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Postoperative nausea and vomiting
Current Anaesthesia & Critical Care (2002) 13, 37^ 43
c 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/cacc.2002.0380, available online at http://www.idealibrary.com on
PHARMACOLOGY
Postoperative nausea and vomiting I. Acalovschi Spitalul Clinic de Adulti Cluj-Napoca, Clinica ATI, STR Croitorilor NR19^21, 3400 Cluj-Napoca, Romania
KEYWORDS postoperative nausea and vomiting, risk factors, antiemetics, prophylaxis
Summary Postoperative nausea and vomiting (PONV) is a major cause of morbidity and patient discomfort.Many patients fear vomiting as much as, if not more than pain. PONV may also have an economic impact. In day-case surgery, PONV may result in delayed discharge or even overnight admission. On average, 30% of surgical patients su¡er PONV symptoms but after day-case gynaecological laparoscopic surgery the incidence exceeds 50%. In the last decades, a vast amount of research has been performed in this area and new antiemetic drugs and interventions have been introduced. However, no ‘gold standard’ antiemetic intervention has been found and the incidence of PONV is still signi¢cant.The mechanism of stimulation of emesis and the factors incriminated in the development of PONV are discussed. The impact of these factors on PONV and the calculation of risk scores are presented.The antiemetic drugs as well as the non-pharmacological techniques used for prophylaxis and treatment of PONV are also reviewed.
c 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Despite advances in anaesthetic drugs and techniques, postoperative nausea and vomiting (PONV) remains a frequent complication after anaesthesia and surgery. It may a¡ect between 25% and 30% of surgical patients. After pain, it represents the most distressing subjective symptom that a surgical patient can experience. However, while pain control has received increased attention during the past decades, PONV was considered to be a minor complication of surgical procedures. The improvement in patient care and especially the development of the 5-HT3 receptor antagonists as a new class of antiemetics has led to awareness of the need to correct what has been considered to be ‘the big ‘little problem’ of the postoperative period.1
PHYSIOLOGYOF EMESIS Vomiting and nausea are natural re£exes, which ensure the protection of the body against ingested toxins and also indicate the presence of emetogenic conditions. The vomiting centre, situated in the brainstem, close to the nucleus tractus solitarius, controls the co-ordiCorrespondence to: IA.Tel.: 40 64 433392; Fax: 00 40 64 433335; E-mail: [email protected] 0953-7112/02/$-see front matter
nated sequence of respiratory and gastrointestinal events that leads to vomiting. The vomiting centre is stimulated via the chemoreceptor trigger zone (CTZ) which mediates the emetogenic e¡ect of the anaesthetic drugs and the opioids. The CTZ is situated outside the blood^ brain barrier, on the surface of the fourth ventricle (area postrema) and it is directly exposed to circulating drugs. It contains receptors for serotonin, dopamine, histamine and opioids. Stimulation of the CTZ initiates vomiting independent of the vomiting centre.The vomiting centre may also receive impulses from other sources such as the oropharynx, the gastrointestinal tract, the labyrinthovestibular system and the cerebral cortex. In the gastrointestinal tract, the vomiting re£ex is triggered by mechanoreceptors. Emesis occurs in response to distension and contraction (e.g. bowel obstruction) or manipulation of the bowel (e.g. during abdominal surgery). Another mechanism is stimulation of the chemoreceptors located in the mucosa of the upper gut in response to luminal toxins, e.g. release of 5-HT from enterocroma⁄n cells. Motion can stimulate equilibrium receptors in the inner ear, which may also stimulate the CTZ.The cerebral cortex is stimulated by smell and physiologic stress. The a¡erent neural pathways are mainly represented by sympathetic ¢bres and by the vagus nerves which transmit the information from the gastrointestinal tract
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to the dorsal motor vagal nucleus and to the CTZ in the area postrema. The motor impulses to the diaphragm and abdominal muscles required to cause the mechanical act of vomiting, are transmitted via the cranial nerves V, VII, IX, X and XII.
AETIOLOGY The aetiology of PONV is multifactorial and includes factors dependent on the patient, the underlying disease, the type of operation, factors related to anaesthesia and postoperative factors. Patient-related factors include age, gender, body mass, history of previous PONVor motion sickness, gastroparesis and the presence of excessive anxiety. Children are more likely to vomit postoperatively than adults and women more than men, their symptoms being more severe. Premenstrual women are much more likely to su¡er from nausea as compared with postmenstrual women suggesting that a hormonal factor may be involved. Obesity appears to increase the risk of PONV although a systematic review of the literature provided no evidence for a positive relationship.2 Patients with susceptibility to motion sickness and with a history of PONV are also at increased risk of developing PONV perhaps due to a low threshold for vomiting. The incidence of postoperative nausea is higher in non-smokers (risk 1.79 times than in smokers) and in patients ASA III and IV (risk 1.51times than in patients ASA I and II).3 Several review articles have indicated that a high level of pre-operative anxiety may increase postoperative emesis. However, a recent study suggested that this factor had no predictive value for the occurrence of PONV.4 The incidence of PONV is also in£uenced by the type and duration of surgical procedure, with the highest incidence in women undergoing major gynaecological surgery. Middle-ear surgery is also associated with a high incidence of vomiting, presumably because of the proximity of the vestibular apparatus. In children, strabismus surgery is associated with more vomiting than other ocular procedures (up to 85%). After adenotonsillectomy, the incidence of PONV has been reported to be over 70%. In adults, a high incidence of PONV was noted after intraabdominal, orthopaedic, otorhinolaryngological or laparoscopic surgery. Anaesthesia-related factors include premedication, anaesthetic techniques and duration of anaesthesia. Pre medication with opioids has been associated with an increase in PONV. PONV is more likely to occur after general than regional anaesthesia, and its prevalence increases with the duration of anaesthesia.3 Prevalence is also increased by the use of certain intubation anaesthetic agents and by concomitant use of opioids. Omitting nitrous oxide in patients who have a high risk of PONV signi¢cantly reduced the incidence of vomiting
CURRENT ANAESTHESIA & CRITICAL CARE but the incidence of nausea was not in£uenced.5 The use of propofol as the intravenous anaesthetic agent has lowered the risk of PONV, but only in the short term (up to 6 h after surgery), when given as a maintenance regimen, and when the incidence of PONV with the control anaesthetic was at least 20%.6 Among the muscle relaxants, pancuronium seems to be more emetogenic than vecuronium, atracurium or alcuronium. The reversal of neuromuscular blockade with 2.5 mg neostigmine may be associated with increased PONV7 and omitting anticholinesterase drugs at the end of surgery may have a bene¢cial e¡ect when large doses (42.5 mg of neostigmine) are used.8 An additional anaesthetic factor, which may in£uence the incidence of PONV, is the inspired oxygen concentration. In patients given 80% rather than 30% oxygen during surgery and for 2 h postoperatively, the incidence of PONV was reduced by a factor of two.9 Ondansetron was no more effective than supplemental oxygen for the prevention of PONV.10 Gastric distension from vigorous ventilation via a face mask by a less experienced trainee may result in emesis in the postoperative period. Intraoperative hypoxaemia and hypotension during regional anaesthesia may also induce vomiting. Among the postoperative factors, pain, ambulation, the use of opioid analgesics and the time of ¢rst oral intake can in£uence the incidence of PONV. The management of postoperative pain using patient-controlled analgesia devices increased the incidence of nausea and vomiting up to 50%.5
