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European Review for Medical and Pharmacological Sciences 2006; 10: 121-126 as an anti-emetic

F. RODOLÀ

Istituto di Anestesiologia e Rianimazione, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore – Rome (Italy)

Abstract. – have been Benzodiazepines have been involved dur- involved during the years in the prevention and ing the years in the prevention and/or treat- treatment of Post-Operative and Vomit- ment of PONV: e.g., proved an an- ing (PONV). Midazolam, a short acting ti-emetic effect in younger patients after stra- 5 widely used as a premedicant before surgery, for bismus surgery , as, more recently, diazepam- induction of anaesthesia, and for conscious se- sulfate premedication6. dation, has been particularly studied, sometimes Midazolam has been studied in the last 15-20 with conflicting results. years both for prevention and, less frequently, This paper will discuss the possible mecha- for treatment of established and persistent nisms of action of midazolam in PONV manage- ment and its fields of application (adults and PONV, sometimes with conflicting results. children undergoing surgery, treatment of per- Aim of this paper is to shortly report the sistent postoperative emesis), as far as poten- last researches on this subject, discussing pos- tialities of other non-traditional anti-emetics, sible mechanisms of the anti-emetic effect of maybe ready to get out the arena of case re- midazolam, its fields of application, and con- ports, and the need of further studies on postop- troversy on its use in preventing and treating erative anti-emetics in their efficacy in treating PONV. established PONV.

Key Words: Midazolam Benzodiazepines, Midazolam, Post-Operative Nausea and (PONV), Anti-emetics. Midazolam hydrochloride is a short-acting benzodiazepine CNS . It may be administered before surgery as a premedicant to relieve apprehension and impair memory, Introduction for induction of anaesthesia (although in comparison with barbiturates its use is associ- Post-Operative Nausea and Vomiting ated with a slower onset of action and a more (PONV), well defined by Knapp and prolonged recovery time), and for conscious Beecher1 since 1956, is an undesired and un- sedation7. pleasant side effect of anaesthesia, both gen- Midazolam may be administered by mouth, eral and regional. Although it may induce se- parenterally, or via the intranasal or endorectal rious complications2, it is most often a minor route in children; preservative free intrathecal problem after surgery: it does not become midazolam has been used for postoperative chronic, and almost never kills; however, it analgesia in caesarean section delivery8. may be very distressing for patients3. A great It has been postulated that a possible variety of with different mechanisms of mechanism for the anti-emetic effect of ben- action, used alone or in combination, more or zodiazepines could be an action at the less expensive, have been used through the chemoreceptor trigger zone reducing synthe- years with the intent to prevent and treat it. sis, release and postsynaptic effect of Nevertheless, its incidence seems to remain dopamine9. Whether benzodiazepines reduce quite constant: according to Kovac4 up to 20- release centrally, or by blocking 30% of patients undergoing general anaes- the re-uptake of adenosine, causing an thesia still experience PONV, despite all pro- adenosine-mediated reduction of dopamine phylactic measures. release, has been matter of debate10-14.

Corresponding Author: Ferdinando Rodolà, MD; e-mail: [email protected] 121 F. Rodolà

