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NAUSEA AND VOMITING
Br. J. Anaesth. (1984), 5S, 19
NAUSEA AND VOMITING R. S.J.CLARKE nasopharynx. At this stage, a sudden contraction of the abdominal muscles causes a sharp increase in intrathoracic and intra-abdominal pressure, which in turn is transmitted to the stomach. If the glottis is not closed completely at this stage, forcing of air through it causes the high-pitched sound associated with retching or vomiting. The oesophagus, lower oesophageal sphincter and body of the stomach now relax and there is a strong contraction of the gastric antrum, shifting contents into the upper stomach. Secretion of hydrochloric acid is inhibited although secretion of mucus is increased. There are rapid segmental contractions and later spasms occur in the duodenum and jejunum (but not anti-peristalsis), resulting in forcing up their contents into the The events of vomiting Vomiting may be defined as the forceful expul- stomach. Even the colon may contract during vomsion of gastric or intestinal contents through the iting, but it is rare for ileal or colonic contents to be mouth. The word forceful distinguishes it from the expelled. These intestinal movements appear to be passive regurgitation which occurs in infants or mediated by the vagus as they are abolished by vagal comatose individuals in whom the lower oesophage- section and unaffected by sympathetic denervation. al sphincter may be partly relaxed. It is preceded in The effect of all the intra-abdominal contractions man by a sensation of nausea and retching, but in the against a lowered diaphragm is to force food through infant or in animals under direct stimulation of the the open sphincter and into a relaxed oesophagus. It vomiting centre, projectile vomiting may occur, may not pass further if the inferior constrictor of the unaccompanied by any apparent discomfort or au- pharynx is closed, resulting in abortive retching and tonomic disturbance. In man also, vomiting caused return of the material to the stomach. However, by increased intracranial pressure is not preceded by after several episodes of this when the pharyngeal nausea. The usual precursors in adult man are copi- sphincter does relax, forceful propulsion of stomach ous salivation, swallowing, sweating, pallor and contents through the mouth occurs. The cycle may tachycardia, related presumably to the close prox- be repeated several times before the abdominal musimity of the autonomic centres in the medulla. cles relax and respiration is resumed. Respiration may also be laboured, with the mouth The control of this complicated group of activities partly or entirely closed. The experienced observer involves co-ordination of both striated and visceral learns to recognize these signs in a patient and some muscle in an essentially involuntary activity. This is last-minute action may be taken to prevent vomiting managed through the vomiting centre in the lateral or at least reduce the undesirable consequences. reticular formation deep in the medulla. Stimulation The mechanism of vomiting has been studied by of this area in experimental animals results in a sharp the use of radiography (Lumsden and Holden, inspiration and immediate vomiting, which ceases 1969). There is first a deep inspiration as the diaph- as stimulation ceases. Such vomiting is projectile in ragm moves downwards with closure of the glottis type without concomitant retching (or presumably, and elevation of the soft palate to occlude the nausea). The vomiting centre in turn is influenced by psychic factors, the vestibular nucleus, the Chemoreceptor Trigger Zone (CTZ) and sensory R. S. J. CLARKE, M.D., PH.D., F.F.A.R.CS., Department of afferents from pharynx, gastrointestinal tract or Anaesthetics, The Queen's University of Belfast, Northern genitalia. The CTZ (Borison and Wang, 1953), Ireland. © The Mtcmillan Press Ltd 1984
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Vomiting has long been regarded as one of the most unpleasant aspects of anaesthesia. In addition, it is a feature of many medical and surgical conditions and of travel by land, sea and air. Its effects range from the simply annoying, to life-threatening electrolyte upset. The choice of a cytotoxic drug or the alternative of radiotherapy may be determined by the likelihood of vomiting rather than efficacy against the neoplasm. All these aspects are of importance to the anaesthetist and this review describes the mechanisms and physiology of vomiting, in addition to the pharmacology of its causes and means of prevention.
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TTte effects of vomiting
The most worrying effect to the anaesthetist is the possibility of aspiration of stomach content into the trachea. It is usually believed that true vomiting is unlikely to be aspirated because the laryngeal reflex ensures against soiling of the respiratory tract. However, there is clearly an intermediate zone of hazard if the patient is supine following an injury or a surgical operation, when impaired reflexes are unable to protect the trachea. In these patients, prevention of active vomiting is useful in addition to prevention of regurgitation or aspiration, although impractical in the emergency situation. Prolonged vomiting is a feature of many patients coming for surgery and its effects depend on the main substances which are lost. Gastric juice has two components—the mucus secretion of the surface epithelial cells and the acid secretion of the parietal or oxyntic cells. The former has a pH of approximately 7.7 and electrolyte components (mmol litre"1) are: Na + = 150-160, K + = 10-20, Ca+ = 3-4, Cl = 125, HCO3 = 35 (Hunt, 1959). The composition of the acid secretion is less certain because there is nearly always some admixture with mucus. It does seem, however, that at high rates of secretion it approximates to an isotonic solution of pure hydrochloric acid with a small quantity of potassium and sodium chlorides. At high rates of secretion, as when stimulated by histamine, the acidity is high and as the rate diminishes there is an increase in the relative proportion of Na+ to H + . Gastric juice is isotonic with plasma and when it is secreted H + and Cl~ are removed from plasma, together with enough water for isotonicity. However, the H + is manufactured by the mucosa and HCO3~ reabsorbed to balance the Cl~ secreted so
that, overall, water is lost from the plasma in this phase of digestion, with an increase in tonicity. Normally, the whole gastric juice is reabsorbed in the intestine but, if not, as in prolonged vomiting, the loss of water is an important effect as part of an overall extracellular dehydration. However, water is usually the easiest substance to replace and, if replaced, loss of ions becomes the more notable effect of vomiting. The loss of H+ in continual vomiting leads to a gradual increase of HCO3" in the plasma (metabolic alkalosis). The excess of HCO3~ is excreted by the kidney, in the initial phase at least. However, the other electrolyte changes conflict with the renal compensation and limit its effectiveness. There is some loss of Na+ in the gastric juice and the proportion to H + depends on the acidity of the juice. As vomiting continues, the acidity of gastric juice is reduced and the loss of Na+ increases, until the latter becomes a limiting factor. Loss of Cl" is always severe because it is the anion associated with H + or Na+ and cannot be spared while gastric juice is secreted. Potassium is present in gastric juice in a concentration at least twice that of plasma, but the main reason for hypokalaemia in prolonged vomiting is the selective excretion of K+ in the renal tubules as H + is conserved. The result is depletion of extracellular and later intracellular potassium, which cannot easily be assessed by blood sampling. It can be assumed, however, in treating any patient with metabolic alkalosis losing gastric juice, even though plasma potassium concentration is within normal limits. Causes of nausea and vomiting
Motion sickness (Glaser, 1959) results essentially from actions on the vestibular apparatus of the ear. Patients with congenital inner ear deafness or destruction of the vestibular apparatus do not suffer. The stimulus appears to be a sequence of bursts of linear acceleration which set the endolymph in the semicircular canals in motion, resulting in the stimulation of the otoliths in the utricle. Waves of impulses pass back by the vestibular part of the eighth nerve to the chemoreceptor trigger zone in the medulla, with relays to the cerebral cortex involving nausea and to the cerebellum and vomiting centre for the motor response. Destruction of the CTZ eliminates the response to centrally applied emetics and the vomiting accompanying uraemia, radiation sickness and motion sickness.
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which is in the floor of the fourth ventricle, is probably the most important to anaesthetists for drugs do not act on the vomiting centre directly, but rather on this distinct medullary area. Electrical stimulation of this area does not cause vomiting, although stimulation of the vomiting centre itself is effective. Likewise, ablation of the CTZ in the dog prevents the emetic response to apomorphine, opiates and digoxin. All these areas will be considered separately but they often summate, as for instance, in postoperative sickness in gynaecology, where the analgesic, the stimulus of cervical dilatation, the movement of sitting up and the thought of eating even a light meal, may be enough to provoke active vomiting.
BRITISH JOURNAL OF ANAESTHESIA
NAUSEA AND VOMITING
peripherally as it does not readily penetrate the blood-brain barrier. Anaesthesia and analgesia form the causes of sickness which most concern the anaesthetist and which are still not entirely eliminated. The non-drugrelated components have been discussed already, but the various groups of drugs implicated merit separate discussion. Inhalation
anaesthetics.
The
older
volatile
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The role of the cerebral cortex in initiating vomiting has been mentioned but, conversely, sufficient mental distraction may also inhibit the reflex. Habituation may eventually terminate motion sickness so that it becomes less likely in those who travel regularly by the same type of vehicle. Certain other measures also reduce the risk of vomiting in susceptible individuals, for example lying down to reduce vestibular stimulation or looking at the sky or vessel wall to avoid rhythmical visual stimulation from a moving horizon. Other labyrinthine disorders come into the same group, including the vertigo and nausea associated with Meniere's disease and middle ear surgery.