RISK SCORES FOR PREDICTING PONV Meta-analyses have shown that the e⁄cacy of prophylactic antiemetic strategies is limited and prophylactic antiemetics appear justi¢ed only in patients at an increased risk for PONV. It became necessary to quantify the impact of the risk factors arising from the patient, surgery and anaesthesia on the absolute probability for PONV. A few studies have tried to examine this point and have set up risk models for the prediction of PONV. An initial step was to construct a risk score based mainly on patient-related factors. These were sex, age, history of previous PONV, motion sickness, duration of anaesthesia and use of postoperative opioids. All scores were based on logistic regression analysis to identify and generate weights for each risk factor. A simpli¢ed score was published by Koivuranta et al, based on the ¢ve strongest predictors of PONV, each having the same weight. These were female gender, previous PONV, duration of operation over 60 min, history of motion sickness, and non-smoking. For the presence of one of these factors, the risk of nausea increases from 17% (no factor present) to 18%, 42%, 54%, 74% and ¢nally to 87%, when all ¢ve risk factors were present.11 Recently, two centres have
POSTOPERATIVE NAUSEA ANDVOMITING
independently developed a risk score for patients submitted to various types of surgery.12 The risk score was simpli¢ed to the four most important predictive factors with similar discriminating power: female gender, prior history of motion sickness or PONV, non-smoking and the use of postoperative opioids. The type of operation was not a strong independent predictor for PONV. Identi¢cation of at least two of the above-mentioned predictors may justify a prophylactic antiemetic strategy. However, the power to discriminate which individual will su¡er from PONV, remains limited.13
PREVENTIONOF PONV Not all surgical patients require medication for the prophylaxis of nausea and vomiting since o30% of patients experience postoperative emetic sequelae. The decision to provide antiemetic therapy should be based on the presence of risk factors and the potential for serious sequelae from vomiting (e.g. aspiration pneumonia in patients with head and neck surgery). A patient who has three or four risk factors would be considered at high risk 12 and antiemetic medication should be used. At lower risk score, selection of regional anaesthesia or TIVA with diminished dose of opioids should represent prophylactic measures. Optimization of the administration of volatile anaesthetics using the bispectral index (BIS) may also decrease the incidence of postoperative vomiting.14 Numerous antiemetic agents have been used for prophylaxis of PONV.These include antagonists to dopaminergic, cholinergic, 5-HT3, histaminic and NK1 receptors, agonists to cannabinoid receptors, dexamethasone and non-pharmacological techniques such as acupuncture and acupressure. Several controlled trials have analysed their e⁄cacy as compared with placebo in preventing PONV. Many trials reported surrogate outcome measures, such as incidence of PONV and the number of emetic episodes per patient. A quantitative measure of the absolute e⁄cacy of the drug is the calculation of the‘number needed to treat to prevent’ (NNTP) one episode of PONV. For example, if for the prevention of postoperative nausea, the best NNTP for droperidol was 5,15 this suggested that ¢ve high-risk patients needed to undergo droperidol administration for one not to have nausea who would have had it if droperidol would have been omitted. Another measure that helps to assess the clinical usefulness of a drug is the ‘number needed to treat to harm’ (to cause one adverse event) (NNTH). Besides these therapeutic outcome measures, other end-points, such as patient satisfaction, hospital stay and the unanticipated hospital admission caused by intractable PONV should be taken into consideration. These represent true outcome measures. The pharmaco-economic outcome measures are also important. A
39
higher cost of an antiemetic could limit its routine prophylactic use. The cost to bene¢t a patient can be calculated as NNTP times the acquisition cost of the drug per patient. For example, in preventing PONV after paediatric strabismus repair, the cost to bene¢t a child with dexamethasone was approximately 22 times less than that of ondansetron.16 The duration of the antiemetic e¡ect may have an impact on the outcome measures. A short-term e⁄cacy (up to 6 h) has an economic impact mainly in day surgery, facilitating the discharge of the patients within hours after the procedure. The long-term e⁄cacy (up to 24 or 48 h) will facilitate the evaluation of patient’s satisfaction. The choice of an antiemetic drug should be based on evidence of greater e¡ectiveness and increased patient satisfaction, achieved with reduction of total costs.
Metoclopramide Metoclopramide is one of the antiemetics most frequently used during the last 40 years. Metoclopramide acts on central dopaminergic receptors, on both central and peripheral 5-HT3 receptors and on peripheral 5HT4 receptors.The antiemetic e¡ect of metoclopramide is attributed to its a⁄nity for the dopaminergic D2 receptors. In addition, metoclopramide has a prokinetic effect, increasing the lower oesophageal sphincter tone and enhancing gastric and small-bowel motility, via its action on the 5-HT4 receptors. The side-e¡ects include sedation, drowsiness, and diarrhoea. Extrapyramidal effects may also occur, more frequently in children and at higher doses. At low doses (0.1^ 0.2 mg/kg i.v.), metoclopramide has been used in the prophylaxis and treatment of PONV in adults and children. Studies of the e⁄cacy and safety of metoclopramide for postoperative nausea and vomiting have yielded mixed results. The usual dose of 10 mg metoclopramide did not show any clinically relevant anti-emetic e⁄cacy in adults. In a randomized trial in patients undergoing total abdominal hysterectomy, there was no signi¢cant di¡erence between metoclopramide and placebo.17 However, in children, administration of a dose of 0.25 mg/kg i.v. metoclopramide prevented PONV (NNTP was about 6) with no increase in sedation or drowsiness.18 A recent new metoclopramide formulation with a neutral pH might have fewer side-e¡ects and, administered in high doses, could be useful for the control of PONV.
Droperidol Droperidol is a butyrphenone derivative, which exerts its antiemetic properties by blocking dopaminergic D2 receptors and to a lesser extent histamine and serotonin receptors. Several trials showed that droperidol was effective in preventing nausea and vomiting in a variety of
40
surgical interventions, when compared with placebo, and better results were obtained in comparison with metoclopramide. Droperidol was as e¡ective as the 5-HT3 receptor antagonists ondansetron, tropisetron and dolasetron. Droperidol is more e¡ective for nausea than for vomiting. The anti-emetic e¡ect is evident at doses as low as 0.25^ 0.5 mg i.v. in adults.The prophylactic administration of 0.625 mg of i.v. droperidol was very e¡ective in decreasing PONV with no increase in adverse sidee¡ects.19 Higher doses of droperidol (2.5^5 mg i.v.) with duration of action up to 12 h are more e¡ective in higher risk patients (e.g. strabismus surgery). However, the risk of adverse e¡ects may be increased and the patients should be monitored for sedation, dysphoria and extrapyramidal symptoms. Hypotension may also occur, as a result of alpha-adrenergic blockade. There was evidence that in adults sedation was dose-dependent (NNTH about 7 with 2.5 mg i.v.) and extrapyramidal symptoms were rare (NNTH about 400).15 When the dose of droperidol was limited to 1.25 mg i.v., the incidence of these central nervous system (CNS) events did not di¡er in comparison with ondansetron. 20 Extrapyramidal reactions may occur more frequently in paediatric patients (NNTH about 90 after a dose of 75 mg/kg droperidol i.v.). Therefore, in children, smaller doses (50 mg/ kg i.v.) are recommended, which are still antiemetic, but with a lower risk of adverse e¡ects. When given at the end of surgery, droperidol was more e¡ective compared with the same dose given at induction or during surgery. Droperidol is mostly recommended for the prevention of PONV induced by opioids (morphine) administered via PCA devices. In this circumstance, droperidol had the highest antiemetic e⁄cacy (NNTP about 3).5 Although the e⁄cacy of droperidol was well established, it has now been withdrawn in United Kingdom because of its propensity to cause prolonged Q-T interval.
