canine model. the start of surgery, s9 Ketamine has been used in the treatment and emergency intubation of paediatrie patients with status asthmati- EFFECTS ON INFRAOCULAR PRESSURE CUS,78-80 The effects of ketamine (with atracurium) on intraocular pressure (IOP) were recently reviewed and studied by AIRWAYMAINTENANCE Badrinath et al. 9~ They found that IOP decreased signifi- Ketamine generally preserves airway patency and respira- cantly after anaesthetic induction, but before intubation. tory function. Nevertheless, there are rare reported cases Following inmbation, IOP returned to the preinduction of pulmonary aspiration, prolonged apnoea 81 and arterial control level and remained stable. Ketamine was not hypoxaemia, s2 Salivary and trachea-bronchial secretions superior to thiopentone or etomidate for this purpose. are increased by ketamine, and a prophylactic antisial- ogogue is required. Glycopyrrolate and atropine are EFFECTS ON COAGULATION equally effective for reducing these secretions during Atkinson et al. have shown that intramuscular ketamine ketamine/diazepam anaesthesiafl3 irreversibly inhibits the aggregation of platelets in ba- boons. 91 The inhibition may be similar to that produced by Optical isomers aspirin. However, there was no increased bleeding from After initial animal research showed potential advantages the experimental animals' exposed carotid arteries, and Reich and Silvay: KETAMINE, TWENTY-FIVE YEARS CLINICAL EXPERIENCE 191

no bleeding times were performed. Heller et al. found no 150 ng. m[ -L, respectively). The levels of norketamine significant haemostatic changes in humans undergoing were also higher in those receiving oral ketamine. The ketamine/midazolam anaesthesia. 92 authors attribute these results to first-pass metabolism, and propose that norketamine contributed to the analgesic Clinical uses effect. Morgan and Dutkiewicz reported the case of a three-year-01d child who received oral ketamine, I Epidural and intrathecal ketamine mg. kg- t, as an analgesic for daily burn dressing changes The recent popularity of epidural and intrathecal opiates, for ten days. io2 and ketamine's proposed interaction with opiate recep- Rectal ketamine, 8,7 mg. kg -I, was administered to tors, have generated several investigations into the effica- children for the induction of anaesthesia, and loss of cy of epidural and intrathecal ketamine. Theoretically, consciousness took place after 7 to 15 minutes. Peak ketamine should not have the occasional severe respira- serum concentrations were reached at 40 minutes and tory depressant side-effects associated with epidural or there was a high level of norketamine, similar to the intrathecal . A preliminary study showed no results with oral ketamine. 1~ Malaquin administered neurotoxic effects in baboons injected intrathecally with rectal ketamine, 10 mg 'kg t, to children, with onset of preservative-containing ketamine. 93 Following this, there action at nine minutes, and peak effect at 25 minutes, io4 was a report of patients with intractable cancer pain, who Cetina compared oral and rectal ketamine in children, and obtained relief lasting 30 minutes to over six hours recommended rectal ketamine, 15 mg.kg -~, combined following epidural ketamine. 94 with droperidol, 0.0125 mg.kg -~, for induction of The series of clinical studies of epidural ketamine that anaesthesia. ~o5 followed are difficult to interpret because many of the authors' conclusions are based on uncontrolled experi- Obstetrics mental data. lslas et al. claimed potent analgesia from 4 The initial experience with standard IV doses (2 mg. kg-~) mg of epidural ketamine in a study of 50 patients. 95 In of ketamine in parturients for vaginal delivery was notable another study comparing intramuscular ketamine, 30 rag, for a high incidence of maternal complications and epidural ketamine, 10 mg, and epidural ketamine, 30 mg, neonatal depression. However, using lower IV doses of the investigators claimed a good analgesic effect. How- ketamine (0.2-1.0 rag. kg-L), these problems were mark- ever, even in the 30 mg epidural dose group, 46 per cent of edly reduced. In a study comparing low spinal anaesthesia the patients required supplemental analgesia within 24 and IV ketamine, 1 mg'kg -~, maternal and neonatal hours. 