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anaesthetics, diethyl ether and chloroform, were notorious for their prolonged emetic action, lasting in many for more than 12 h. There are few comparative figures for halothane and the older agents, but Bamforth and his colleagues (1960) in a small series Sensory stimulation, either somatic as from tactile found chloroform to be much more emetic than stimulation of the back of the throat or stretch halothane. Dundee, Kirwan and Clarke (1965) pubresponses from one of the viscera can initiate nausea lished a comparison in minor gynaecological surgery or vomiting. The visceral group include distension of different anaesthetic agents and the influence of of or injury to the uterine cervix, renal pelvis or premedication (fig. 1). Intermittent thiopentone bladder, injury to the testes or a blow to the upper was followed by significantly fewer sequelae than abdomen, in addition to many inflammatory condi- halothane during the first hour after anaesthesia, tions within the abdomen. although the difference was entirely in respect of nausea. Cyclopropane caused much more sickness Metabolic disturbances or intoxications includein the first hour than the other drugs tested. Howhyperemesis gravidarum, radiation therapy, ever, it is notable that overall, less than 5% of uraemia and hypo- or hyper-glycaemia, and it seems patients were still vomiting 1 h after operation in the that these are mediated through the CTZ, as in the absence of premedication. Gold (1969) also showed case of motion sickness. that in more than 1000 gynaecological patients cyclopropane was associated with significantly more Increased intracranial pressure acts presumably by sickness than were halothane or thiopentone direct stimulation of the vomiting centre in the nitrous oxide -oxygen. It was also seen that thiopenmedulla. tone induction followed by a primary inhalation agent was associated with a smaller frequency of Spinal anaesthesia is commonly accompanied by emesis than was induction with the inhalation agent nausea and vomiting and it has been suggested that alone. Emphasizing the lack of sickness after this is a result of the accompanying hypotension. halothane anaesthesia, some workers (Novoa, 1960; Recently Datta and his colleagues (1982) have con- Haumann and Foster, 1963) have actually demonfirmed this relationship and shown that, if the arteri- strated an anti-emetic effect from it, for instance al pressure was maintained after the spinal anaesthe- when it was added to trichloroethylene anaesthesia. tic by immediate administration of ephedrine i.v., there was no significant hypotension. The frequenI.v. anaesthetics. The study by Dundee, Kirwan cy of nausea and vomiting was then similar (10%) to and Clarke (1965) showed that anaesthesia with that in the control group whose pressure remained intermittent thiopentone and nitrous oxide, for unchanged, compared with 66% in the hypotensive minor gynaecological surgery, was followed by group whose treatment was delayed. nausea or vomiting in approximately 12% of patients. The frequency following propanidid is apCytotoxic drugs cause severe nausea and vomiting proximately 38%. Table I analyses the percentage of in a high proportion of patients and this has been patients vomiting in the first 6h after the eight largely ignored until recent years (Seigel and Longo, principal i.v. anaesthetics given under standard con1981). The CTZ has been implicated with some of ditions. It appears that drugs with a moderately slow the drugs, but cisplatin at least appears to act and smooth recovery, for example diazepam, di-
BRITISH JOURNAL OF ANAESTHESIA
22 1st hour
1-6h
Premedication 2O
4O
6O
O
2O
4O
Anaesthetic 6O
Atropine J Thiopentone J Propanidid J Cyclopropane J Halothane Atropine Thiopentone Propanidid Cyclopropane Halothane Pethidme Atropine Thiopentone Propanidid Cyclopropane Halothane FIG. 1. The emetic sequelae of anaesthesia with four different anaesthetics and three premedicants, the patients being seen 1 and 6 h after surgery. Dark area - vomiting; hatched area - nausea only. (Reproduced by permission of the editor, Acta Anaesthtsiologica Scandinamca, from Dundee, Kirwan and Clarke, 1965.)
isopropyl phenol, Althesin and thiopentone, have an acceptably low frequency of sickness. A high frequency of excitatory effects during or after anaesthesia (etomidate and ketamine) and rapid recovery (propanidid and methohexitone) are associated with frequent sickness after operation. However, it was noted that most of the sickness with propanidid and methohexitone was "emergence vomiting", that is, immediately after waking up. At this stage it could be more hazardous for the patient, but less unpleasant than prolonged vomiting. Analgesics. As long ago as 1955, anaesthetists in the U.S.A. were recommending the avoidance of narcotic premedication and Riding (1960) stressed the role of morphine as a cause of postoperative sickness. Morphine stimulates the CTZ and, although it depresses the vomiting centre, frequently causes nausea and vomiting by the former mechanism. It also decreases gastric motility and prolongs emptying time. In common with the other sideeffects of morphine, sickness is dose-related and its
severity continues to increase when the upper analgesic dose is reached. It is therefore desirable to restrict the dose to the minimum necessary. The majority of other analgesics also cause sickness, but it is notable that when morphine 10 mg and pethidine 100 mg (both with atropine 0.6 mg) are given as premedicants, the emetic effects of TABLE I. Ptrcenxage frequency of nausta and vomiting during the first 6h afur minor gynaecological surgery with atropint premedication and intermittent i.v. nitrous oxide-oxygen anaesthesia. (Data taken from partly unpublishedfiguresin the Department of Anaesthetics, The Queen's University of Belfast) Main anaesthetic Thiopentone 4 mg kg"' Methohexitone 1.6mgkg~' Propanidid 4 mg kg" Diazepam 0.6-0.8 mg kg"1 Althesin 50 fJ kg" 1 Ketamine 1.0-3.0mgkg~' Etomidate 0.3 mg kg*' Di-isopropyl phenol 2.0 mg kg ~'
Vomiting
Nausea
Nil
11 14 25 5 5 18 27 0
6 12 18 3 7 23 12 5
83 74 57 92 88 59 61 95
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Morphine
NAUSEA AND VOMITING
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ing drugs would act by preventing this. However, pharmacological evidence does not support this theory. Synthetic anticholinergic agents which have no central action have been shown to be ineffective in the prevention of motion sickness (Chinn and Smith, 1955). Glycopyrrolate is a quaternary amine with a long-acting antisialagogue action which causes a reduction in gastric volume and increase in pH (Mirakhur, Reid and Elliott, 1979) and, while it does not cause tachycardia, does effectively block the bradycardia of neostigmine (Mirakhur, Dundee and Clark, 1977). However, it has no central sedative action, indicating its inability to cross the blood-brain barrier, and Mirakhur and Dundee (1981) have shown that, when given to patients in combination with morphine, there is no less sickness than with morphine alone. ANTI-EMETIC DRUGS In contrast, atropine and hyoscine are tertiary These are used for the sympatomatic control of nausea and vomiting, but it is essential to make a amines which cross the blood-brain barrier, hyosdiagnosis before administration. It is axiomatic that cine being the more potent anti-emetic as anticithey are not given when there is a cause which can be pated from its more powerful central sedative aceliminated, but with motion sickness, vestibular tion. Hyoscine is usually given orally as the hydrodisorders, certain drug treatments or intoxications bromide (Scopolamine), 1 mg of which contains (for example pregnancy or uraemia,) it is clearly 0.7 mg of L-hyoscine base. Commercially available legitimate to give an anti-emetic. As with most drug tablets contain 0.3 mg, and two are the dose usually treatment, the choice is a balance between the most recommended for adults. This dose also causes sedaeffective drug for the type of sickness, and the one tion and dryness of the mouth, but pupillary dilatation and effects on the cardiac vagus are rare. The causing the least side-effects. The exact mode of action of the drugs is not drug is, however, poorly absorbed from the gastroalways known and (surprisingly) some appear to intestinal tract, a dose of 2.0mg by mouth being have two widely differing modes of action. All have approximately equipotent with 0.3 mg i.m. some central action on CTZ or the vomiting centre, (Mirakhur, 1978). Larger doses (1.0 mg i.m.) cause but some such as metoclopramide and the anti- blurring of vision by pupillary dilatation, bradycarcholinergics, accelerate gastric emptying. Others dia, mental confusion and urinary retention, espeof diverse chemical groups, including metoclop- cially in older people. The other central action of ramide and domperidone, increase the tone of the hyoscine is the production of anterograde amnesia, lower oesophageal sphincter. It is not always possi- and Pandit and Dundee (1970) confirmed this effect ble to predict the efficacy of an anti-emetic from its for 0-.4mg i.m., both when given alone and in pharmacological group and only well-controlled combination with diazepam or an opiate. studies in a particular type of clinical situation can provide reliable information. Atropine is more completely absorbed by the oral route since the ratio of oral to i.m. dose is only 2:1 compared with approximately 7:1 for hyoscine Parasympatholytic drugs—hyoscine and atropine This is the oldest group of anti-emetics and has (Mirakhur, 1978). It has a more marked peripheral been used for many centuries in the form of crude parasympatholytic action since 0.5 ing i.m. causes extracts of hyoscyamus or belladonna. Interest was tachycardia, dilatation of the pupil and inhibition of renewed during World War II and many drugs were secretions. This dose has little cortical action, but tried out in experimental situations to simulate the larger doses may cause mental confusion, as with motion of a ship or life-raft at sea. As described hyoscine. above, the vagus has an important role in initiating Both these drugs have a useful anti-emetic action vomiting and it might be assumed that vagal block- in anaesthetic practice and this should not be forgotpethidine occur mainly before operation and in the first hour after operation, whereas those of morphine persist for 6h or more after operation (fig. 1) (Dundee, Clark and Loan, 1965). Comparative studies (Dundee, Loan and Clarke, 1966; Loan, Dundee and Clarke, 1966) have shown that neither diamorphine nor papaveretum had any less emetic action than morphine, although the duration of action and side-effects of diamorphine were shorter. Certain synthetic analgesics, however, including dipipanone, dihydrocodeine, dextromoramide, and pentazocine may have a less marked emetic action in the period after operation (Dundee, Loan and Morrison, 1970). In addition these may be given by the oral route and, therefore, have a place as premedicants and in the ambulant patient.