5-HT3 receptor antagonists This class of anti-emetics contains ondansetron as prototype and the more recently developed granisetron, dolasetron, tropisetron and ramosetron. Ondansetron is a carbazalone derivative, which possesses speci¢c 5-HT3 subtype receptor antagonist properties, without altering dopamine, histamine, adrenergic or cholinergic receptor activity. Ondansetron, 4 mg i.v. in adults and 0.05 mg/kg in children, is highly e¡ective in decreasing the incidence of PONV. Although a larger dose of 8 mg i.v. may be more e⁄cacious, especially in patients with a history of motion sickness or previous PONV, a recent meta-analysis demonstrated that ondansetron showed an increased anti-vomiting ef¢cacy in this subgroup of patients irrespective of the administered dose.21 Ondansetron is also available for oral administration, e¡ective as a single dose of 16 mg. It
CURRENT ANAESTHESIA & CRITICAL CARE
was shown that the antivomiting e¡ect of ondansetron was consistently more pronounced than the antinausea e¡ect. Some studies showed that in comparison with droperidol, ondansetron was equivalent in prevention of postoperative vomiting, but droperidol prevented nausea to a greater degree.20 Ondansetron may be superior in children, and provides anti-emetic control for a signi¢cantly longer period (up to 24 h), whereas droperidol is more cost-e¡ective. In children undergoing strabismus repair, 75 mg/kg ondansetron was very e¡ective (NNTP 2) and improved the ‘true’ outcome measures.22 The most signi¢cant feature of ondansetron prophylaxis is the low incidence of side-e¡ects which include headache, lightheadedness and constipation. Sedation, dysphoria, hypotension and extrapyramidal symptoms that may accompany administration of other antiemetics do not accompany administration of ondansetron. With the newer 5-HT3 antagonists, larger trials are needed to evaluate their antiemetic e⁄cacy. Granisetron is a more selective 5-HT3 receptor antagonist than ondansetron.The elimination half-time of 9 h is 2.5 times longer than that of ondansetron and a single dose of granisetron may be e¡ective for 24 h. For prevention of PONV, the studies support the use of a single i.v. dose of 20 ^ 40 mg/kg. Dolasetron 12.5 mg i.v. is as e¡ective as 4 and 8 mg ondansetron but achieves the same degree of patient satisfaction at a lower cost.23 For oral use, the 100 mg oral dose of dolasetron is most e¡ective. Ramosetron has the longest antiemetic e¡ect up to 48 h. The optimal dose for the prevention of PONVafter gynaecological surgery was 0.3 mg i.v.24
Dexamethasone Dexamethasone is a corticosteroid with strong antiin£ammatory and prolonged antiemetic e¡ects.The mechanism of action of dexamethasone in emesis is unknown. One theory is that it exerts its antiemetic e¡ect via prostaglandin antagonism. There may also be a reduced serotonin release from the gut. As monotherapy, the minimum e¡ective dose for preventing PONV was 2.5 mg i.v. given immediately before the induction and the usual doses of10 and 5 mg did not o¡er any therapeutic advantage over 2.5 mg.The onset time of dexamethasone’s antiemetic e¡ect may be approximately 2 h.25 The prophylactic administration of dexamethasone immediately before induction, rather than at the end of anaesthesia was more e¡ective in preventing PONV. As the biological life of dexamethasone is 36^72 h, the antiemetic e⁄cacy is prolonged (up to 24 h).With a single prophylactic dose of dexamethasone, the NNT to prevent early and late vomiting compared with placebo was 7.1 in adults and 3.8 in children.26 Late e⁄cacy was more pronounced. In adults, the NNTP for late nausea was 4.3.
POSTOPERATIVE NAUSEA ANDVOMITING
When compared with ondansetron, dexamethasone had similar NNTP for PONV and similar satisfaction scores but was more cost-e¡ective.16 Administered in a single dose, dexamethasone had no signi¢cant side-e¡ects. Best antiemetic e⁄cacy was achieved when dexamethasone was combined with a 5-HT3 receptor antagonist.
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were more e¡ective than placebo within 6 h of surgery in adults, but there was no bene¢t in children. NNT to prevent early nausea or vomiting is about 5. These techniques could be recommended in patients with known adverse reactions to anti-emetic drugs and in patients who wish to minimize drug intake in the clinical setting.31
Other antiemetic drugs Phenothiazines such as chlorpromazine and promethazine have been used for years in the prevention and treatment of PONV, but can produce hypotension and signi¢cant sedation and lethargy during recovery. The more recently introduced prochloperazine and perphenazine are associated with a relatively high incidence of extrapyramidal side-e¡ects. Antihistaminics such as hydroxyzine and cyclizine are particularly useful in motion sickness and in the control of emesis following middle-ear surgery.Cyclizine was also e⁄cacious for the prevention of PONV after day-case gynaecological surgery. Among the anticholinergics, transdermal scopolamine was e¡ective in controlling motion sickness and signi¢cantly decreased the incidence of severe PONV after laparoscopic surgery. The most common adverse e¡ects associated with the use of a transdermal scopolamine patch were dry mouth and visual disturbances. Other anticholinergics such as atropine and glycopyrolate reduced nausea during spinal anaesthesia. Cannabinoids may be e¡ective in treating PONV as was demonstrated in a recent study on ferrets. 27 However, in clinical practice their role is limited because of the high incidence of CNS side-e¡ects. Antagonists at the NK1 receptor represent another new class of antiemetics. Pre-operative administration of the orally active NK1 antagonist CP-122,721was found to be similar to ondansetron in decreasing emetic symptoms after abdominal hysterectomy procedures.28 Although preliminary data have demonstrated the e⁄cacy of NK1 receptor antagonists, further studies are needed to clarify their role as anti-emetics. Ephedrine, an indirect-acting sympathomimetic drug, had a signi¢cant antiemetic e¡ect up to 3 h after administration, with no evident side-e¡ects.29
Non-pharmacological techniques Acupuncture, transcutaneous electrical nerve stimulation, acupoint stimulation, and acupressure showed an antiemetic e⁄cacy comparable with available antiemetics.30 Stimulation of the P- 6 acupuncture point (Neiguan) resulted in a signi¢cant reduction of postoperative emesis. Application of pressure every 2 h to this acupuncture point was reported to produce an anti-emetic action for up to 24 h. Non-pharmacological techniques
Combination antiemetic therapy Despite the introduction of new antiemetics over the past decade, no completely e¡ective antiemetic exists for the prevention of PONV. None of the above presented drugs and interventions consistently showed both antinausea and antivomiting e⁄cacy. Only 20% of adult patients will bene¢t (NNTP about 5) from the best prophylactic antiemetic interventions. A combination of anti-emetic drugs with action at different sites (‘balanced anti-emesis’) could be more e⁄cacious and less toxic as compared with monotherapy.32 For instance, ondansetron which shows less antinausea and more antivomiting e⁄cacy can be combined with droperidol which has more antinausea e⁄cacy. The increased risk of headache after ondansetron can be reduced by the addition of droperidol which o¡ers protection against headache. Another recommended combination is dexamethasone plus a 5-HT3 receptor antagonist, which is likely to be the most e¡ective antiemetic regimen currently available.5 A recent study demonstrated the superiority of the combination between ondansetron and cyclizine over placebo for the prevention of PONV. In a high-risk surgical population, the use of combined pharmacological (e.g. anti-emetic) and nonpharmacological (e.g. acupuncture, transcutaneous acupoint stimulation) therapies may o¡er advantages over either modality alone. Prophylaxis with three anti-emetic drugs may be justi¢ed in patients with the highest risk for PONV (e.g. a patient with the four strongest predictors of PONV on Apfel’s risk score: a non-smoking woman with previous PONV, undergoing laparoscopy and receiving postoperative opioids). A multimodal management algorithm consisting of total intravenous anaesthesia (propofol and remifentanil), no N2O, no neuromuscular blockade, aggressive intravenous hydration (25 ml/kg), triple prophylactic antiemetics (ondansetron 1mg, droperidol 0.625 mg and dexamethasone 10 mg), and ketorolac 30 mg, resulted in a 98% reduction of postoperative vomiting. However, this improved e⁄cacy relative to PONV, did not result in an increased level of patient satisfaction when compared with routine monotherapy prophylaxis. 33 Further research is needed to evaluate the e⁄cacy of combination strategies (‘balanced anti-emesis’) and to identify the most e¡ective combinations of anti-emetics and their doses.