96 In a study of 40 patients who received epidural arterial blood gases were not significantly different. ~o6 In ketamine, 15 mg, analgesia began at five minutes and an acidotic fetal lamb model, ketamine anaesthesia lasted an average of four hours. However, there was also a preserved fetal organ perfusion, and did not worsen the ten per cent incidence of psychotomimetic reactions. 97 acidosis. ~o7 In two studies comparing epidural ketamine with Intravenous ketamine offers certain advantages in the epidural morphine, morphine was the more potent and rapid-sequence induction of the parturient for Caesarean longer-acting analgesic.9s'99 The study of Kawana et al. section. In comparison with thiopentone, ketamine is is the only double-blinded, controlled comparison of advantageous for hypovolaemic patients (e.g., abruptio epidural ketamine and morphine published to date. placenta, placenta praevia) or patients with broncho- The only human study of intrathecal ketamine for spasm. Dich-Nielsen and Holasek reported their satisfac- surgical anaesthesia (50 mg in 3 ml five per cent dextrose tory experience with 100 Caesarean section patients, with 0. I mg adrenaline) reported good motor and sensory using primarily ketamine) ~ Comparing ketamine, l blockade, but of limited duration (mean 58 minutes). mg.kg -I, with thiopentone, 4 mg.kg -~, there were no However, motor blockade did not occur without adrena- differences in neonatal PaO2, acid-base balance, or line, and higher dermatomal levels of blockade were Apgar scores.~~ Schultetus el al. used the same doses associated with CNS side-effects. ~0o of ketamine and thiopentone as above, and found that ketamine better attenuated the haemodynamie response Oral and rectal ketamine to laryngoscopy and intubation, with no difference in The analgesic effects of 0.5 mg.kg t ketamine adminis- neonatal outcome)t~ Ketamine, 1 mg. kg -~, also was tered orally versus intramuscular administration of the more effective than thiopentone, 4 rag' kg -~, or a keta- same dose were studied by Grant et al. I~ Onset of mine (0.5 mg- kg-t) / thiopentone (2 mg. kg-t) combina- analgesia was delayed with oral ketamine (30 minutes), tion in preventing intraoperative awareness. ~~ and was associated with a lower serum level (40 ng. ml- ~) It was claimed that ketamine anaesthesia resulted in compared with the intramuscular dose (15 minutes and decreased blood loss during first trimester abortions, due 192 CANADIAN JOURNAL OF ANAESTHESIA to an increase in uterine tone. However, a recent study Cardiac surgery comparing ketamine-midazolam with methohexitone The use of ketamine in cardiac surgery has been largely found no difference in blood loss. ~2 overshadowed by high-dose narcotic techniques during Teratologic effects ofketamine have been demonstrated the last ten years. However, in a randomized, prospective in rats. 1~3 A generalized degenerative effect was depen- comparison of high-dose fentanyl with diazepam- dent on the dose and duration of treatment. However, no ketamine anaesthesia for single-valve replacement and human data on ketamine teratogenicity are available. myocardial revascularization, the following results were found: ketamine-diazepam anaesthesia was associated Paediatric radiation therapy and burned patients with decreased postoperative fluid and vasopressor re- Ketamine is useful in maintaining sedation and immo- quirements, decrease pulmonary shunt fraction, and bility in paediatric patients requiring repeated radiation shorter intensive care unit stay. Both techniques resulted therapy. J ~4'~~s These early reports noted that tolerance to in a stable intraoperative haemodynamic picture. ~22 IV and IM ketamine developed with repeated administra- tion. Byer and Gould reported the case of an 1 l-week-old Miscellaneous topics infant whose ketamine requirement increased 250 per cent Ketamine has been used uneventfully in patients with by the 13th treatment.~6 previous episodes of malignant hyperthermia. Postopera- Burned patients require frequent painful procedures. tively, there were no complications and no significant The use of ketamine analgesia in burn units is remarkable changes in creatine phosphokinase levels. ~z3 However, a for the development of tolerance with repeated adminis- fatal case of malignant hyperthermia has been reported tration. The possibility of using oral or rectal ketamine following a ketamine anaesthetic for a diagnostic muscle should be investigated further, especially in patients with biopsy in a five-year-old child. 