Inflamm. res. 53, Supplement 2 (2004) S154–S158
`1023-3830/04/02S154-05
`DOI 10.1007/s00011-004-0367-0
`
`© Birkhäuser Verlag, Basel, 2004
`Inflammation Research
`
`Premedication with H1 and H2 blocking agents reduces
`the incidence of postoperative nausea and vomiting
`
`A. W. Doenicke 1, R. Hoernecke 1 and I. Celik 2
`1 Institute of Anaesthesiology, Klinikum Innenstadt, Ludwig-Maximilians-University, Pettenkoferstr. 8a, 80336 Munich, Germany,
`Fax: ++49 89 5160 4742, e-mail: doenickeaw@aol.com
`2 Institute of Theoretical Surgery, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany, Fax: ++49 6421 2868926,
`e-mail: celic@mailer.uni-marburg.de
`
`Abstract. Objective: Patients undergoing anaesthesia and
`surgery frequently complain about postoperative nausea and
`vomiting (PONV). Whether pretreatment with H1 and H2
`blocking agents reduces the incidence of PONV remains
`controversial. To answer this question, we performed a ran-
`domised, prospective, placebo-controlled clinical study to
`evaluate the efficacy of a premedication with H1 and H2
`receptor antagonists.
`Material and subjects: 1149 patients (both sexes) undergo-
`ing surgery were randomly assigned to three treatment
`groups and one control group.
`Patients in the treatment groups were premedicated with the
`following H1 + H2 receptor antagonists:
`∑ Group 1 (n = 335): 5 mg/kg cimetidine i.v. + 0.1 mg/kg
`dimetindene i.v.
`20 min before induction of anaesthesia
`∑ Group 2 (n = 337): 1.25 mg/kg ranitidine i.v. + 0.1 mg/kg
`dimetindene i.v.
`20 min before induction of anaesthesia
`∑ Group 3 (n = 316): 300 mg ranitidine p.o. + 0.1 mg/kg
`dimetindene i.v.
`1 to 2 h before induction of anaesthesia
`∑ Group 4 (n = 161): 20 ml saline solution i.v.
`20 min before induction of anaesthesia
`
`Patients from the treatment groups 1, 2 and 3 received
`regional or general anaesthesia depending on the clinical
`decision. All control patients received general anaesthesia
`consisting of fentanyl, a thiobarbiturate, enflurane, nitrous
`oxide, oxygen, and vecuronium.
`Results: The incidence of nausea and vomiting was 8.5%,
`6.8% and 5.4% in patients from the treatment groups (1, 2
`and 3) who underwent general anaesthesia (n = 545), with no
`statistically significant differences between groups. The inci-
`dence of nausea and vomiting in the control group (n = 161)
`was 28.3% (nausea) and 27.5% (vomiting), respectively. In
`patients who underwent regional anaesthesia (n = 443), the
`
`Correspondence to: I. Celik
`This work was supported by GlaxoSmithKline Pharmaceuticals.
`
`incidence of nausea and vomiting was 2.5% and 1.1%,
`respectively.
`Conclusions: Premedication with H1 and H2 blocking agents
`significantly reduces the incidence of postoperative nausea
`and vomiting.
`
`Key words: Antihistamines – Ranitidine – Cimetidine –
`Nausea – Vomiting – General anaesthesia
`
`Introduction
`
`Prior to surgery, many patients worry about postoperative
`nausea and vomiting (PONV) [1, 2]. Nausea and vomiting in
`the post-operative phase (PONV) are the most frequent side
`effects of anaesthesia with an incidence of 20–30% [2–4].
`PONV is therefore described as the ‘big little problem’ of
`anaesthesia [5]. PONV is unpleasant for the patient and has
`negative effects on the patient’s satisfaction. Indeed when
`patients are asked about their preferences for the immediate
`postoperative period, the first choice is no nausea or vomit-
`ing, this is above freedom from pain or any other postopera-
`tive complications [2, 6]. Major medical complications
`caused by aspiration, ruptured sutures, liquid and electrolyte-
`imbalance in children and deaths from ‘Boerhaave syn-
`drome’ although described in the literature are relatively rare
`[7]. Thus a safe and effective treatment to prevent PONV
`would benefit patients. Indeed patients would even pay the
`costs from their own pockets for a guaranteed PONV free
`anaesthesia [2, 8].
`The aetiology of PONV is complex and multifactorial.
`Several patient-, anaesthesia- and surgery-related factors are
`known to influence an individual’s risk of PONV [2, 9–11].
`There are at least four different types of pharmacological
`receptors, which are involved in the process of vomiting.
`Drugs that are presently used for prophylaxis and/or treat-
`ment of PONV can be classified with respect to their sites of
`action and include dopaminergic, histaminergic, muscarinic
`and serotonergic (5-HT3) receptor antagonists [2, 12–15].