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TREATMENTOF ESTABLISHED PONV If vomiting is protracted, acute hydration with crystalloid solutions and supplemental oxygen via a face mask will represent the ¢rst therapeutic measures. Among the anti-emetic drugs, droperidol and 5-HT3 receptor antagonists are recommended for patients with established postoperative nausea and vomiting. When ondansetron is used to treat PONV, doses of 1^ 4 mg i.v. are e¡ective. With ondansetron, 1mg i.v., the symptoms are relieved for 24 h in about 40% of nauseated or vomiting patients in comparison with about 20% of the patients with placebo. The recommended dose for paediatric patients is 50 mg/kg. Ondansetron combined with cyclizine given sequentially was more e¡ective than either drug alone.34 Dolasetron was also evaluated for the treatment of established PONV. The e¡ective dose in adults was 12.5 mg i.v.
CONCLUSIONS Although the actual morbidity associated with nausea and vomiting is relatively low in healthy patients, it represents a major source of discomfort for the surgical patient and a challenge for ambulatory surgery. Anaesthesiologists have control over the anaesthetic-related factors a¡ecting PONV. Avoidance of nitrous oxide and administration of propofol as a maintenance anaesthetic agent for total intravenous anaesthesia, will reduce the incidence of PONV. Regional nerve-block procedures are associated with less PONV than general anaesthesia. In high-risk patients, the prophylactic use of anti-emetic drugs is necessary. Nausea is more di⁄cult to prevent than is vomiting. Of the multitude of pharmacological agents tested, the 5-HT3 antagonists, droperidol and dexamethasone have proven to be the most e¡ective. When administration of a single anti-emetic is not e¡ective, a combination of anti-emetic drugs with di¡erent sites of action (‘balanced anti-emesis’) should be considered. Postoperatively, non-opioid analgesics are recommended to control the pain. If emesis does occur, antiemetic therapy in combination with aggressive intravenous hydration and pain management should be started.
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CURRENT ANAESTHESIA & CRITICAL CARE
5. Tramer M R. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part I. Ef¢cacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001; 45: 4 ^13. 6. Tramer M, Moore A, McQuay H. Propofol anaesthesia and postoperative nausea and vomiting: quantitative systematic review of randomized controlled studies. Br J Anaesth 1997; 78: 247^255. 7. Ding Y, Fredman B, White P F. Use of mivacurium during laparoscopic surgery: e¡ect of reversal drugs on postoperative recovery. Anesth Analg 1994; 78: 450 ^ 454. 8. Tramer M R, Fuchs-Buder T. Omitting antagonism of neuromuscular block: e¡ect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth 1999; 82: 379^386. 9. Greif R, Laciny S, Rapf B, Hickle R S, Sessler D I. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999; 91: 1246 ^1252. 10. Goll V, Akca O, Greif R et al. Ondansetron is no more e¡ective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001; 92: 112^117. 11. Koivuranta M, Laara E, Snare L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia 1997; 52: 443^ 449. 12. Apfel C C, Laara E, Koivuranta M,Greim C A, Roewer N. A simpli¢ed risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology1999; 91: 693^700. 13. Apfel C C, Kranke P,Greim C A, Roewer N.What can be expected from risk scores for predicting postoperative nausea and vomiting? Br J Anaesth 2001; 86: 822^ 827. 14. Nelskyla K A,Yli-Hankala A M, Puro P H, Korttila K T. Sevo£urane titration using bispectral index decreases postoperative vomiting in phase II recovery after ambulatory surgery. Anesth Analg. 2001; 93: 1165^1169. 15. Henzi I, Sonderegger J, Tramer M R. E⁄cacy, dose-response, and adverse e¡ects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth 2000; 47: 537^551. 16. Subramaniam B, Madan R, Sadhasivam S et al. Dexamethasone is a cost-e¡ective alternative to ondansetron in preventing PONV after paediatric strabismus repair. Br J Anaesth 2001; 86: 84 ^ 89. 17. Desilva P H, Darvish A H, McDonald S M,Cronin M K,Clark K.The e⁄cacy of prophylactic ondansetron, droperidol, perphenazine, and metoclopramide in the prevention of nausea and vomiting after major gynecologic surgery. Anesth Analg 1995; 81: 139^143. 18. Henzi I, Walder B, Tramer M R. Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth 1999; 83: 761^771. 19. Kreisler N S, Spiekermann B F, Ascari C M et al. Small-dose droperidol e¡ectively reduces nausea in a general surgical adult patient population. Anesth Analg 2000; 91: 1256^1261. 20. Fortney J T, GanT J, Graczyk S et al. A comparison of the e⁄cacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures. S3A- 409 and S3A- 410 Study Groups. Anesth Analg 1998; 86: 731^738. 21. Figueredo E, Canosa L. Prophylactic ondansetron for post-operative emesis: meta-analysis of its e¡ectiveness in patients with and without a previous history of motion sickness. Eur J Anaesthesiol 1999; 16: 556 ^564. 22. Sadhasivam S, Shende D, Madan R. Prophylactic ondansetron in prevention of postoperative nausea and vomiting following pediatric strabismus surgery: a dose ^ response study. Anesthesiology 2000; 92: 1035^1042. 23. Zarate E, Watcha M F, White P F, Klein K W, Sa Rego M, Stewart D G. A comparison of the costs and e⁄cacy of ondansetron versus dolasetron for antiemetic prophylaxis. Anesth Analg 2000; 90: 1352^1358.