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Phenothiazines
These are broadly anti-histamines, tranquillizers and sedatives and all of this group of drugs have some anti-emetic action (Dundee et al., 1965), chlorpromazine being one of the first to be used in the control of nausea and vomiting They appear to be particularly effective against drugs acting on the CTZ, while larger doses may also depress the vomiting centre. In general the group is best for the prevention of opiate-induced nausea and vomiting, but less effective against motion sickness and with no direct effect on gastric emptying. This group is of limited benefit in treating sickness from cytotoxic drugs (Seigel and Longo, 1981). The phenothiazines based on the piperazine ring, are more effective as anti-emetics than the other groups, but they carry a high risk of causing extrapyramidal effects. These are more likely when the drugs are repeated 6-8 hourly as the side-effect liability is cumulative and outlasts the anti-emetic
action. These effects, which occur with several different groups of anti-emetics, fall into four groups (Ayd, 1961;Dundee, Clarke and Carruthers, 1975): (1) Akathisia or motor restlessness may be described aptly as "the jitters"; the patient is unable to sit or lie still. While it frequently requires some days of continuous medication to develop, it has been seen following a single dose. (2) Acute dystonia involves painless spasmodic contractions of one or more muscle groups, producing trismus, torticollis and opisthotonos. The best known condition of this group is the oculogyric crisis during which the eyes, after being fixed in a stare, move to one side while the head tilts backward towards the same side. These are common in young males and it is particularly important to be aware of this condition in the differential diagnosis of tetanus. The history of drug administration and lack of pain are the main points in confirming their origin. (3) Pseudo-parkinsonism is characterized by immobility, muscular weakness and excessive salivation, while tremor is unusual. (4) Persistent "tardive" dyskinesia, like pseudoparkinsonism, is mainly a phenomenon of prolonged administration of these drugs for schizophrenia and both problems occur particularly in the elderly. All these side-effects subside with discontinuation of the drug therapy, but the acute episode can be terminated rapidly with promethazine (12.5mgi.v. + 12.5mgi.m.)—another phenothiazine, but lacking the incriminated piperazine ring. Perhaps the most important practical point is that extrapyramidal side-effects are much less common when the drugs are given in combination with opiates, as indeed they usually are. The anti-emetic efficacy of the phenothiazines is compared in figure 2, showing the greater effectiveness of those with a piperazine ring. Members of this group include perphenazine, prochlorperazine, thiethylperazine and trifluoperazine. Perphenazine (Fentazin) is the most widely used of this group, in a dose of 2.5-5 mgi.m. or2-4mg orally. It is effective i.m. as a prophylactic against the emetic effects of morphine 10 and 15mg or pethidine 100 mg when both opiate and anti-emetic are given together, but its action does not last as long as that of morphine (Dundee et al., 1975). The oral route is more commonly used for prevention of sickness in patients having radiotherapy or
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ten when their use as antisialagogues is Himinishing (Mirakhur et al., 1978). Their main role is probably to reduce the emetic action of the opiates, although these drugs are now often replaced by diazepam for sedation and aruriolysis before operation. Hyoscine 0.4mgi.m. and, to a lesser extent, atropine 0.6mgi.m., reduce the emetic effects of pethidine 100 mg or morphine 10 mg (Dundee, Moore and Clarke, 1964; Clarke, Dundee and Love, 1965) in the periods before and early after operation. However, the emetic action of morphine may last for at least 6h and the protective action of hyoscine or atropine is considerably shorter. The disadvantage of the use of hyoscine or atropine as anticholinergic anti-emetics is that they both decrease the tone of the lower oesophageal sphincter (Brock-Utne et al., 1977) and facilitate the reflux of gastric contents into the oesophagus. While the significance of these findings in the context of clinical vomiting is not clear, it is presumably desirable to use a drug such as metoclopramide which contracts the sphincter, in the preoperative patient. In summary, therefore, hyoscine is an effective anti-emetic, especially when sedative action is also required. Because it has less central action generally, atropine is a weaker anti-emetic. Both are effective by the oral route and both are more effective against vomiting than against nausea. Hyoscine may be given for prevention or treatment of motion sickness and labyrinthine disorders, but its sideeffects limit its usefulness.
BRITISH JOURNAL OF ANAESTHESIA
NAUSEA AND VOMITING
25 Post-operative emetic score
Pethidine 100 mg Atropine 0 6 mg plus
0.2
03
0.4
05
0.6
Average ndit
Promazine 50 mg Promazine 25 mg
Propiomazine 40 mg Propiomazine 20 mg Perptienazine 5 mg Thiethylperazine B m g Promethazme
50 mg
Promethazine
25 mg
Promethazme
10 mg
Promethazine 50 mg Hyoscine 0.4 mg
FIG. 2. Ridit analysis of the postoperative "emetic scores" following premedicant combinations as listed. (Reproduced by permission of the editor, British Journal of Anaathesia (from Dundee et al., 1965).)
chemotherapy, but with repeated dosage in the absence of an opiate the likelihood of toxic sideeffects is considerable.
Piperazines are closely related chemically to the phenothiazines, and cyclizine is the most effective and least toxic of the group. It is available in tablet form as the hydrochloride (Marzine) and in injectable form as the lactate (Valoid), the usual dose being 50 mg for an adult. It is absorbed rapidly from the gastrointestinal tract, its effect commencing in 15-30 min and lasting 3-6 h. It is used widely in the prevention of motion sickness or postoperative vomiting and Dundee and co-workers (1975) have demonstrated its efficacy when given with morphine or pethidine. Cyclizine 50 mg appears to be as effective as perphenazine 5 mg, but again its duration of action may be exceeded by that of morphine. It frequently causes drowsiness and drying of the mouth, but extrapyramidal effects are rare, apart from some restlessness with high or repeated doses. With high and repeated doses, teratogenic lesions have been found in rats, mice and rabbits, but several extensive studies when it was given in the management of morning sickness (McBride, 1963; Stalsberg, 1965; Midwinter, 1971) have not demonstrated these effects in man. Other drugs of this family include meclozine (Ancoloxin) buclizine (Equivert) and cinnarizine (Stugeron), but they have no clear advantages over the better known cyclizine.
Trifluoperazine (Stelazine) is used in a dose of 1-2 mg, but mainly in psychiatric practice.
Ethanolamines constitute a third group of antihistamines which is also anti-emetic. They include diphenhydramine hydrochloride (Benadryl), and dimenhydrinate (Dramamine, Gravol). They are more effective as. antdhistamines with significant atropine-like and sedative activity in the 50-mg oral dose. Unlike the phenothiazines, they have been used more in the prevention of travel sickness and vertigo and the fact that they are more likely to cause sedation than extrapyramidal effects makes them safer for use outside hospital. Dimenhydrinate is, however, less effective than hyoscine in prevention of motion sickness (Brand and Perry, 1966) while causing greater disturbance in co-ordination.
Promethazine (Phenergan) is used widely in a dose of 25-50 mg as a premedicant, singly and in combination with pethidine (Pamergan). It is a potent sedative and anti-emetic, but does cause some
Butyrophenona include haloperidol and droperidol, both powerful anti-emetics in clinical doses, but the high frequency of motor restlessness and anxiety when they are given alone prevents their use
Prochlorperazine (Stemetil; Compazine) is less potent than perphenazine and the effective dose is 5-20mgi.m. or oral. It is similar in action to perphenazine, although its lesser sedative action may commend it as an alternative. Thiethylperazine (Torecan) is available as a 10-mg tablet or injection and is indistinguishable clinically from the above. It is used mainly for the relief of dizziness and nausea in middle ear disturbances.
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Tnflupromazine 10 mg
restlessness and an increase in the excitatory effects of methohexitone anaesthesia (Dundee etal., 1965). It should be used only when the sedative action is required.
26
BRITISH JOURNAL OF ANAESTHESIA
for anti-emesis (Morrison, Clarke and Dundee, 1970; Patton, Moon and Dannemiller, 1974). Droperidol also has a sedative action and in conjunction with an opiate it may be used as a premedicant in doses of 2.5-5.0mgi.m., although there seems little place for a compound with such troublesome effects, outside the operating theatre or in treating the severe vomiting associated with cytotoxic therapy.
Domperidone (Motilium) is a benzimidazole derivative, chemically unrelated to the phenothiazines or butyrophenones, and experimental work showed
Chinn, H. I., and Smith, P. K. (1955). Motion sickness. Pharmacol. Rtv., 7, 33. dark, M. M., and Storrs, J. A. (1969). The prevention of postoperative vomiting after abortion: metoclopramide. Br. J. Anatsth., 41, 890.