`
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`

`Inflamm. res., Supplement 2 (2004)
`
`Premedication with antihistamines reduces postoperative nausea
`
`S155
`
`The efficacy of the combined use of H1- and H2-receptor
`antagonists for prevention of PONV was previously demon-
`strated and suggested a role for histamine in the pathogene-
`sis of PONV [16, 17]. More recently, cyclizine (H1 receptor
`antagonist) proved to be at least as effective as ondansetron
`in preventing PONV after gynaecological laparoscopy and
`was even superior to ondansetron concerning the use of res-
`cue antiemetics in patients undergoing diagnostic laparo-
`scopy [18]. A recently published study investigating changes
`in the mediator levels of histamine and serotonin metabolites
`after gynaecological laparoscopy demonstrate an association
`between these changes in mediator levels and PONV [19,
`20]. In accordance with these results, a recently published
`metaanalysis showed that dimenhydrinate, another H1 antag-
`onist with some antimuscarinic activity, has a similar effica-
`cy with respect to the prophylaxis of PONV when compared
`to more common antiemetics such as 5HT3 antagonists and
`droperidol [2, 21].
`The aim of our study was to compare the potential of two
`H2-receptor antagonists, cimetidine and ranitidine, each in
`combination with the H1-receptor antagonist dimetindene, in
`preventing postoperative nausea and vomiting.
`
`Patients and methods
`
`After ethical approval and with written informed consent from each
`patient, patients were recruited at the University Hospital Munich for
`this open, prospective, randomised, placebo-controlled clinical study.
`
`Study design
`
`Patients undergoing surgery from different disciplines (general surgery,
`orthopaedic surgery and urology) were randomly assigned to either one
`of three treatment groups or the placebo group. Exclusion criteria for
`study participation were: age <18 years; pregnancy or lactation; emer-
`gency patient; allergy or intolerance to study medication; intake of
`study medication prior to study participation; oral administration of
`study medication not possible; planned discharge during observation
`period; operation outside normal h.
`
`Course for the individual patient
`
`Patients in the treatment groups received either general or regional
`anaesthesia, depending on the clinical decision. All patients in the con-
`trol group received general anaesthesia (Table 1).
`
`Induction of general anaesthesia consisted of thiopental, fentanyl,
`and vecuronium followed by nitrous oxide/oxygen and enflurane. Nau-
`sea and vomiting were documented after surgery with a patient-com-
`pleted questionnaire indicating ‘present’ or ‘none’ over a time period of
`24 h after operation (observation period). Patients with severe postop-
`erative nausea and vomiting were treated with a rescue medication con-
`sisting of 10 mg metoclopramide.
`Patients in the four study groups were premedicated with the fol-
`lowing H1 + H2 receptor antagonist combinations or placebo (saline):
`∑ Group 1 (n = 335): 5 mg/kg cimetidine i.v. + 0.1 mg/kg dimetindene
`i.v.
`20 min before induction of anaesthesia
`∑ Group 2 (n = 337): 1.25 mg/kg ranitidine i.v. + 0.1 mg/kg dimetin-
`dene i.v.
`20 min before induction of anaesthesia
`∑ Group 3 (n = 316): 300 mg ranitidine p.o. + 0.1 mg/kg dimetindene
`i.v.
`1 to 2 h before induction of anaesthesia
`∑ Group 4 (n = 161): 20 ml saline solution i.v.
`20 min before induction of anaesthesia
`
`Statistical analysis
`
`Data are presented as number or the mean (range). Comparisons of
`mean values between the groups were performed using the Kruskal-
`Wallis test. Incidences (frequencies, rates) were compared using Chi2-
`test. Treatment differences were considered significant at p £ 0.05.
`
`Results
`
`Of 1438 patients enrolled in this study, 1149 were included in
`the analysis of efficacy (Table 1). Of the 289 patients exclud-
`ed from the statistical evaluation, surgery had to be resched-
`uled in 172 patients because of incoming emergency cases.
`In 38 patients, surgery was delayed for more than 2 h after
`premedication; 5 patients allocated to group 3 had not
`received oral ranitidine according to the protocol; and
`66 patients withdrew consent to participate in the study
`before induction of anaesthesia.
`The patients enrolled in this study belonged to the fol-
`lowing ASA physical status groups: I (21.8%), II (37.8%),
`III (35.5%) and IV (4.9%). There were no statistically sig-
`nificant differences between the four groups in terms of ASA
`classification of physical status, age (mean 42 y), height
`(mean 171 cm), weight (mean 71 kg), or gender (approx.
`65% male/35% female in all groups). There were no signif-
`icant demographic differences between patients who com-
`pleted the study and those who did not.
`
`Table 1. Premedication with H1/H2 blocking agents. Subjects enrolled in the study.