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24. Fujii Y, SaitohY, Tanaka H, Toyooka H. Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery. Anesth Analg 2000; 90: 472^ 475. 25. Wang J J, Ho S T, Tzeng J I, Tang C S. The e¡ect of timing of dexamethasone administration on its e⁄cacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000; 91: 136^139. 26. Henzi I, Walder B, Tramer M Q. Dexamethasone for the prevention of postoperative nauseau and vomiting; a quantitative Systemic review. Anesth Analg 2000; 90: 186 ^194. 27. Simoneau I I, Hamza M S, Mata H P et al. The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001; 94: 882^ 887. 28. Gesztesi Z, Scuderi P E, White P F et al. Substance P (Neurokinin1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000; 93: 931^937. 29. Hagemann E, Halvorsen A, Holgersen O,Tveit T, Raeder J C. Intramuscular ephedrine reduces emesis during the ¢rst three hours after abdominal hysterectomy. Acta Anaesthesiol Scand 2000; 44: 107^111. 30. Lee A, Done M L.The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999; 88:1362^1369. 31. Zarate E, Mingus M, White P F et al. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001; 92: 629^ 635.
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32. He¡ernan A M, Rowbotham D J. Postoperative nausea and vomitingFtime for balanced antiemesis? Br J Anaesth 2000; 85: 675^ 677. 33. Scuderi P E, James R L, Harris L, Mims 3rd. G R Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000; 91: 1408 ^1414. 34. Kyriakides K, Hussain S, Harrison J, Webb A, Hobbs G J. Comparison of ondansetron and cyclizine in the treatment of early postoperative nausea and vomiting. Br J Anaesth 1998; 80: A459.
FURTHER READING Gralla R J, Osoba D, Kris M G et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999; 17: 2971^2994. Tramer M R. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part II. Recommendations for prevention and treatment, and research agenda. Acta Anaesthesiol Scand 2001; 45: 14 ^19. Lynch L. Antiemetic drugs. The Royal College of anaesthetists 2001; Bulletin 9: 415^ 418. Eberhart L H, Hogel J, Seeling W, Staack A M, Geldner G, Georgie¡ M. Evaluation of three risk scores to predict postoperative nausea and vomiting. Acta Anaesthesiol Scand2000; 44: 480 ^ 488.
c 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/cacc.2002.0380, available online at http://www.idealibrary.com on
PHARMACOLOGY
Postoperative nausea and vomiting I. Acalovschi Spitalul Clinic de Adulti Cluj-Napoca, Clinica ATI, STR Croitorilor NR19^21, 3400 Cluj-Napoca, Romania
KEYWORDS postoperative nausea and vomiting, risk factors, antiemetics, prophylaxis
Summary Postoperative nausea and vomiting (PONV) is a major cause of morbidity and patient discomfort.Many patients fear vomiting as much as, if not more than pain. PONV may also have an economic impact. In day-case surgery, PONV may result in delayed discharge or even overnight admission. On average, 30% of surgical patients su¡er PONV symptoms but after day-case gynaecological laparoscopic surgery the incidence exceeds 50%. In the last decades, a vast amount of research has been performed in this area and new antiemetic drugs and interventions have been introduced. However, no ‘gold standard’ antiemetic intervention has been found and the incidence of PONV is still signi¢cant.The mechanism of stimulation of emesis and the factors incriminated in the development of PONV are discussed. The impact of these factors on PONV and the calculation of risk scores are presented.The antiemetic drugs as well as the non-pharmacological techniques used for prophylaxis and treatment of PONV are also reviewed.
c 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Despite advances in anaesthetic drugs and techniques, postoperative nausea and vomiting (PONV) remains a frequent complication after anaesthesia and surgery. It may a¡ect between 25% and 30% of surgical patients. After pain, it represents the most distressing subjective symptom that a surgical patient can experience. However, while pain control has received increased attention during the past decades, PONV was considered to be a minor complication of surgical procedures. The improvement in patient care and especially the development of the 5-HT3 receptor antagonists as a new class of antiemetics has led to awareness of the need to correct what has been considered to be ‘the big ‘little problem’ of the postoperative period.1
PHYSIOLOGYOF EMESIS Vomiting and nausea are natural re£exes, which ensure the protection of the body against ingested toxins and also indicate the presence of emetogenic conditions. The vomiting centre, situated in the brainstem, close to the nucleus tractus solitarius, controls the co-ordiCorrespondence to: IA.Tel.: 40 64 433392; Fax: 00 40 64 433335; E-mail: [email protected] 0953-7112/02/$-see front matter
nated sequence of respiratory and gastrointestinal events that leads to vomiting. The vomiting centre is stimulated via the chemoreceptor trigger zone (CTZ) which mediates the emetogenic e¡ect of the anaesthetic drugs and the opioids. The CTZ is situated outside the blood^ brain barrier, on the surface of the fourth ventricle (area postrema) and it is directly exposed to circulating drugs. It contains receptors for serotonin, dopamine, histamine and opioids. Stimulation of the CTZ initiates vomiting independent of the vomiting centre.The vomiting centre may also receive impulses from other sources such as the oropharynx, the gastrointestinal tract, the labyrinthovestibular system and the cerebral cortex. In the gastrointestinal tract, the vomiting re£ex is triggered by mechanoreceptors. Emesis occurs in response to distension and contraction (e.g. bowel obstruction) or manipulation of the bowel (e.g. during abdominal surgery). Another mechanism is stimulation of the chemoreceptors located in the mucosa of the upper gut in response to luminal toxins, e.g. release of 5-HT from enterocroma⁄n cells. Motion can stimulate equilibrium receptors in the inner ear, which may also stimulate the CTZ.The cerebral cortex is stimulated by smell and physiologic stress. The a¡erent neural pathways are mainly represented by sympathetic ¢bres and by the vagus nerves which transmit the information from the gastrointestinal tract
38
to the dorsal motor vagal nucleus and to the CTZ in the area postrema. The motor impulses to the diaphragm and abdominal muscles required to cause the mechanical act of vomiting, are transmitted via the cranial nerves V, VII, IX, X and XII.