Dopaminergic neuronal activity and 5-hy- All but one of these studies21 showed at droxytryptamine release may also be reduced least the same beneficial effect of midazolam by binding of midazolam to the GABA ben- on PONV if compared with other premed- zodiazepine complex9,12,15: thus, anxiolysis as a icants, traditional anti-emetic , or secondary effect may also contribute to anti- placebo; the institution of a continuous infu- emesis. However, Wang and Klein16, in a sion of midazolam after cardiac surgery24 has cross-sectional study exploring a possible as- been found to be more effective than the ad- sociation between preoperative anxiety and ministration of by I.V. boluses. PONV in a group of children undergoing out- patient surgery did not find any predictive Paediatric Surgery value of children’s anxiety for the occurrence Midazolam has been studied as an anti- of PONV. emetic mostly in small patients undergoing strabismus surgery26 or ear-nose-throat (ENT) operations: actually, it is reported that Midazolam in preventing and up to 80% of children not receiving an anti- treating PONV emetic and undergoing adenotonsillectomy may suffer PONV27,28. Avoiding intra- and Midazolam has been used as an anti-emetic peri-operative emetic agents as nitrous oxide in adults and children, both as a preventive and morphine based opioids29, using non- medicine and a rescue . Up to the steroidal anti-inflammatory drugs (NSAIDs) turn of century almost only case reports have or codeine as premedicants30, and administer- been published, but in the last few years the ing systematically anti-emetics31 may reduce first randomised controlled studies started to PONV rate down to less than 20%. appear, although dosage, route and modality Safety and effectiveness of midazolam as of administration are still far to be standard- oral , after assessment of seda- ized, and almost every group of Authors used tion, quality of induction and effects on gas- midazolam in a different way. tric contents (residual volume and pH) have been demonstrated by Riva et al32; neverthe- Adult Surgical Population less, papers investigating its ability in pre- Studies reporting postoperative emetic venting PONV, even when not specifically de- symptoms in adults have been performed in signed, report conflicting results. various surgical settings. Midazolam has been Splinter et al33 found a lower incidence of used for monitored sedation in adult patients PONV than a placebo group: 42% vs 57%, scheduled for central venous access17, for still a quite high rate, but used for anaesthe- breast biopsy18, for plastic surgery under sia nitrous oxide and halothane, both known high-volume tumescent local anaesthesia19 or to be emetic. other kind of local anaesthesia20. All but one Zedie et al34 used the same kind of anaes- of these studies20 were not specifically de- thesia for paediatric outpatient surgery, but re- signed to investigate PONV occurrence, and ported a very low 6% of PONV. The Bergen- reported it at a variable rate, whereas more dahl group35 did not find, in a prospective, ran- specific comparative, prospective and con- domized, controlled clinical trial in children trolled investigations on anti-emetic effect of undergoing ENT surgery any particular ad- midazolam have been recently carried out in vantage in administering midazolam as a pre- patients undergoing . medication. Results of another recent study36 Midazolam has been used for premedica- showed that significantly reduce the tion in patients undergoing orthopaedic21, incidence of PONV, but usual anti-emetic outpatient22 and abdominal surgery23, and as agents, as well as drugs known to possess a preventive instituted as a continuous antiemetic properties such as midazolam lack infusion after tracheal extubation in patients any significant protective effect against emesis. undergoing cardiac surgery involving car- diopulmonary bypass24. Its effectiveness for Persistent Emesis the treatment of established PONV has been Persistent (not only postoperative) emesis studied in gynaecological and abdominal may rise to a priority to deal with both for pa- surgery25. tients and physicians, and lead to unanticipat-

122 Midazolam as an anti-emetic ed admissions of up to 1% ambulatory mercial product labelling adverse effects may surgery patients37. Three cases of persistent include hypotension, tachycardia, antero- PONV treated with low dose midazolam giv- grade amnesia (actually in most perioperative en by I.V. infusion have been reported by Di situations a beneficial effect), psychomotory Florio in 19929; the same Author38 later com- excitation, respiratory depression, and even pared midazolam to placebo in patients resis- nausea and vomiting. tant to standard anti-emetic medications, All but amnesia are rare on the whole and achieving statistically significant good results, midazolam may be considered as a quite safe although with a limited number of patients. drug; nevertheless, literature reports some A case of a female patient presenting, ac- conditions that is worth mentioning. cording to a widely used simplified PONV One minor trouble of intranasal adminis- risk score39, two or maybe more predictive tration of midazolam in paediatric patients is characteristics, has been quite recently re- irritation, and children are likely to cry, more ported40. She received a subarachnoid block than after the administration of other drugs for orthopaedic surgery, and developed in the by the same route34. recovery room a severe emetic status resis- A further problem in children may be repre- tant to all class of available anti-emetics. On- sented by paradoxical reactions following I.V. ly midazolam, actually administered primari- administration of midazolam: they include rest- ly to reduce anxiety and prevent bad memo- lessness, violent behaviour against relatives and ries of the event, stopped all emetic symp- medics, and acts of self-injury, sometimes need- toms. In this case the Authors suspected that ing for restraints. Rescue medications may be a timely coincidence with a delayed onset of needed: recently, a controlled trial has shown action of one or more of the anti-emetics the that paradoxical reactions can be aborted by patient received could not be excluded. ketamine, with a not yet clear mechanism45. A curious case of severe postoperative One more concern is the administration of nausea (but not vomiting), successfully treat- midazolam as treatment of persistent PONV. ed with I.V. midazolam, has been described in Midazolam is normally given by I.V. infusion a known epileptic female patient41. Actually, at subhypnotic doses (a 0.5-1 mg bolus as reviewed by the anaesthesiological team, she starter, followed by a 1 mg per hour infusion). admitted that she had a severe feeling of nau- Low dose midazolam is safe to use periopera- sea prior to her fits; the Authors of the case tively, and respiratory depression usually report concluded that is worth bearing in does not occur, even in combination with opi- mind that in epileptic patients, warning signs oids46,47; however oxygen supplementation of impending seizures may manifest as a post- and pulse oximetry monitoring are recom- operative problem, in this case emesis. mended48. Elderly people are especially sensi- Interestingly, midazolam and parenteral nu- tive to such effect of midazolam. trition have proven their effectiveness in a non surgical case of persistent and life threatening hyperemesis gravidarum42, while, more recent- ly, a case of a teenage boy affected by CVS Discussion (Cyclical Vomiting Syndrome: a condition that recent literature suggests to be linked with mi- Although case reports and controlled trials graine and adrenergic autonomic dysfunction) are now numerous, it has been observed that successfully treated with a combination of I.V. midazolam does not have still widely earned midazolam and clonidine has been reported43. acceptance as an anti-emetic medication49; it Midazolam has been also found to be an effec- looks to be popular in the Australasian tive anti-emetic during chemotherapy44. area9,13,38,48,50, where postoperative services seem to have reached a good experience with low-dose midazolam as a therapy for severe Side Effects PONV recalcitrant to anti-emetics43. Nevertheless, there is a general agreement A number of drug interactions, side effects that low dose midazolam is one of the drugs and complications could be associated with that can form part of the combination for dif- the use of midazolam. According to the com- ficult patients. Other non-traditional anti-