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that it inhibited the CTZ and increased gastric emptying. Clinical studies (Fragen and Caldwell, 1978) in which domperidone 4 mg or 10 mg i.v. was given for treatment of established vomiting showed that it was significantly more effective than a placebo. Brock-Utne and his colleagues (1980), giving O^mgkg"1 to pregnant and non-pregnant patients, demonstrated an increase in the tone of the lower oesophageal sphincter which could contribute to this. However, the drug has a short duration of Metoclopramide (Maxolon) has the specific prop- action (2 - 4 h) and Wilson and Dundee (1979) found erty of hastening emptying of the stomach and that it was not effective as a prophylactic against movement along the upper gastrointestinal tract pethidine- or morphine-induced emesis when given (Jacoby and Brodie, 1967). It has also been shown to in a 10- or 15-mg dose with the opiate. inhibit both the vomiting centre and the CTZ and to The catmabmoids (THC) and particularly the increase the tone in the lower oesophageal sphincter synthetic derivative, nabilone, have recently been (Brock-Utne et al., 1978). It has been of particular evaluated (Vincent et al., 1983) as anti-emetics with value in radiology and gastroenterology, but its chemotherapy, but their high efficacy is marred by place in prevention of emesis after operation is less the expected side-effects. certain. Handley (1967), Clark and Storrs (1969) A useful hypothesis regarding anti-emetics by and Lind and Brcivik (1970) have demonstrated the Peroutka and Snyder (1982) made the point that all effectiveness of metoclopramide 10 and 20 mg these drugs block histamine Hi, muscarinic when given at the end of minor gynaecological cholinergic or dopamine D2 receptors and new adprocedures, but Ellis and Spence (1970) and Dun- vances might be achieved with a drug combining dee and Clarke (1973) found that it did not signific- these actions. antly reduce the frequency of sickness after operation. On the other hand, when given in combination REFERENCES with pethidine 100 mg, it does cause a significant Assaf, R. A. E., Clarke, R. S. J., Dundee, J. W\, and Samuel, I. reduction in the frequency of nausea and vomiting. O. (1974). Studies of drugs given before anaesthesia XXTV. Assaf and his colleagues (1974) accounted for some Metoclopramide with morphine and pethidine. Br. J. of the discrepancy by showing that it had a short Anatsth., 46,514. duration of action and was, therefore, of limited Ayd, J. jr (1961). A survey of drug-induced extrapyramidal reactions. / . A. M. A., 175, 1054. value against morphine-induced nausea or vomitB. J., Siebecker, K. L-, Steinhaus, J. E.,andOrth,O. ing. It is one of the least toxic of the anti-emetics, Bamforth, S. (1960). A clinical comparison of chloroform and halodiane although extrapyramidal symptoms, including by a blind study technique. Antsthtsiology, 21,273. oculogyric crises, have occurred following pro- Borison, H. L., and Wang, S. C. (1953). Physiology and pharmacology of vomiting. Pharmacol. Rto., 5,193. longed use. I.v. injection of normal doses may cause Brand, J. J., and Perry, W. L. M. (1966). Drugs used in motion restlessness. sickness. Pharmacol. Rtv., 18,895. Recently a new regimen of "high dose metoclop- Brock-Utne, J. G., Downing, J. W., Dimopoulos, G. E., Rubin, J., and Moshal, M. G. (1980). Effect of domperidone on lower ramide" has been advocated (Strum et al., 1982) for oesophageal sphincter tone in late pregnancy. Autsthtsiology, the treatment of cisplatin-induced emesis. The dos52,321. age studied has been up to 10 mg kg"1 over 24 h and Rubin, J., McAravey, R., Dow, T. G. B., Welman, S., while there have been sedation and the expected Dimopoulos, G. E., and Moshal, M. G. (1977). The effect of hyoscine and atropine on the lower oesophageal sphincter. side-effects, these were not clinically important. At Anaath. /nuns. Cart, 5,223. present this appears to be the most effective treatWelman, S., Dimopoulos, G. E., Moshal, M. G., and ment for this particularly intractable problem which Downing, J. W. (1978). The action of commonly used antimight otherwise have necessitated discontinuing fTnrrini on the lower oesophageal sphincter. Br. J. Anatstk., therapy. 50,295.
NAUSEA AND VOMITING
of drugs given before anaesthesia. XII: A comparison of papaveretum and morphine. Br. J. Anaath., 38, 891. l'in"H"i, K., and Holden.W.S. (1969). The act of vomiting in man. Gut, 10,173. McBride, W. (1963). Cydizine and congenital abnormalities, fir. Mtd.J., 1,1157. Midwinter, A. (1971). Vomiting in pregnancy. Practitioner, 206, 743. Mirakhur, R. K. (1978). Comparative study of the effects of oral and intramuscular atropine and hyoscine in volunteers. Br. J. Anatsth., 50, 591. Clarke, R. S. J., Dundee, J. W., and McDonald, J. R. (1978). Anticholinergic drugs in anaesthesia: a survey of their present position. Anatsthtsia, 33,133. Dundee, J. W. (1981). Lack of anti-emetic effect of glycopyrrolate. Anattthtsia, 36, 819. Clarke, R. S. J. (1977). Grycopyrrolate-neostigmine mixture for the antagonism of neuromuscular block: comparison with atropine-neostigmine mixture. Br. J. Anatsth., 49, 825. Reid, J., and Elliott, J. (1979). Volume and pH of gastric contents following anticholinergic premedication. Anatsthesia, 34,453. Morrison, J. D., Clarke, R. S. J., and Dundee, J. W. (1970). Studies of drug given before anaesthesia. XXI: Droperidol. Br. J. Anatsth., 42,730. Novoa, R. R. (1960). The anti-emetic action of Fluothane: a comparative study in obstetrical anaesthesia. Can. Anatsth. Soc.J., 7,109. Pandit, S. K., and Dundee, J. W. (1980). Pieopci alive amnnria: the incidence following the intramuscular injection of commonly used premedkants. Anatsthtsia, 25, 493. Patton, C M . , Moon, M. R., and Dannemiller, F. J. (1974). The prophylactic antiemetic effect of droperidol. Antsth. Analg., 53,361. Peroutka, S. J., and Snyder, S. H. (1982). Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lanctt, 1,658. Riding, J. E. (1960). Postoperative vomiting. Proc. R. Soc. Mtd., 53,671. Seigel, L. J., and Longo, D. L. (1981). The control of chemotherapy induced emesis. Ann. Intern. Mtd., 95, 352. Stalsberg, H. (1965). Antiemetics and congenital deformities—meclozine, cydizine, and chlorcyclizine. Norwegian Mtd. /.,85,1840. Strum, S. B., McDermed, J. E., Opfell, R. W.,and Riech, L. P. (1982). Intravenous metoclopramide. An effective antiemetic in cancer chemotherapy. J.A.M.A., 247,2683. Vincent, B. J., McQuiston, D. J., Einhom, L. H.,Nagy,C. M., and Brames, M. J. (1983). Review of cannabinoids and their antiemetic effectiveness. Drugs, 25, (Suppl. 1), 52. Wilson, D. B., and Dundee, J. W. (1979). Evaluation of the anti-emetic action of domperidone. Anaesthtsia, 34,765.