AETIOLOGY The aetiology of PONV is multifactorial and includes factors dependent on the patient, the underlying disease, the type of operation, factors related to anaesthesia and postoperative factors. Patient-related factors include age, gender, body mass, history of previous PONVor motion sickness, gastroparesis and the presence of excessive anxiety. Children are more likely to vomit postoperatively than adults and women more than men, their symptoms being more severe. Premenstrual women are much more likely to su¡er from nausea as compared with postmenstrual women suggesting that a hormonal factor may be involved. Obesity appears to increase the risk of PONV although a systematic review of the literature provided no evidence for a positive relationship.2 Patients with susceptibility to motion sickness and with a history of PONV are also at increased risk of developing PONV perhaps due to a low threshold for vomiting. The incidence of postoperative nausea is higher in non-smokers (risk 1.79 times than in smokers) and in patients ASA III and IV (risk 1.51times than in patients ASA I and II).3 Several review articles have indicated that a high level of pre-operative anxiety may increase postoperative emesis. However, a recent study suggested that this factor had no predictive value for the occurrence of PONV.4 The incidence of PONV is also in£uenced by the type and duration of surgical procedure, with the highest incidence in women undergoing major gynaecological surgery. Middle-ear surgery is also associated with a high incidence of vomiting, presumably because of the proximity of the vestibular apparatus. In children, strabismus surgery is associated with more vomiting than other ocular procedures (up to 85%). After adenotonsillectomy, the incidence of PONV has been reported to be over 70%. In adults, a high incidence of PONV was noted after intraabdominal, orthopaedic, otorhinolaryngological or laparoscopic surgery. Anaesthesia-related factors include premedication, anaesthetic techniques and duration of anaesthesia. Pre medication with opioids has been associated with an increase in PONV. PONV is more likely to occur after general than regional anaesthesia, and its prevalence increases with the duration of anaesthesia.3 Prevalence is also increased by the use of certain intubation anaesthetic agents and by concomitant use of opioids. Omitting nitrous oxide in patients who have a high risk of PONV signi¢cantly reduced the incidence of vomiting
CURRENT ANAESTHESIA & CRITICAL CARE but the incidence of nausea was not in£uenced.5 The use of propofol as the intravenous anaesthetic agent has lowered the risk of PONV, but only in the short term (up to 6 h after surgery), when given as a maintenance regimen, and when the incidence of PONV with the control anaesthetic was at least 20%.6 Among the muscle relaxants, pancuronium seems to be more emetogenic than vecuronium, atracurium or alcuronium. The reversal of neuromuscular blockade with 2.5 mg neostigmine may be associated with increased PONV7 and omitting anticholinesterase drugs at the end of surgery may have a bene¢cial e¡ect when large doses (42.5 mg of neostigmine) are used.8 An additional anaesthetic factor, which may in£uence the incidence of PONV, is the inspired oxygen concentration. In patients given 80% rather than 30% oxygen during surgery and for 2 h postoperatively, the incidence of PONV was reduced by a factor of two.9 Ondansetron was no more effective than supplemental oxygen for the prevention of PONV.10 Gastric distension from vigorous ventilation via a face mask by a less experienced trainee may result in emesis in the postoperative period. Intraoperative hypoxaemia and hypotension during regional anaesthesia may also induce vomiting. Among the postoperative factors, pain, ambulation, the use of opioid analgesics and the time of ¢rst oral intake can in£uence the incidence of PONV. The management of postoperative pain using patient-controlled analgesia devices increased the incidence of nausea and vomiting up to 50%.5
RISK SCORES FOR PREDICTING PONV Meta-analyses have shown that the e⁄cacy of prophylactic antiemetic strategies is limited and prophylactic antiemetics appear justi¢ed only in patients at an increased risk for PONV. It became necessary to quantify the impact of the risk factors arising from the patient, surgery and anaesthesia on the absolute probability for PONV. A few studies have tried to examine this point and have set up risk models for the prediction of PONV. An initial step was to construct a risk score based mainly on patient-related factors. These were sex, age, history of previous PONV, motion sickness, duration of anaesthesia and use of postoperative opioids. All scores were based on logistic regression analysis to identify and generate weights for each risk factor. A simpli¢ed score was published by Koivuranta et al, based on the ¢ve strongest predictors of PONV, each having the same weight. These were female gender, previous PONV, duration of operation over 60 min, history of motion sickness, and non-smoking. For the presence of one of these factors, the risk of nausea increases from 17% (no factor present) to 18%, 42%, 54%, 74% and ¢nally to 87%, when all ¢ve risk factors were present.11 Recently, two centres have
POSTOPERATIVE NAUSEA ANDVOMITING
independently developed a risk score for patients submitted to various types of surgery.12 The risk score was simpli¢ed to the four most important predictive factors with similar discriminating power: female gender, prior history of motion sickness or PONV, non-smoking and the use of postoperative opioids. The type of operation was not a strong independent predictor for PONV. Identi¢cation of at least two of the above-mentioned predictors may justify a prophylactic antiemetic strategy. However, the power to discriminate which individual will su¡er from PONV, remains limited.13
PREVENTIONOF PONV Not all surgical patients require medication for the prophylaxis of nausea and vomiting since o30% of patients experience postoperative emetic sequelae. The decision to provide antiemetic therapy should be based on the presence of risk factors and the potential for serious sequelae from vomiting (e.g. aspiration pneumonia in patients with head and neck surgery). A patient who has three or four risk factors would be considered at high risk 12 and antiemetic medication should be used. At lower risk score, selection of regional anaesthesia or TIVA with diminished dose of opioids should represent prophylactic measures. Optimization of the administration of volatile anaesthetics using the bispectral index (BIS) may also decrease the incidence of postoperative vomiting.14 Numerous antiemetic agents have been used for prophylaxis of PONV.These include antagonists to dopaminergic, cholinergic, 5-HT3, histaminic and NK1 receptors, agonists to cannabinoid receptors, dexamethasone and non-pharmacological techniques such as acupuncture and acupressure. Several controlled trials have analysed their e⁄cacy as compared with placebo in preventing PONV. Many trials reported surrogate outcome measures, such as incidence of PONV and the number of emetic episodes per patient. A quantitative measure of the absolute e⁄cacy of the drug is the calculation of the‘number needed to treat to prevent’ (NNTP) one episode of PONV. For example, if for the prevention of postoperative nausea, the best NNTP for droperidol was 5,15 this suggested that ¢ve high-risk patients needed to undergo droperidol administration for one not to have nausea who would have had it if droperidol would have been omitted. Another measure that helps to assess the clinical usefulness of a drug is the ‘number needed to treat to harm’ (to cause one adverse event) (NNTH). Besides these therapeutic outcome measures, other end-points, such as patient satisfaction, hospital stay and the unanticipated hospital admission caused by intractable PONV should be taken into consideration. These represent true outcome measures. The pharmaco-economic outcome measures are also important. A
39
higher cost of an antiemetic could limit its routine prophylactic use. The cost to bene¢t a patient can be calculated as NNTP times the acquisition cost of the drug per patient. For example, in preventing PONV after paediatric strabismus repair, the cost to bene¢t a child with dexamethasone was approximately 22 times less than that of ondansetron.16 The duration of the antiemetic e¡ect may have an impact on the outcome measures. A short-term e⁄cacy (up to 6 h) has an economic impact mainly in day surgery, facilitating the discharge of the patients within hours after the procedure. The long-term e⁄cacy (up to 24 or 48 h) will facilitate the evaluation of patient’s satisfaction. The choice of an antiemetic drug should be based on evidence of greater e¡ectiveness and increased patient satisfaction, achieved with reduction of total costs.
Metoclopramide Metoclopramide is one of the antiemetics most frequently used during the last 40 years. Metoclopramide acts on central dopaminergic receptors, on both central and peripheral 5-HT3 receptors and on peripheral 5HT4 receptors.The antiemetic e¡ect of metoclopramide is attributed to its a⁄nity for the dopaminergic D2 receptors. In addition, metoclopramide has a prokinetic effect, increasing the lower oesophageal sphincter tone and enhancing gastric and small-bowel motility, via its action on the 5-HT4 receptors. The side-e¡ects include sedation, drowsiness, and diarrhoea. Extrapyramidal effects may also occur, more frequently in children and at higher doses. At low doses (0.1^ 0.2 mg/kg i.v.), metoclopramide has been used in the prophylaxis and treatment of PONV in adults and children. Studies of the e⁄cacy and safety of metoclopramide for postoperative nausea and vomiting have yielded mixed results. The usual dose of 10 mg metoclopramide did not show any clinically relevant anti-emetic e⁄cacy in adults. In a randomized trial in patients undergoing total abdominal hysterectomy, there was no signi¢cant di¡erence between metoclopramide and placebo.17 However, in children, administration of a dose of 0.25 mg/kg i.v. metoclopramide prevented PONV (NNTP was about 6) with no increase in sedation or drowsiness.18 A recent new metoclopramide formulation with a neutral pH might have fewer side-e¡ects and, administered in high doses, could be useful for the control of PONV.