`
`Group 1
`
`Group 2
`
`Group 3
`
`Premedication
`
`Cim/Dim i.v.
`
`Ran/Dim i.v.
`
`Ran/Dim p.o.
`
`General anaesthesia
`Regional anaesthesia
`Total
`
`181
`154
`335
`
`197
`140
`337
`
`167
`149
`316
`
`Treatment groups were premedicated 20 min before induction of anaesthesia.
`Group 1:
`5 mg/kg cimetidine i.v. (Cim) + 0.1 mg/kg dimethindene i.v. (Dim)
`Group 2:
`1.25 mg/kg ranitidine i.v. (Ran) + 0.1 mg/kg dimethindene i.v. (Dim)
`Group 3:
`300 mg ranitidine p.o. (Ran) 1 to 2 h before induction of anaesthesia
`Group 4:
`Placebo (20 ml saline solution i.v.) 20 min before induction of anaesthesia
`
`Group 4
`
`Saline
`
`161
`
`161
`
`Total
`
`706
`443
`1149
`
`

`

`S156
`
`A. W. Doenicke, R. Hoernecke and I. Celik
`
`Inflamm. res., Supplement 2 (2004)
`
`Discussion
`
`The reported incidence of postoperative nausea and vomiting
`varies, ranging from 19.4% to 55% and even higher after
`gynaecological surgery, causing problems during the recov-
`ery period [2–4, 15, 22, 23]. The incidence in our control
`group (28.3%), was consistent with previously published
`papers [2, 12, 15, 16]. The incidence of vomiting reported in
`the literature is ca. 20% in male patients treated with
`ondansetron [2, 12, 15, 22].
`The H1 and H2 receptor antagonists used in this study sig-
`nificantly reduced the incidence of nausea and vomiting,
`with oral ranitidine being as effective as the intravenous for-
`mulation. The combination of ranitidine/dimethindene did
`not differ from cimetidine/dimetindene in its ability to reduce
`nausea and vomiting. Cimetidine binds reversibly to cyto-
`chrome P450 isoenzymes and inhibits hepatic oxidative drug
`metabolism of agents like theophylline, phenytoin, lidocaine,
`and the benzodiazepines [24, 25]. Thus cimetidine may cause
`higher plasma levels of these drugs, an undesired effect in
`drugs that have a narrow therapeutic range [26]. Ranitidine,
`however, does not affect the pharmacokinetics of these drugs
`[24, 25]. In addition to previously published data on the effi-
`cacy of a H1 + H2 antihistamine prophylaxis for PONV [16,
`17], a recently published study using a H1 + H2 antihistamine
`prophylaxis (cimetidine and dimetindene) clearly demon-
`strated a marked reduction in the incidence of PONV in
`patients undergoing general anaesthesia and surgery com-
`pared to patients without prophylaxis [27].
`Often, the question for the anaesthetist is not whether an
`antiemetic should be given but rather which antiemetic by
`which route (i.v. or p.o.). Although studies investigating the
`effect of ondansetron on postoperative nausea and vomiting
`are interesting (Table 2) [22], most studies report superiority
`of ondansetron in doses of 4–8 mg over placebo [2, 12, 15,
`28]. Outcome studies comparing ondansetron with other
`therapies showed it was significantly better than metoclo-
`pramide, but not better than droperidol [12, 15, 22, 28].
`Antiemetics may not only increase patient’s satisfaction
`with anaesthesia, but may also decrease the incidence of
`aspiration pneumonia. Hypnotics, anaesthetics and muscle
`relaxants appear to increase acidity and volume of gastric
`juice during the induction phase via histamine receptors in
`the stomach [29]. Drugs given throughout the course of
`anaesthesia may also stimulate histamine release which, in
`turn, stimulates the production of gastric juice and leads to
`cardiovascular instabilities due to histamine release during
`anaesthesia and surgery [29, 30]. H2 receptor antagonists
`
`Table 2. Incidence of nausea and vomiting within 24 h post general
`anaesthesia.
`
`Group 1
`
`Group 2
`
`Symptoms
`
`Ondansetron i.v.
`
`Placebo i.v.
`
`Nausea female
`Nausea male
`Vomiting female
`Vomiting male
`
`60% (n = 259)
`42% (n = 204)
`31% (n = 272)
`37% (n = 204)
`
`70% (n = 269)
`51% (n = 223)
`55% (n = 282)
`70% (n = 223)
`
`Premedication: Ondansetron 4 mg i.v. (adapted from Pearman [22]).
`
`Fig. 1. Incidence of nausea and vomiting within 24 h after general
`anaesthesia. CIM = cimetidene; RAN = ranitidine; DIM = dimetindene;
`i.v. = intravenous; p.o. = peroral; Placebo = saline.