124 extensive bums, where intravenous access is limited. A case of diabetes insipidus induced by a ketamine infusion was reported in a patient receiving ketamine for Outpatient anaesthesia chronic pain, The condition responded to intranasal The trend towards more ambulatory surgery has fostered desmopressin acetate, and resolved on discontinuation of an interest in ketamine because of its acceptably short the ketamine infusion, t 25 duration of action and postoperative analgesic effects. Unfortunately, supplemental agents administered to de- Summary crease the incidence of psychic emergence phenomena In nearly 25 years of clinical experience, the benefits and (e.g., benzodiazepines) also prolong recovery time. limitations of ketamine analgesia and anaesthesia have White reported that continuous infusions of ketamine (as a generally been well-defined. The extensive review of supplement to nitrous oxide) were preferable to bolus White et al. 2 and the cardiovascular review of Reves et administration in outpatient anaesthesia. ~7 However, al. 43 are broad in their scope and have advanced the fentanyl infusions led to more rapid emergence than understanding of dissociative anaesthesia. Nevertheless, ketamine infusions in a followup study, t~8 recent research continues to illuminate different aspects of ketamine pharmacology, and suggests new clinical uses Critically ill patients for this drug. The role of ketamine for the induction and maintenance of The identification of the N-methylaspartate receptor anaesthesia in patients with hypovolaemia, pericardial gives further support to the concept that ketamine's tamponade, constrictive pericarditis, and cardiogenic analgesic and anaesthetic effects are mediated by separate shock is well documented. In the battlefield or catastroph- mechanisms. The stereospecific binding of (+)ketamine ic setting, ketamine might be advantageous, considering to opiate receptors in vitro, more rapid emergence from the likelihood of encountering hypovolaemic patients. anaesthesia, and the lower incidence of emergence Bion compared low-dose ketamine and sequelae, make (+)ketamine a promising drug for future infusions for analgesia, and found that ketamine better research. preserved arterial blood pressure and respiratory rate, Clinical applications-of ketamine that have emerged although pentazocine provided better anxiolysis. ~9 Jago recently, and are likely to increase in the future, are the use et al. used ketamine anaesthesia with heavy papaveretum of oral, rectal, and intranasal preparations for the purposes premedication, and found that emergence sequelae were of analgesia, sedation, and anaesthetic induction. Keta- very common in the battlefield setting.~2~ Restall er al. mine is now considered a reasonable option for anaesthetic utilized a fixed combination intravenous infusion of induction in the hypotensive preteml neonate. The initial ketamine, midazolam, and vecuronium with satisfactory experience with epidural and intrathecal ketamine admin- results, and have recommended it for military surgery. 121 istration has not been very promising but the data are only Reich and Silvay: KETA/'aINE, TWENTY-FIVE YEARS CLINICAL EXPERIENCE 193 preliminary in this area, The use of ketamine in rnilitary regional anaesthesia with ketamine. Anaesthesia 1985; and catastrophic settings is likely to become more 40: 899-901. common. 11 Bion JF. lntrathecal kelamine for war surgery. A prelimi- The clinical availability of midazolam will complement nary study under field conditions. Anaesthesia 1984; 39: ketamine anaesthesia in several ways. This rapidly 1023-8. metabolized benzodiazepine reduces ketamine's cardio- 12 Collins JG. Effects of ketamine on low intensity tactile vascular stimulation and emergence phenomena, and sensory input are not dependent upon a spinal site of does not have active metabolites. It is dispensed in an action. Anesth Analg 1986; 65: 1123-29. aqueous medium, which is usually non-irritating on intra- 13 Anis NA, Berry SC, Burton NR, Lodge D, The dissociative venous injection, unlike diazepam. The combination of anaesthetics, ketamine and pheneyelidine, selectively ketamine and midazolam is expected to achieve high reduce excitation of central mammalian nearones by patient acceptance, which never occurred with ketamine N-methyl-aspartate. Br J Pharmacol 1983; 79: 565-75, as a sole agent. 