Droperidol Droperidol is a butyrphenone derivative, which exerts its antiemetic properties by blocking dopaminergic D2 receptors and to a lesser extent histamine and serotonin receptors. Several trials showed that droperidol was effective in preventing nausea and vomiting in a variety of
40
surgical interventions, when compared with placebo, and better results were obtained in comparison with metoclopramide. Droperidol was as e¡ective as the 5-HT3 receptor antagonists ondansetron, tropisetron and dolasetron. Droperidol is more e¡ective for nausea than for vomiting. The anti-emetic e¡ect is evident at doses as low as 0.25^ 0.5 mg i.v. in adults.The prophylactic administration of 0.625 mg of i.v. droperidol was very e¡ective in decreasing PONV with no increase in adverse sidee¡ects.19 Higher doses of droperidol (2.5^5 mg i.v.) with duration of action up to 12 h are more e¡ective in higher risk patients (e.g. strabismus surgery). However, the risk of adverse e¡ects may be increased and the patients should be monitored for sedation, dysphoria and extrapyramidal symptoms. Hypotension may also occur, as a result of alpha-adrenergic blockade. There was evidence that in adults sedation was dose-dependent (NNTH about 7 with 2.5 mg i.v.) and extrapyramidal symptoms were rare (NNTH about 400).15 When the dose of droperidol was limited to 1.25 mg i.v., the incidence of these central nervous system (CNS) events did not di¡er in comparison with ondansetron. 20 Extrapyramidal reactions may occur more frequently in paediatric patients (NNTH about 90 after a dose of 75 mg/kg droperidol i.v.). Therefore, in children, smaller doses (50 mg/ kg i.v.) are recommended, which are still antiemetic, but with a lower risk of adverse e¡ects. When given at the end of surgery, droperidol was more e¡ective compared with the same dose given at induction or during surgery. Droperidol is mostly recommended for the prevention of PONV induced by opioids (morphine) administered via PCA devices. In this circumstance, droperidol had the highest antiemetic e⁄cacy (NNTP about 3).5 Although the e⁄cacy of droperidol was well established, it has now been withdrawn in United Kingdom because of its propensity to cause prolonged Q-T interval.
5-HT3 receptor antagonists This class of anti-emetics contains ondansetron as prototype and the more recently developed granisetron, dolasetron, tropisetron and ramosetron. Ondansetron is a carbazalone derivative, which possesses speci¢c 5-HT3 subtype receptor antagonist properties, without altering dopamine, histamine, adrenergic or cholinergic receptor activity. Ondansetron, 4 mg i.v. in adults and 0.05 mg/kg in children, is highly e¡ective in decreasing the incidence of PONV. Although a larger dose of 8 mg i.v. may be more e⁄cacious, especially in patients with a history of motion sickness or previous PONV, a recent meta-analysis demonstrated that ondansetron showed an increased anti-vomiting ef¢cacy in this subgroup of patients irrespective of the administered dose.21 Ondansetron is also available for oral administration, e¡ective as a single dose of 16 mg. It
CURRENT ANAESTHESIA & CRITICAL CARE
was shown that the antivomiting e¡ect of ondansetron was consistently more pronounced than the antinausea e¡ect. Some studies showed that in comparison with droperidol, ondansetron was equivalent in prevention of postoperative vomiting, but droperidol prevented nausea to a greater degree.20 Ondansetron may be superior in children, and provides anti-emetic control for a signi¢cantly longer period (up to 24 h), whereas droperidol is more cost-e¡ective. In children undergoing strabismus repair, 75 mg/kg ondansetron was very e¡ective (NNTP 2) and improved the ‘true’ outcome measures.22 The most signi¢cant feature of ondansetron prophylaxis is the low incidence of side-e¡ects which include headache, lightheadedness and constipation. Sedation, dysphoria, hypotension and extrapyramidal symptoms that may accompany administration of other antiemetics do not accompany administration of ondansetron. With the newer 5-HT3 antagonists, larger trials are needed to evaluate their antiemetic e⁄cacy. Granisetron is a more selective 5-HT3 receptor antagonist than ondansetron.The elimination half-time of 9 h is 2.5 times longer than that of ondansetron and a single dose of granisetron may be e¡ective for 24 h. For prevention of PONV, the studies support the use of a single i.v. dose of 20 ^ 40 mg/kg. Dolasetron 12.5 mg i.v. is as e¡ective as 4 and 8 mg ondansetron but achieves the same degree of patient satisfaction at a lower cost.23 For oral use, the 100 mg oral dose of dolasetron is most e¡ective. Ramosetron has the longest antiemetic e¡ect up to 48 h. The optimal dose for the prevention of PONVafter gynaecological surgery was 0.3 mg i.v.24
Dexamethasone Dexamethasone is a corticosteroid with strong antiin£ammatory and prolonged antiemetic e¡ects.The mechanism of action of dexamethasone in emesis is unknown. One theory is that it exerts its antiemetic e¡ect via prostaglandin antagonism. There may also be a reduced serotonin release from the gut. As monotherapy, the minimum e¡ective dose for preventing PONV was 2.5 mg i.v. given immediately before the induction and the usual doses of10 and 5 mg did not o¡er any therapeutic advantage over 2.5 mg.The onset time of dexamethasone’s antiemetic e¡ect may be approximately 2 h.25 The prophylactic administration of dexamethasone immediately before induction, rather than at the end of anaesthesia was more e¡ective in preventing PONV. As the biological life of dexamethasone is 36^72 h, the antiemetic e⁄cacy is prolonged (up to 24 h).With a single prophylactic dose of dexamethasone, the NNT to prevent early and late vomiting compared with placebo was 7.1 in adults and 3.8 in children.26 Late e⁄cacy was more pronounced. In adults, the NNTP for late nausea was 4.3.
POSTOPERATIVE NAUSEA ANDVOMITING
When compared with ondansetron, dexamethasone had similar NNTP for PONV and similar satisfaction scores but was more cost-e¡ective.16 Administered in a single dose, dexamethasone had no signi¢cant side-e¡ects. Best antiemetic e⁄cacy was achieved when dexamethasone was combined with a 5-HT3 receptor antagonist.