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Clarke, R. S. J., Dundee, J. W., and Love, W. J. (1965). Studies of drugs given before anaesthesia. Vlll: Morphine alone and with atropine or hyoscine. Br.J. Anatsth.,37,772. Datta, S., Alper, M. M., Ostheimer, G. W., and Weiss, J. B. (1982). Methods of ephedrine administration and M"iw and hypotension during spinal anesthesia for Cesarean section. Antsthtsiotogy, 56,68. Dundee, J. W., Assaf, R. A. E., Loan, W. B., and Morrison, J. D. (1975). A comparison of the efficacy of cydizine and pcrphenazine in reducing the emetic effects of morphine and pethidine. Br. J. Clm. Pharmacol., 2,81. Clarke, R. S. J. (1973). The premedtcant and antiemetic action of metoclopramide. Postgrad. Mtd. J., 48, 34. Carruthers, S. G. (1975). Drug-induced extrapyramidaldisorders. PrtscribtrsJ., 15, 26. Loan, W. B. (1965). A comparison of the sedative and toxic effects of morphine and pethidine. Lanctt, 2,1262. Kirwan, M. J., and Clarke, R. S. J. (1965). Anaesthesia and premedication as factors in post-operative vomiting. Aaa Anatsthtsiol. Scand., 9,223. Loan.W. B., and Clarke, R . S . J . (1966). Studies of drugs given before anaesthesia. XI: Diamorphine (Heroin) and morphine. Br. J. Anatsth., 38,610. Morrison, J. D. (1970). Studies of drugs given before anaesthesia. XEX: The opiates. Br. J. Anatsth., 42, 54. Moore, J., and Clarke, R. S. J. (1964). Studies of drugs given before anaesthesia. V: Pethidine 100 mg alone and with atropine or hyoscine. Br. J. Anatsth., 36, 703. Nicholl.R.M., Clarke, R.S.J., Moore, J., and Love, W.J. (1965). Studies of drugs given before anaesthesia. VII: Pethidine and phenothiazine combinations. Br. J. Anaesth., 37,601. Ellis, F. R., and Spence, A. A. (1970). Clinical trials of metoclopramide (Mazolon) as an antiemetic in anaesthesia. Anatsthtsia, 25,368. Fragen, R. J., and Caldwell, N. (1978). A new benzimidazole antiemetic, domperidone, for the treatment of postoperative nausea and vomiting. Antsthtsiology, 49, 289. Glaser, E. M. (1959). Prevention and treatment of motion sickness. Proc. R. Soc. Mtd., 52,965. Gold, M. I. (1969). Post-anaesthetic vomiting in the recovery room. Br. J. Anatsth., 41,143. Handley, A. J. (1967). Metoclopramide in the prevention of postoperative nausea and vomiting. Br. J. CUn. Pract., 21,460. Haumann, J. le R., and Foster, P. A. (1963). The anti-emetic effect of halothane. Br. J. Anatsth., 35,114. Hunt, J. N. (1959). Gastric emptying and secretion in man. Physiol. Rev., 39,491. Jacoby, H. I., and Brodie, D. A. (1967). Gastrointestinal effects of metoclopramide. Gastrotnterology, 52, 676. Iind, B., and Breivik, H. (1970). Metoclopramide and perphiinr>™«- Ln the prevention of postoperative nausea and vomiting. Br. J. Anatsth., 42,614. Loan, W. B., Dundee, J. W., and Clarke, R. S. J. (1966). Studies
27
NAUSEA AND VOMITING R. S.J.CLARKE nasopharynx. At this stage, a sudden contraction of the abdominal muscles causes a sharp increase in intrathoracic and intra-abdominal pressure, which in turn is transmitted to the stomach. If the glottis is not closed completely at this stage, forcing of air through it causes the high-pitched sound associated with retching or vomiting. The oesophagus, lower oesophageal sphincter and body of the stomach now relax and there is a strong contraction of the gastric antrum, shifting contents into the upper stomach. Secretion of hydrochloric acid is inhibited although secretion of mucus is increased. There are rapid segmental contractions and later spasms occur in the duodenum and jejunum (but not anti-peristalsis), resulting in forcing up their contents into the The events of vomiting Vomiting may be defined as the forceful expul- stomach. Even the colon may contract during vomsion of gastric or intestinal contents through the iting, but it is rare for ileal or colonic contents to be mouth. The word forceful distinguishes it from the expelled. These intestinal movements appear to be passive regurgitation which occurs in infants or mediated by the vagus as they are abolished by vagal comatose individuals in whom the lower oesophage- section and unaffected by sympathetic denervation. al sphincter may be partly relaxed. It is preceded in The effect of all the intra-abdominal contractions man by a sensation of nausea and retching, but in the against a lowered diaphragm is to force food through infant or in animals under direct stimulation of the the open sphincter and into a relaxed oesophagus. It vomiting centre, projectile vomiting may occur, may not pass further if the inferior constrictor of the unaccompanied by any apparent discomfort or au- pharynx is closed, resulting in abortive retching and tonomic disturbance. In man also, vomiting caused return of the material to the stomach. However, by increased intracranial pressure is not preceded by after several episodes of this when the pharyngeal nausea. The usual precursors in adult man are copi- sphincter does relax, forceful propulsion of stomach ous salivation, swallowing, sweating, pallor and contents through the mouth occurs. The cycle may tachycardia, related presumably to the close prox- be repeated several times before the abdominal musimity of the autonomic centres in the medulla. cles relax and respiration is resumed. Respiration may also be laboured, with the mouth The control of this complicated group of activities partly or entirely closed. The experienced observer involves co-ordination of both striated and visceral learns to recognize these signs in a patient and some muscle in an essentially involuntary activity. This is last-minute action may be taken to prevent vomiting managed through the vomiting centre in the lateral or at least reduce the undesirable consequences. reticular formation deep in the medulla. Stimulation The mechanism of vomiting has been studied by of this area in experimental animals results in a sharp the use of radiography (Lumsden and Holden, inspiration and immediate vomiting, which ceases 1969). There is first a deep inspiration as the diaph- as stimulation ceases. Such vomiting is projectile in ragm moves downwards with closure of the glottis type without concomitant retching (or presumably, and elevation of the soft palate to occlude the nausea). The vomiting centre in turn is influenced by psychic factors, the vestibular nucleus, the Chemoreceptor Trigger Zone (CTZ) and sensory R. S. J. CLARKE, M.D., PH.D., F.F.A.R.CS., Department of afferents from pharynx, gastrointestinal tract or Anaesthetics, The Queen's University of Belfast, Northern genitalia. The CTZ (Borison and Wang, 1953), Ireland. © The Mtcmillan Press Ltd 1984
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Vomiting has long been regarded as one of the most unpleasant aspects of anaesthesia. In addition, it is a feature of many medical and surgical conditions and of travel by land, sea and air. Its effects range from the simply annoying, to life-threatening electrolyte upset. The choice of a cytotoxic drug or the alternative of radiotherapy may be determined by the likelihood of vomiting rather than efficacy against the neoplasm. All these aspects are of importance to the anaesthetist and this review describes the mechanisms and physiology of vomiting, in addition to the pharmacology of its causes and means of prevention.
20
TTte effects of vomiting
The most worrying effect to the anaesthetist is the possibility of aspiration of stomach content into the trachea. It is usually believed that true vomiting is unlikely to be aspirated because the laryngeal reflex ensures against soiling of the respiratory tract. However, there is clearly an intermediate zone of hazard if the patient is supine following an injury or a surgical operation, when impaired reflexes are unable to protect the trachea. In these patients, prevention of active vomiting is useful in addition to prevention of regurgitation or aspiration, although impractical in the emergency situation. Prolonged vomiting is a feature of many patients coming for surgery and its effects depend on the main substances which are lost. Gastric juice has two components—the mucus secretion of the surface epithelial cells and the acid secretion of the parietal or oxyntic cells. The former has a pH of approximately 7.7 and electrolyte components (mmol litre"1) are: Na + = 150-160, K + = 10-20, Ca+ = 3-4, Cl = 125, HCO3 = 35 (Hunt, 1959). The composition of the acid secretion is less certain because there is nearly always some admixture with mucus. It does seem, however, that at high rates of secretion it approximates to an isotonic solution of pure hydrochloric acid with a small quantity of potassium and sodium chlorides. At high rates of secretion, as when stimulated by histamine, the acidity is high and as the rate diminishes there is an increase in the relative proportion of Na+ to H + . Gastric juice is isotonic with plasma and when it is secreted H + and Cl~ are removed from plasma, together with enough water for isotonicity. However, the H + is manufactured by the mucosa and HCO3~ reabsorbed to balance the Cl~ secreted so
that, overall, water is lost from the plasma in this phase of digestion, with an increase in tonicity. Normally, the whole gastric juice is reabsorbed in the intestine but, if not, as in prolonged vomiting, the loss of water is an important effect as part of an overall extracellular dehydration. However, water is usually the easiest substance to replace and, if replaced, loss of ions becomes the more notable effect of vomiting. The loss of H+ in continual vomiting leads to a gradual increase of HCO3" in the plasma (metabolic alkalosis). The excess of HCO3~ is excreted by the kidney, in the initial phase at least. However, the other electrolyte changes conflict with the renal compensation and limit its effectiveness. There is some loss of Na+ in the gastric juice and the proportion to H + depends on the acidity of the juice. As vomiting continues, the acidity of gastric juice is reduced and the loss of Na+ increases, until the latter becomes a limiting factor. Loss of Cl" is always severe because it is the anion associated with H + or Na+ and cannot be spared while gastric juice is secreted. Potassium is present in gastric juice in a concentration at least twice that of plasma, but the main reason for hypokalaemia in prolonged vomiting is the selective excretion of K+ in the renal tubules as H + is conserved. The result is depletion of extracellular and later intracellular potassium, which cannot easily be assessed by blood sampling. It can be assumed, however, in treating any patient with metabolic alkalosis losing gastric juice, even though plasma potassium concentration is within normal limits. Causes of nausea and vomiting
Motion sickness (Glaser, 1959) results essentially from actions on the vestibular apparatus of the ear. Patients with congenital inner ear deafness or destruction of the vestibular apparatus do not suffer. The stimulus appears to be a sequence of bursts of linear acceleration which set the endolymph in the semicircular canals in motion, resulting in the stimulation of the otoliths in the utricle. Waves of impulses pass back by the vestibular part of the eighth nerve to the chemoreceptor trigger zone in the medulla, with relays to the cerebral cortex involving nausea and to the cerebellum and vomiting centre for the motor response. Destruction of the CTZ eliminates the response to centrally applied emetics and the vomiting accompanying uraemia, radiation sickness and motion sickness.