123 F. Rodolà emetics, as propofol51, clonidine52, dexam- tics of simplified scores appear, according to ethasone53 and even thiopentone54 may be Apfel and colleagues63 and Pierre and col- successfully used to stop emesis, and may de- leagues64 to be as good as more complex mod- serve more attention, as well: the use is not els, and easier to handle. included in the labelling, but, once a drug has One more concern may be represented by been approved for a certain use, experience the discrepancy between the great number of may show its usefulness for other problems. trials on prevention of PONV and a much It may be worth to lay stress on that most lesser number of papers on its treatment. Ac- of these drugs fulfil the need to cut down cording to some Authors65 the whole thing is costs of PONV treatment55; more, there is not not so surprising: therapeutic trials are logis- a clear evidence that prophylaxis actually de- tically more difficult to perform, and manu- creases the likelihood of unanticipated admis- facturers may have not any commercial inter- sions56. Furthermore, patients might be put at est in the treatment of established emesis, risk of suffering from unnecessary adverse since a preventive strategy may be worth- drug reactions, e.g. headache related to 5- while, assuming that all patients will receive HT3 receptor antagonists administration4,57, if the anti-emetic drug, and not only who needs a widespread prophylaxis policy is adopted. it: that is, treatment of established symptoms Postoperative emesis is a difficult multifactor- is likely to be in many cases more cost-effec- ial problem involving both patient’s aptitude, tive than prevention66. More, manufacturers type of surgery and perioperative administra- seem sometimes not to be keen to compare tion of drugs, mostly given for anaesthesia their drugs with new and old comparators, and analgesia after surgery. In patients at high and data on nausea occurrence are often dis- risk of PONV a multimodal approach should regarded or underreported. be adopted58, avoiding all avoidable risk fac- Valid data on the actual efficacy of anti- tors depending on the anaesthesia technique emetics, classic, new, and even non-tradition- itself (e.g. opiates, volatile agents, and nitrous al as midazolam and others, are still needed, oxide), administering intravenous anaesthetic as far as their ability for established PONV agents with a recognized anti-emetic action, treatment is not completely investigated and assuring anxiolysis and effective postoperative understood. analgesia, and adopting combination prophy- laxis with drugs working via different recep- tors50,59. Unfortunately, both in controlled tri- als and case reports, it is not uncommon that References heterogeneity in dosage, route and timing in administration of anti-emetics, and the goal of 1) KNAPP MR, BEECHER HK. Postanesthetic nausea, the study itself, compromise the reliability of vomiting and retching. JAMA 1956; 160: 376-385. data to allow meaningful conclusion; further- 2) BREMNER WGM, KUMAR CM. Delayed surgical em- physema, pneumomediastinum and bilateral more, there is still debate about a possible pneumothoraces after postoperative vomiting. Br “hard core” of patients suffering PONV what- J Anaesth 1993; 71: 296-297. ever anaesthetic technique is adopted60. In the 3) TRAMER MR, REYNOLDS JM, MOORE RA, MCQUAY HJ. last few years reliable and validated simplified When placebo controlled trials are essential and PONV risk scores, operation independent, in- equivalence trials are inadequate. Br Med J 1998; stead of endless listing of often doubtful risk 317: 875-880. 39,61,62 factors have been elaborated . The simpli- 4) KOVAC AL. Prevention and treatment of postopera- fied risk score by Apfel and colleagues39 al- tive nausea and vomiting. Drugs 2000; 59: 213- lows to assess the probability of PONV by the 243. small number of the most relevant risk fac- 5) KHALIL SN, BERRY JM, HOWARD G, LAWSON K, HANIS tors, i.e. female gender, non-smoking status, C, MAZOW ML, STANLEY TH. The antiemetic effect of history of and/or PONV, ad- lorazepam after outpatient strabismus surgery in children. Anesthesiology 1992; 77: 915-919. ministration of for postoperative anal- gesia. According to the Authors, if none or all 6) OZCAN AA, GUNES Y, H ACIYAKUPOGLU G. Using di- azepam and atropine before strabismus surgery four risk factors are present, PONV risk may to prevent postoperative nausea and vomiting: a increase from 10% (no risk factors) to 80% randomised, controlled study. J AAPOS 2003; 7: (all four risk factors). Predictive characteris- 210-212.

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