41
were more e¡ective than placebo within 6 h of surgery in adults, but there was no bene¢t in children. NNT to prevent early nausea or vomiting is about 5. These techniques could be recommended in patients with known adverse reactions to anti-emetic drugs and in patients who wish to minimize drug intake in the clinical setting.31
Other antiemetic drugs Phenothiazines such as chlorpromazine and promethazine have been used for years in the prevention and treatment of PONV, but can produce hypotension and signi¢cant sedation and lethargy during recovery. The more recently introduced prochloperazine and perphenazine are associated with a relatively high incidence of extrapyramidal side-e¡ects. Antihistaminics such as hydroxyzine and cyclizine are particularly useful in motion sickness and in the control of emesis following middle-ear surgery.Cyclizine was also e⁄cacious for the prevention of PONV after day-case gynaecological surgery. Among the anticholinergics, transdermal scopolamine was e¡ective in controlling motion sickness and signi¢cantly decreased the incidence of severe PONV after laparoscopic surgery. The most common adverse e¡ects associated with the use of a transdermal scopolamine patch were dry mouth and visual disturbances. Other anticholinergics such as atropine and glycopyrolate reduced nausea during spinal anaesthesia. Cannabinoids may be e¡ective in treating PONV as was demonstrated in a recent study on ferrets. 27 However, in clinical practice their role is limited because of the high incidence of CNS side-e¡ects. Antagonists at the NK1 receptor represent another new class of antiemetics. Pre-operative administration of the orally active NK1 antagonist CP-122,721was found to be similar to ondansetron in decreasing emetic symptoms after abdominal hysterectomy procedures.28 Although preliminary data have demonstrated the e⁄cacy of NK1 receptor antagonists, further studies are needed to clarify their role as anti-emetics. Ephedrine, an indirect-acting sympathomimetic drug, had a signi¢cant antiemetic e¡ect up to 3 h after administration, with no evident side-e¡ects.29
Non-pharmacological techniques Acupuncture, transcutaneous electrical nerve stimulation, acupoint stimulation, and acupressure showed an antiemetic e⁄cacy comparable with available antiemetics.30 Stimulation of the P- 6 acupuncture point (Neiguan) resulted in a signi¢cant reduction of postoperative emesis. Application of pressure every 2 h to this acupuncture point was reported to produce an anti-emetic action for up to 24 h. Non-pharmacological techniques
Combination antiemetic therapy Despite the introduction of new antiemetics over the past decade, no completely e¡ective antiemetic exists for the prevention of PONV. None of the above presented drugs and interventions consistently showed both antinausea and antivomiting e⁄cacy. Only 20% of adult patients will bene¢t (NNTP about 5) from the best prophylactic antiemetic interventions. A combination of anti-emetic drugs with action at different sites (‘balanced anti-emesis’) could be more e⁄cacious and less toxic as compared with monotherapy.32 For instance, ondansetron which shows less antinausea and more antivomiting e⁄cacy can be combined with droperidol which has more antinausea e⁄cacy. The increased risk of headache after ondansetron can be reduced by the addition of droperidol which o¡ers protection against headache. Another recommended combination is dexamethasone plus a 5-HT3 receptor antagonist, which is likely to be the most e¡ective antiemetic regimen currently available.5 A recent study demonstrated the superiority of the combination between ondansetron and cyclizine over placebo for the prevention of PONV. In a high-risk surgical population, the use of combined pharmacological (e.g. anti-emetic) and nonpharmacological (e.g. acupuncture, transcutaneous acupoint stimulation) therapies may o¡er advantages over either modality alone. Prophylaxis with three anti-emetic drugs may be justi¢ed in patients with the highest risk for PONV (e.g. a patient with the four strongest predictors of PONV on Apfel’s risk score: a non-smoking woman with previous PONV, undergoing laparoscopy and receiving postoperative opioids). A multimodal management algorithm consisting of total intravenous anaesthesia (propofol and remifentanil), no N2O, no neuromuscular blockade, aggressive intravenous hydration (25 ml/kg), triple prophylactic antiemetics (ondansetron 1mg, droperidol 0.625 mg and dexamethasone 10 mg), and ketorolac 30 mg, resulted in a 98% reduction of postoperative vomiting. However, this improved e⁄cacy relative to PONV, did not result in an increased level of patient satisfaction when compared with routine monotherapy prophylaxis. 33 Further research is needed to evaluate the e⁄cacy of combination strategies (‘balanced anti-emesis’) and to identify the most e¡ective combinations of anti-emetics and their doses.
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TREATMENTOF ESTABLISHED PONV If vomiting is protracted, acute hydration with crystalloid solutions and supplemental oxygen via a face mask will represent the ¢rst therapeutic measures. Among the anti-emetic drugs, droperidol and 5-HT3 receptor antagonists are recommended for patients with established postoperative nausea and vomiting. When ondansetron is used to treat PONV, doses of 1^ 4 mg i.v. are e¡ective. With ondansetron, 1mg i.v., the symptoms are relieved for 24 h in about 40% of nauseated or vomiting patients in comparison with about 20% of the patients with placebo. The recommended dose for paediatric patients is 50 mg/kg. Ondansetron combined with cyclizine given sequentially was more e¡ective than either drug alone.34 Dolasetron was also evaluated for the treatment of established PONV. The e¡ective dose in adults was 12.5 mg i.v.
CONCLUSIONS Although the actual morbidity associated with nausea and vomiting is relatively low in healthy patients, it represents a major source of discomfort for the surgical patient and a challenge for ambulatory surgery. Anaesthesiologists have control over the anaesthetic-related factors a¡ecting PONV. Avoidance of nitrous oxide and administration of propofol as a maintenance anaesthetic agent for total intravenous anaesthesia, will reduce the incidence of PONV. Regional nerve-block procedures are associated with less PONV than general anaesthesia. In high-risk patients, the prophylactic use of anti-emetic drugs is necessary. Nausea is more di⁄cult to prevent than is vomiting. Of the multitude of pharmacological agents tested, the 5-HT3 antagonists, droperidol and dexamethasone have proven to be the most e¡ective. When administration of a single anti-emetic is not e¡ective, a combination of anti-emetic drugs with di¡erent sites of action (‘balanced anti-emesis’) should be considered. Postoperatively, non-opioid analgesics are recommended to control the pain. If emesis does occur, antiemetic therapy in combination with aggressive intravenous hydration and pain management should be started.
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24. Fujii Y, SaitohY, Tanaka H, Toyooka H. Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery. Anesth Analg 2000; 90: 472^ 475. 25. Wang J J, Ho S T, Tzeng J I, Tang C S. The e¡ect of timing of dexamethasone administration on its e⁄cacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000; 91: 136^139. 26. Henzi I, Walder B, Tramer M Q. Dexamethasone for the prevention of postoperative nauseau and vomiting; a quantitative Systemic review. Anesth Analg 2000; 90: 186 ^194. 27. Simoneau I I, Hamza M S, Mata H P et al. The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001; 94: 882^ 887. 28. Gesztesi Z, Scuderi P E, White P F et al. Substance P (Neurokinin1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000; 93: 931^937. 29. Hagemann E, Halvorsen A, Holgersen O,Tveit T, Raeder J C. Intramuscular ephedrine reduces emesis during the ¢rst three hours after abdominal hysterectomy. Acta Anaesthesiol Scand 2000; 44: 107^111. 30. Lee A, Done M L.The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999; 88:1362^1369. 31. Zarate E, Mingus M, White P F et al. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001; 92: 629^ 635.
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32. He¡ernan A M, Rowbotham D J. Postoperative nausea and vomitingFtime for balanced antiemesis? Br J Anaesth 2000; 85: 675^ 677. 33. Scuderi P E, James R L, Harris L, Mims 3rd. G R Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000; 91: 1408 ^1414. 34. Kyriakides K, Hussain S, Harrison J, Webb A, Hobbs G J. Comparison of ondansetron and cyclizine in the treatment of early postoperative nausea and vomiting. Br J Anaesth 1998; 80: A459.
FURTHER READING Gralla R J, Osoba D, Kris M G et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999; 17: 2971^2994. Tramer M R. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part II. Recommendations for prevention and treatment, and research agenda. Acta Anaesthesiol Scand 2001; 45: 14 ^19. Lynch L. Antiemetic drugs. The Royal College of anaesthetists 2001; Bulletin 9: 415^ 418. Eberhart L H, Hogel J, Seeling W, Staack A M, Geldner G, Georgie¡ M. Evaluation of three risk scores to predict postoperative nausea and vomiting. Acta Anaesthesiol Scand2000; 44: 480 ^ 488.