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which is in the floor of the fourth ventricle, is probably the most important to anaesthetists for drugs do not act on the vomiting centre directly, but rather on this distinct medullary area. Electrical stimulation of this area does not cause vomiting, although stimulation of the vomiting centre itself is effective. Likewise, ablation of the CTZ in the dog prevents the emetic response to apomorphine, opiates and digoxin. All these areas will be considered separately but they often summate, as for instance, in postoperative sickness in gynaecology, where the analgesic, the stimulus of cervical dilatation, the movement of sitting up and the thought of eating even a light meal, may be enough to provoke active vomiting.
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NAUSEA AND VOMITING
peripherally as it does not readily penetrate the blood-brain barrier. Anaesthesia and analgesia form the causes of sickness which most concern the anaesthetist and which are still not entirely eliminated. The non-drugrelated components have been discussed already, but the various groups of drugs implicated merit separate discussion. Inhalation
anaesthetics.
The
older
volatile
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The role of the cerebral cortex in initiating vomiting has been mentioned but, conversely, sufficient mental distraction may also inhibit the reflex. Habituation may eventually terminate motion sickness so that it becomes less likely in those who travel regularly by the same type of vehicle. Certain other measures also reduce the risk of vomiting in susceptible individuals, for example lying down to reduce vestibular stimulation or looking at the sky or vessel wall to avoid rhythmical visual stimulation from a moving horizon. Other labyrinthine disorders come into the same group, including the vertigo and nausea associated with Meniere's disease and middle ear surgery.
21
anaesthetics, diethyl ether and chloroform, were notorious for their prolonged emetic action, lasting in many for more than 12 h. There are few comparative figures for halothane and the older agents, but Bamforth and his colleagues (1960) in a small series Sensory stimulation, either somatic as from tactile found chloroform to be much more emetic than stimulation of the back of the throat or stretch halothane. Dundee, Kirwan and Clarke (1965) pubresponses from one of the viscera can initiate nausea lished a comparison in minor gynaecological surgery or vomiting. The visceral group include distension of different anaesthetic agents and the influence of of or injury to the uterine cervix, renal pelvis or premedication (fig. 1). Intermittent thiopentone bladder, injury to the testes or a blow to the upper was followed by significantly fewer sequelae than abdomen, in addition to many inflammatory condi- halothane during the first hour after anaesthesia, tions within the abdomen. although the difference was entirely in respect of nausea. Cyclopropane caused much more sickness Metabolic disturbances or intoxications includein the first hour than the other drugs tested. Howhyperemesis gravidarum, radiation therapy, ever, it is notable that overall, less than 5% of uraemia and hypo- or hyper-glycaemia, and it seems patients were still vomiting 1 h after operation in the that these are mediated through the CTZ, as in the absence of premedication. Gold (1969) also showed case of motion sickness. that in more than 1000 gynaecological patients cyclopropane was associated with significantly more Increased intracranial pressure acts presumably by sickness than were halothane or thiopentone direct stimulation of the vomiting centre in the nitrous oxide -oxygen. It was also seen that thiopenmedulla. tone induction followed by a primary inhalation agent was associated with a smaller frequency of Spinal anaesthesia is commonly accompanied by emesis than was induction with the inhalation agent nausea and vomiting and it has been suggested that alone. Emphasizing the lack of sickness after this is a result of the accompanying hypotension. halothane anaesthesia, some workers (Novoa, 1960; Recently Datta and his colleagues (1982) have con- Haumann and Foster, 1963) have actually demonfirmed this relationship and shown that, if the arteri- strated an anti-emetic effect from it, for instance al pressure was maintained after the spinal anaesthe- when it was added to trichloroethylene anaesthesia. tic by immediate administration of ephedrine i.v., there was no significant hypotension. The frequenI.v. anaesthetics. The study by Dundee, Kirwan cy of nausea and vomiting was then similar (10%) to and Clarke (1965) showed that anaesthesia with that in the control group whose pressure remained intermittent thiopentone and nitrous oxide, for unchanged, compared with 66% in the hypotensive minor gynaecological surgery, was followed by group whose treatment was delayed. nausea or vomiting in approximately 12% of patients. The frequency following propanidid is apCytotoxic drugs cause severe nausea and vomiting proximately 38%. Table I analyses the percentage of in a high proportion of patients and this has been patients vomiting in the first 6h after the eight largely ignored until recent years (Seigel and Longo, principal i.v. anaesthetics given under standard con1981). The CTZ has been implicated with some of ditions. It appears that drugs with a moderately slow the drugs, but cisplatin at least appears to act and smooth recovery, for example diazepam, di-
BRITISH JOURNAL OF ANAESTHESIA
22 1st hour
1-6h
Premedication 2O
4O
6O
O
2O
4O
Anaesthetic 6O
Atropine J Thiopentone J Propanidid J Cyclopropane J Halothane Atropine Thiopentone Propanidid Cyclopropane Halothane Pethidme Atropine Thiopentone Propanidid Cyclopropane Halothane FIG. 1. The emetic sequelae of anaesthesia with four different anaesthetics and three premedicants, the patients being seen 1 and 6 h after surgery. Dark area - vomiting; hatched area - nausea only. (Reproduced by permission of the editor, Acta Anaesthtsiologica Scandinamca, from Dundee, Kirwan and Clarke, 1965.)
isopropyl phenol, Althesin and thiopentone, have an acceptably low frequency of sickness. A high frequency of excitatory effects during or after anaesthesia (etomidate and ketamine) and rapid recovery (propanidid and methohexitone) are associated with frequent sickness after operation. However, it was noted that most of the sickness with propanidid and methohexitone was "emergence vomiting", that is, immediately after waking up. At this stage it could be more hazardous for the patient, but less unpleasant than prolonged vomiting. Analgesics. As long ago as 1955, anaesthetists in the U.S.A. were recommending the avoidance of narcotic premedication and Riding (1960) stressed the role of morphine as a cause of postoperative sickness. Morphine stimulates the CTZ and, although it depresses the vomiting centre, frequently causes nausea and vomiting by the former mechanism. It also decreases gastric motility and prolongs emptying time. In common with the other sideeffects of morphine, sickness is dose-related and its
severity continues to increase when the upper analgesic dose is reached. It is therefore desirable to restrict the dose to the minimum necessary. The majority of other analgesics also cause sickness, but it is notable that when morphine 10 mg and pethidine 100 mg (both with atropine 0.6 mg) are given as premedicants, the emetic effects of TABLE I. Ptrcenxage frequency of nausta and vomiting during the first 6h afur minor gynaecological surgery with atropint premedication and intermittent i.v. nitrous oxide-oxygen anaesthesia. (Data taken from partly unpublishedfiguresin the Department of Anaesthetics, The Queen's University of Belfast) Main anaesthetic Thiopentone 4 mg kg"' Methohexitone 1.6mgkg~' Propanidid 4 mg kg" Diazepam 0.6-0.8 mg kg"1 Althesin 50 fJ kg" 1 Ketamine 1.0-3.0mgkg~' Etomidate 0.3 mg kg*' Di-isopropyl phenol 2.0 mg kg ~'
Vomiting
Nausea
Nil
11 14 25 5 5 18 27 0
6 12 18 3 7 23 12 5
83 74 57 92 88 59 61 95
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Morphine
NAUSEA AND VOMITING
23
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ing drugs would act by preventing this. However, pharmacological evidence does not support this theory. Synthetic anticholinergic agents which have no central action have been shown to be ineffective in the prevention of motion sickness (Chinn and Smith, 1955). Glycopyrrolate is a quaternary amine with a long-acting antisialagogue action which causes a reduction in gastric volume and increase in pH (Mirakhur, Reid and Elliott, 1979) and, while it does not cause tachycardia, does effectively block the bradycardia of neostigmine (Mirakhur, Dundee and Clark, 1977). However, it has no central sedative action, indicating its inability to cross the blood-brain barrier, and Mirakhur and Dundee (1981) have shown that, when given to patients in combination with morphine, there is no less sickness than with morphine alone. ANTI-EMETIC DRUGS In contrast, atropine and hyoscine are tertiary These are used for the sympatomatic control of nausea and vomiting, but it is essential to make a amines which cross the blood-brain barrier, hyosdiagnosis before administration. It is axiomatic that cine being the more potent anti-emetic as anticithey are not given when there is a cause which can be pated from its more powerful central sedative aceliminated, but with motion sickness, vestibular tion. Hyoscine is usually given orally as the hydrodisorders, certain drug treatments or intoxications bromide (Scopolamine), 1 mg of which contains (for example pregnancy or uraemia,) it is clearly 0.7 mg of L-hyoscine base. Commercially available legitimate to give an anti-emetic. As with most drug tablets contain 0.3 mg, and two are the dose usually treatment, the choice is a balance between the most recommended for adults. This dose also causes sedaeffective drug for the type of sickness, and the one tion and dryness of the mouth, but pupillary dilatation and effects on the cardiac vagus are rare. The causing the least side-effects. The exact mode of action of the drugs is not drug is, however, poorly absorbed from the gastroalways known and (surprisingly) some appear to intestinal tract, a dose of 2.0mg by mouth being have two widely differing modes of action. All have approximately equipotent with 0.3 mg i.m. some central action on CTZ or the vomiting centre, (Mirakhur, 1978). Larger doses (1.0 mg i.m.) cause but some such as metoclopramide and the anti- blurring of vision by pupillary dilatation, bradycarcholinergics, accelerate gastric emptying. Others dia, mental confusion and urinary retention, espeof diverse chemical groups, including metoclop- cially in older people. The other central action of ramide and domperidone, increase the tone of the hyoscine is the production of anterograde amnesia, lower oesophageal sphincter. It is not always possi- and Pandit and Dundee (1970) confirmed this effect ble to predict the efficacy of an anti-emetic from its for 0-.4mg i.m., both when given alone and in pharmacological group and only well-controlled combination with diazepam or an opiate. studies in a particular type of clinical situation can provide reliable information. Atropine is more completely absorbed by the oral route since the ratio of oral to i.m. dose is only 2:1 compared with approximately 7:1 for hyoscine Parasympatholytic drugs—hyoscine and atropine This is the oldest group of anti-emetics and has (Mirakhur, 1978). It has a more marked peripheral been used for many centuries in the form of crude parasympatholytic action since 0.5 ing i.m. causes extracts of hyoscyamus or belladonna. Interest was tachycardia, dilatation of the pupil and inhibition of renewed during World War II and many drugs were secretions. This dose has little cortical action, but tried out in experimental situations to simulate the larger doses may cause mental confusion, as with motion of a ship or life-raft at sea. As described hyoscine. above, the vagus has an important role in initiating Both these drugs have a useful anti-emetic action vomiting and it might be assumed that vagal block- in anaesthetic practice and this should not be forgotpethidine occur mainly before operation and in the first hour after operation, whereas those of morphine persist for 6h or more after operation (fig. 1) (Dundee, Clark and Loan, 1965). Comparative studies (Dundee, Loan and Clarke, 1966; Loan, Dundee and Clarke, 1966) have shown that neither diamorphine nor papaveretum had any less emetic action than morphine, although the duration of action and side-effects of diamorphine were shorter. Certain synthetic analgesics, however, including dipipanone, dihydrocodeine, dextromoramide, and pentazocine may have a less marked emetic action in the period after operation (Dundee, Loan and Morrison, 1970). In addition these may be given by the oral route and, therefore, have a place as premedicants and in the ambulant patient.