`
`The average duration of surgery for patients in group 1
`was 78 min (range: 10 to 465 min); 80 min (range: 10 to
`395 min) for group 2; 75 min (range: 10 to 395 min) for
`group 3; and 114 min (range: 25 to 480 min) for group 4
`(control group). The duration of surgery in the control group
`differed significantly from those in each of the treatment
`groups (p £ 0.05). In the three treatment groups, 443
`patients received regional anaesthesia and 545 patients
`underwent general anaesthesia. All 161 patients of the con-
`trol group received general anaesthesia according to the
`study protocol.
`The other agents given to patients who underwent gener-
`al anaesthesia with isoflurane or enflurane were: N2O2
`(99.8% of patients), vecuronium (98% of patients), fentanyl
`(95% of patients), thiopental (95% of patients) and etomi-
`date (5% of patients). Patients undergoing regional anaes-
`thesia received bupivacaine, mepivacaine, or prilocaine
`depending on the expected duration of surgery.
`The incidence of nausea and vomiting was significantly
`lower (p £ 0.01) in patients who received regional anaesthe-
`sia: 1.9% of patients in group 1 (n = 154); 2.9% in group 2
`(n = 140); and 2.7% in group 3 (n = 149) suffered from nau-
`sea, and 1.3%, 1.4%, and 0.7%, respectively, suffered from
`vomiting. In all treatment groups, the mean incidence of nau-
`sea (8%) and vomiting (5.4%) was significantly lower after
`general anaesthesia compared to the placebo group (28.3%
`and 27.5%, respectively; p £ 0.01 and p £ 0.001) (Fig. 1).
`The three different treatment groups were not statistically
`significantly different. However, the incidence of PONV in
`the treatment groups receiving Ran/Dim i.v. and Ran/Dim
`p.o. was slightly lower than in the Cim/Dim i.v. group.
`Comparing the gender of the patients, there was a high
`incidence of nausea in females in the placebo group (36.6%)
`compared to the treatment groups (12.8%). In male patients
`19.6% suffered from nausea in the placebo group and 5.2%
`in the treatment groups. In female patients, vomiting
`occurred in 9.8% of the treated patients compared to 45.4%
`in the placebo group; 13.8% of the male individuals vomit-
`ed in the placebo group but only 2.9% after H1/H2 pretreat-
`ment.
`
`

`

`Inflamm. res., Supplement 2 (2004)
`
`Premedication with antihistamines reduces postoperative nausea
`
`S157
`
`such as ranitidine and cimetidine may decrease nausea and
`vomiting by inhibiting secretion of gastric acid; the central
`antiemetic properties of the H1 blocker dimetindene may
`contribute to the overall effect.
`Oral administration of H1/H2 antihistamines 1 to 2 h before
`the beginning of anaesthesia was as effective as intravenous
`administration 20 min before anaesthesia. We hypothesize that
`ranitidine (300 mg p.o.) may have a specific effect on the H2
`receptors of the stomach, thus reducing the excretion of gastric
`juice before anaesthetics are given. Prophylaxis with H1/H2
`receptor antagonists lessens the amount of histamine release
`after administration of hypnotics, analgesics and muscle relax-
`ants and also reduces cutaneous reactions and changes in
`blood pressure [30–32]. For example, oral premedication with
`H1 and H2 antagonists prevents the haemodynamic and cuta-
`neous adverse effects caused by mivacurium [33].
`The newest class of antiemetics used for the prevention
`and treatment of PONV are the serotonin receptor antago-
`nists. These have been shown to reduce the incidence of
`PONV [34, 35]. The 5-HT3 receptor antagonists are superior
`to conventional antiemetic agents for the prevention of
`PONV [36], however, they are relatively expensive. In con-
`trast, it has been reported that ondansetron and cyclizine
`show equal effectiveness for the prevention of PONV [18].
`Furthermore, the combined use of ondansetron and cyclizine
`was shown to be more effective in preventing PONV than just
`using ondansetron [37].
`An optimal antiemetic efficacy may be achieved with a
`combination of different receptor antagonists in order to
`block various emetic stimuli acting at different receptor sites
`suggested by Kovac [2, 10, 15] and others. Thus for patients
`at high risk for PONV, a combination of antiemetics acting at
`different receptors should be considered. Accordingly a com-
`bined antiemetic prophylaxis has been shown to improve
`results in high-risk patients [12, 15, 28, 38, 39]. These strate-
`gies include: providing routine therapy with antiemetics and
`using rescue agents for postoperative nausea and vomiting.
`The reduction of both nausea and vomiting in our study by
`more than two-thirds (treatment compared with placebo)
`may have benefits: shorter stays in the post-anaesthesia care
`unit, use of fewer nursing resources, and decreased expenses
`are possible advantages of this preventive treatment as well
`as improved patient’s satisfaction.
`
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