14 Thomson AM, West DC, Lodge D. An N-methylaspartate Finally, it is necessary to point out the potential for receptor-mediated synapse in rat cerebral cortex: a site abuse of ketamine, le6 While ketamine is not a controlled ~lf action of ketamine? Nature 1985; 313: 479-81. substance (in the United States), the prudent physician 15 Parsons CG, Gibbens H, Magnago TSI, Headley PM. At should take appropriate precautions against the unautho- which "sigma" site are the spinal actions of ketamine rized use of this drug. mediated? Neurosci Left 1988; 85: 322-8. 16 Bennett DA, Bernard PS, Amrick CL. A comparison of Acknowledgements PCP-like compounds for NMDA antagonism in two in The authors gratefully acknowledge the assistance of viva models. Li[e Sci 1988; 42: 447-54. James B. Eisenkraft, M.D., and Raymond Miller, M.D., 17 Davies SN, Chureh J, Blake Jet ol. Is metaphit a for their review of the manuscript. phencyclidine antagonist? Life Sci 1986; 30: 2441-5. i8 Smith DJ, Pekoe GM, Martin LL, Coalgate B. 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prcmedication and althcsin induction on the incidence of ftl~'ons. Cette benzodiaz~pine es't rtlpidement m~tabolisde. Elle emergence phenomena. Anaesthesia 1984; 39: 925-7. r~r la stimulation cardiovasculaire de la kdlamnitie ainsi que 121 RestalIJ, Tully AM, Ward PJ, Kidd AG. Total intra- les ph(nomdnes d'Emergence sans avoir des mElaboliles aelif~. venous anaesthesia for mititary surgery. A technique Elle est disponible sous une forme oqueuse et n'est pus irrituute using ketamine, midazolam, and vecuronium. Anaesthe- lors de I'iajeclinu intrn-veitieuse comme le diaz~p~uu. La sia 1988; 43: 46-9. cnmbinaison de la k~lamine et du midnzolam sern bien nceeplde 122 Tumati KJ, Keane DM, Spiess BD et al. Effects of par les patients cotitrairement 6 ce qui arrit,e quaud on alilise la high-dose fentanyl on fluid and vasopressor require- k~lamiue seule. Finalemenl, il est ti&essuire tie n~etiliotmer la ments after cardiac surgery. J Cardiothorac Anesth 1988; possibilitE d'abus de In k~tnmitie, t26 AIors qne In k~latitine n'esl 2: 419-29. pus tree substance eontr61de (au.r Etats-Unis) la pr~denc'e 123 Lees DE, Kim YD, Mactiamara TE. The safety of sugg~re att~" m~decius de prendre des pr~cataions approprit~es ketaminc in pediatric neuromuscular disease. Anesthe- contre son utilisation non-autorisde. siology Review 1982; 9(6): 17-21. 124 Rasore-Quartino A, De Bellis P, Bermmitin F, Ravel S. Atypical malignant hypertherrnia. Observation of a case caused by ketamine. [Italian] Pathologica 1985; 77: 609-17. 125 Sakai T, Baba S, lshihnra H el al. Sudden diabetes insipidus induced by ketamine infusion. Agressologie 1986; 27: 499-500. 126 FDA Drug Bulletin: "Ketaminc abuse." FDA Drug Bulletin 1979; 9(4): 24.

R6sum6 Pendant presque 25 ans d'expdrience clinique, les bEti~fices er les limitations de l'aneslhf'sie z'r la k~lamine ant ~l~ g~ndrale- merit bien d~fitiis. Les revues extensives de White et a1.2 ainsi que eelles de Reeves et al. 4J ant ~norm(ment nid~ ~ comprendre I'anesth~sie dissociative. N~anmoins, des dtudes r~cenles con- linuent h nous gclairer sur les diff~retits aspects de In pharma- cnlngie de In kgtnmitie et suggErent de tiouvelles utilisaliotis cliniques de cette drogue. L'identifi'cation du rEcepteur du N-MethyI-Aspnrtale amdne une preuve que I'aneslh~Me el I'ntitilg~sie d la k~tnmine ant chncune an m~eanisme d'ocrion diffdrent. La liaison st~rt;ospdcifique de la (+) kdtamine attx rdeeptenrs npiac~s in vitro, I'(mergence plus rapide de l'anes- thL~sie, et utie incidence plus basse de s~quelles Iors de I'~mergenee, rend hr (+) kEtamine une drogue prolneltatile pour ties recherches futures. Les applications cliniques de la k~tamine qui ressortetit r~cemmenl, et qoi probablement aug- menleront dans le fulur soul relides E l'utilisatioti orale, reclale et intra-tiasale de la kdtamine pour des fins d'analgdsie, de s~dalioti ou induction anesth~sique. La k~tamine est octuelle- meat consid~r~e comme utie option raisonnnble pout" I' induction atiesth~sique chez les nouveau-ngs prdmatur~s en hypotensiou. L'expdrience initiale avee [a k~tamine en injection ~pidurale et intrath~cnle tie fat pas promelteuse et les donn~es sont encore pr~liminaires datis ce domaine, L'utilisatioti de In kdtamine dons les catastrophes el les manoeuvres' militaires va probable- meat ~tre plus frEquetite. La dispotiibilit~ clinique du midazo- lum va compldmenter l'anesth~sie ft la kdtamine de plusieurs