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Phenothiazines
These are broadly anti-histamines, tranquillizers and sedatives and all of this group of drugs have some anti-emetic action (Dundee et al., 1965), chlorpromazine being one of the first to be used in the control of nausea and vomiting They appear to be particularly effective against drugs acting on the CTZ, while larger doses may also depress the vomiting centre. In general the group is best for the prevention of opiate-induced nausea and vomiting, but less effective against motion sickness and with no direct effect on gastric emptying. This group is of limited benefit in treating sickness from cytotoxic drugs (Seigel and Longo, 1981). The phenothiazines based on the piperazine ring, are more effective as anti-emetics than the other groups, but they carry a high risk of causing extrapyramidal effects. These are more likely when the drugs are repeated 6-8 hourly as the side-effect liability is cumulative and outlasts the anti-emetic
action. These effects, which occur with several different groups of anti-emetics, fall into four groups (Ayd, 1961;Dundee, Clarke and Carruthers, 1975): (1) Akathisia or motor restlessness may be described aptly as "the jitters"; the patient is unable to sit or lie still. While it frequently requires some days of continuous medication to develop, it has been seen following a single dose. (2) Acute dystonia involves painless spasmodic contractions of one or more muscle groups, producing trismus, torticollis and opisthotonos. The best known condition of this group is the oculogyric crisis during which the eyes, after being fixed in a stare, move to one side while the head tilts backward towards the same side. These are common in young males and it is particularly important to be aware of this condition in the differential diagnosis of tetanus. The history of drug administration and lack of pain are the main points in confirming their origin. (3) Pseudo-parkinsonism is characterized by immobility, muscular weakness and excessive salivation, while tremor is unusual. (4) Persistent "tardive" dyskinesia, like pseudoparkinsonism, is mainly a phenomenon of prolonged administration of these drugs for schizophrenia and both problems occur particularly in the elderly. All these side-effects subside with discontinuation of the drug therapy, but the acute episode can be terminated rapidly with promethazine (12.5mgi.v. + 12.5mgi.m.)—another phenothiazine, but lacking the incriminated piperazine ring. Perhaps the most important practical point is that extrapyramidal side-effects are much less common when the drugs are given in combination with opiates, as indeed they usually are. The anti-emetic efficacy of the phenothiazines is compared in figure 2, showing the greater effectiveness of those with a piperazine ring. Members of this group include perphenazine, prochlorperazine, thiethylperazine and trifluoperazine. Perphenazine (Fentazin) is the most widely used of this group, in a dose of 2.5-5 mgi.m. or2-4mg orally. It is effective i.m. as a prophylactic against the emetic effects of morphine 10 and 15mg or pethidine 100 mg when both opiate and anti-emetic are given together, but its action does not last as long as that of morphine (Dundee et al., 1975). The oral route is more commonly used for prevention of sickness in patients having radiotherapy or
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ten when their use as antisialagogues is Himinishing (Mirakhur et al., 1978). Their main role is probably to reduce the emetic action of the opiates, although these drugs are now often replaced by diazepam for sedation and aruriolysis before operation. Hyoscine 0.4mgi.m. and, to a lesser extent, atropine 0.6mgi.m., reduce the emetic effects of pethidine 100 mg or morphine 10 mg (Dundee, Moore and Clarke, 1964; Clarke, Dundee and Love, 1965) in the periods before and early after operation. However, the emetic action of morphine may last for at least 6h and the protective action of hyoscine or atropine is considerably shorter. The disadvantage of the use of hyoscine or atropine as anticholinergic anti-emetics is that they both decrease the tone of the lower oesophageal sphincter (Brock-Utne et al., 1977) and facilitate the reflux of gastric contents into the oesophagus. While the significance of these findings in the context of clinical vomiting is not clear, it is presumably desirable to use a drug such as metoclopramide which contracts the sphincter, in the preoperative patient. In summary, therefore, hyoscine is an effective anti-emetic, especially when sedative action is also required. Because it has less central action generally, atropine is a weaker anti-emetic. Both are effective by the oral route and both are more effective against vomiting than against nausea. Hyoscine may be given for prevention or treatment of motion sickness and labyrinthine disorders, but its sideeffects limit its usefulness.
BRITISH JOURNAL OF ANAESTHESIA
NAUSEA AND VOMITING
25 Post-operative emetic score
Pethidine 100 mg Atropine 0 6 mg plus
0.2
03
0.4
05
0.6
Average ndit
Promazine 50 mg Promazine 25 mg
Propiomazine 40 mg Propiomazine 20 mg Perptienazine 5 mg Thiethylperazine B m g Promethazme
50 mg
Promethazine
25 mg
Promethazme
10 mg
Promethazine 50 mg Hyoscine 0.4 mg
FIG. 2. Ridit analysis of the postoperative "emetic scores" following premedicant combinations as listed. (Reproduced by permission of the editor, British Journal of Anaathesia (from Dundee et al., 1965).)
chemotherapy, but with repeated dosage in the absence of an opiate the likelihood of toxic sideeffects is considerable.
Piperazines are closely related chemically to the phenothiazines, and cyclizine is the most effective and least toxic of the group. It is available in tablet form as the hydrochloride (Marzine) and in injectable form as the lactate (Valoid), the usual dose being 50 mg for an adult. It is absorbed rapidly from the gastrointestinal tract, its effect commencing in 15-30 min and lasting 3-6 h. It is used widely in the prevention of motion sickness or postoperative vomiting and Dundee and co-workers (1975) have demonstrated its efficacy when given with morphine or pethidine. Cyclizine 50 mg appears to be as effective as perphenazine 5 mg, but again its duration of action may be exceeded by that of morphine. It frequently causes drowsiness and drying of the mouth, but extrapyramidal effects are rare, apart from some restlessness with high or repeated doses. With high and repeated doses, teratogenic lesions have been found in rats, mice and rabbits, but several extensive studies when it was given in the management of morning sickness (McBride, 1963; Stalsberg, 1965; Midwinter, 1971) have not demonstrated these effects in man. Other drugs of this family include meclozine (Ancoloxin) buclizine (Equivert) and cinnarizine (Stugeron), but they have no clear advantages over the better known cyclizine.
Trifluoperazine (Stelazine) is used in a dose of 1-2 mg, but mainly in psychiatric practice.
Ethanolamines constitute a third group of antihistamines which is also anti-emetic. They include diphenhydramine hydrochloride (Benadryl), and dimenhydrinate (Dramamine, Gravol). They are more effective as. antdhistamines with significant atropine-like and sedative activity in the 50-mg oral dose. Unlike the phenothiazines, they have been used more in the prevention of travel sickness and vertigo and the fact that they are more likely to cause sedation than extrapyramidal effects makes them safer for use outside hospital. Dimenhydrinate is, however, less effective than hyoscine in prevention of motion sickness (Brand and Perry, 1966) while causing greater disturbance in co-ordination.
Promethazine (Phenergan) is used widely in a dose of 25-50 mg as a premedicant, singly and in combination with pethidine (Pamergan). It is a potent sedative and anti-emetic, but does cause some
Butyrophenona include haloperidol and droperidol, both powerful anti-emetics in clinical doses, but the high frequency of motor restlessness and anxiety when they are given alone prevents their use
Prochlorperazine (Stemetil; Compazine) is less potent than perphenazine and the effective dose is 5-20mgi.m. or oral. It is similar in action to perphenazine, although its lesser sedative action may commend it as an alternative. Thiethylperazine (Torecan) is available as a 10-mg tablet or injection and is indistinguishable clinically from the above. It is used mainly for the relief of dizziness and nausea in middle ear disturbances.
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Tnflupromazine 10 mg
restlessness and an increase in the excitatory effects of methohexitone anaesthesia (Dundee etal., 1965). It should be used only when the sedative action is required.
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BRITISH JOURNAL OF ANAESTHESIA
for anti-emesis (Morrison, Clarke and Dundee, 1970; Patton, Moon and Dannemiller, 1974). Droperidol also has a sedative action and in conjunction with an opiate it may be used as a premedicant in doses of 2.5-5.0mgi.m., although there seems little place for a compound with such troublesome effects, outside the operating theatre or in treating the severe vomiting associated with cytotoxic therapy.
Domperidone (Motilium) is a benzimidazole derivative, chemically unrelated to the phenothiazines or butyrophenones, and experimental work showed
Chinn, H. I., and Smith, P. K. (1955). Motion sickness. Pharmacol. Rtv., 7, 33. dark, M. M., and Storrs, J. A. (1969). The prevention of postoperative vomiting after abortion: metoclopramide. Br. J. Anatsth., 41, 890.
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that it inhibited the CTZ and increased gastric emptying. Clinical studies (Fragen and Caldwell, 1978) in which domperidone 4 mg or 10 mg i.v. was given for treatment of established vomiting showed that it was significantly more effective than a placebo. Brock-Utne and his colleagues (1980), giving O^mgkg"1 to pregnant and non-pregnant patients, demonstrated an increase in the tone of the lower oesophageal sphincter which could contribute to this. However, the drug has a short duration of Metoclopramide (Maxolon) has the specific prop- action (2 - 4 h) and Wilson and Dundee (1979) found erty of hastening emptying of the stomach and that it was not effective as a prophylactic against movement along the upper gastrointestinal tract pethidine- or morphine-induced emesis when given (Jacoby and Brodie, 1967). It has also been shown to in a 10- or 15-mg dose with the opiate. inhibit both the vomiting centre and the CTZ and to The catmabmoids (THC) and particularly the increase the tone in the lower oesophageal sphincter synthetic derivative, nabilone, have recently been (Brock-Utne et al., 1978). It has been of particular evaluated (Vincent et al., 1983) as anti-emetics with value in radiology and gastroenterology, but its chemotherapy, but their high efficacy is marred by place in prevention of emesis after operation is less the expected side-effects. certain. Handley (1967), Clark and Storrs (1969) A useful hypothesis regarding anti-emetics by and Lind and Brcivik (1970) have demonstrated the Peroutka and Snyder (1982) made the point that all effectiveness of metoclopramide 10 and 20 mg these drugs block histamine Hi, muscarinic when given at the end of minor gynaecological cholinergic or dopamine D2 receptors and new adprocedures, but Ellis and Spence (1970) and Dun- vances might be achieved with a drug combining dee and Clarke (1973) found that it did not signific- these actions. antly reduce the frequency of sickness after operation. On the other hand, when given in combination REFERENCES with pethidine 100 mg, it does cause a significant Assaf, R. A. E., Clarke, R. S. J., Dundee, J. W\, and Samuel, I. reduction in the frequency of nausea and vomiting. O. (1974). Studies of drugs given before anaesthesia XXTV. Assaf and his colleagues (1974) accounted for some Metoclopramide with morphine and pethidine. Br. J. of the discrepancy by showing that it had a short Anatsth., 46,514. duration of action and was, therefore, of limited Ayd, J. jr (1961). A survey of drug-induced extrapyramidal reactions. / . A. M. A., 175, 1054. value against morphine-induced nausea or vomitB. J., Siebecker, K. L-, Steinhaus, J. E.,andOrth,O. ing. It is one of the least toxic of the anti-emetics, Bamforth, S. (1960). A clinical comparison of chloroform and halodiane although extrapyramidal symptoms, including by a blind study technique. Antsthtsiology, 21,273. oculogyric crises, have occurred following pro- Borison, H. L., and Wang, S. C. (1953). Physiology and pharmacology of vomiting. Pharmacol. Rto., 5,193. longed use. I.v. injection of normal doses may cause Brand, J. J., and Perry, W. L. M. (1966). Drugs used in motion restlessness. sickness. Pharmacol. Rtv., 18,895. Recently a new regimen of "high dose metoclop- Brock-Utne, J. G., Downing, J. W., Dimopoulos, G. E., Rubin, J., and Moshal, M. G. (1980). Effect of domperidone on lower ramide" has been advocated (Strum et al., 1982) for oesophageal sphincter tone in late pregnancy. Autsthtsiology, the treatment of cisplatin-induced emesis. The dos52,321. age studied has been up to 10 mg kg"1 over 24 h and Rubin, J., McAravey, R., Dow, T. G. B., Welman, S., while there have been sedation and the expected Dimopoulos, G. E., and Moshal, M. G. (1977). The effect of hyoscine and atropine on the lower oesophageal sphincter. side-effects, these were not clinically important. At Anaath. /nuns. Cart, 5,223. present this appears to be the most effective treatWelman, S., Dimopoulos, G. E., Moshal, M. G., and ment for this particularly intractable problem which Downing, J. W. (1978). The action of commonly used antimight otherwise have necessitated discontinuing fTnrrini on the lower oesophageal sphincter. Br. J. Anatstk., therapy. 50,295.
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Clarke, R. S. J., Dundee, J. W., and Love, W. J. (1965). Studies of drugs given before anaesthesia. Vlll: Morphine alone and with atropine or hyoscine. Br.J. Anatsth.,37,772. Datta, S., Alper, M. M., Ostheimer, G. W., and Weiss, J. B. (1982). Methods of ephedrine administration and M"iw and hypotension during spinal anesthesia for Cesarean section. Antsthtsiotogy, 56,68. Dundee, J. W., Assaf, R. A. E., Loan, W. B., and Morrison, J. D. (1975). A comparison of the efficacy of cydizine and pcrphenazine in reducing the emetic effects of morphine and pethidine. Br. J. Clm. Pharmacol., 2,81. Clarke, R. S. J. (1973). The premedtcant and antiemetic action of metoclopramide. Postgrad. Mtd. J., 48, 34. Carruthers, S. G. (1975). Drug-induced extrapyramidaldisorders. PrtscribtrsJ., 15, 26. Loan, W. B. (1965). A comparison of the sedative and toxic effects of morphine and pethidine. Lanctt, 2,1262. Kirwan, M. J., and Clarke, R. S. J. (1965). Anaesthesia and premedication as factors in post-operative vomiting. Aaa Anatsthtsiol. Scand., 9,223. Loan.W. B., and Clarke, R . S . J . (1966). Studies of drugs given before anaesthesia. XI: Diamorphine (Heroin) and morphine. Br. J. Anatsth., 38,610. Morrison, J. D. (1970). Studies of drugs given before anaesthesia. XEX: The opiates. Br. J. Anatsth., 42, 54. Moore, J., and Clarke, R. S. J. (1964). Studies of drugs given before anaesthesia. V: Pethidine 100 mg alone and with atropine or hyoscine. Br. J. Anatsth., 36, 703. Nicholl.R.M., Clarke, R.S.J., Moore, J., and Love, W.J. (1965). Studies of drugs given before anaesthesia. VII: Pethidine and phenothiazine combinations. Br. J. Anaesth., 37,601. Ellis, F. R., and Spence, A. A. (1970). Clinical trials of metoclopramide (Mazolon) as an antiemetic in anaesthesia. Anatsthtsia, 25,368. Fragen, R. J., and Caldwell, N. (1978). A new benzimidazole antiemetic, domperidone, for the treatment of postoperative nausea and vomiting. Antsthtsiology, 49, 289. Glaser, E. M. (1959). Prevention and treatment of motion sickness. Proc. R. Soc. Mtd., 52,965. Gold, M. I. (1969). Post-anaesthetic vomiting in the recovery room. Br. J. Anatsth., 41,143. Handley, A. J. (1967). Metoclopramide in the prevention of postoperative nausea and vomiting. Br. J. CUn. Pract., 21,460. Haumann, J. le R., and Foster, P. A. (1963). The anti-emetic effect of halothane. Br. J. Anatsth., 35,114. Hunt, J. N. (1959). Gastric emptying and secretion in man. Physiol. Rev., 39,491. Jacoby, H. I., and Brodie, D. A. (1967). Gastrointestinal effects of metoclopramide. Gastrotnterology, 52, 676. Iind, B., and Breivik, H. (1970). Metoclopramide and perphiinr>™«- Ln the prevention of postoperative nausea and vomiting. Br. J. Anatsth., 42,614. Loan, W. B., Dundee, J. W., and Clarke, R. S. J. (1966). Studies
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