王丽珺仓 静薛张纲

(1复旦大学附属眼耳鼻喉科医院麻醉科 上海 200031；2复旦大学附属中山医院麻醉科 上海 200032)

6种方法预防低危患者术后恶心呕吐（p ONV）的成本效果分析

王丽珺1仓 静2△薛张纲2

(1复旦大学附属眼耳鼻喉科医院麻醉科 上海 200031；2复旦大学附属中山医院麻醉科 上海 200032)

目的比较6种方法预防相对低危患者在腹腔镜胆囊切除术后发生恶心呕吐的成本和效果。方法180名择期行腹腔镜胆囊切除术并符合入选标准的男性患者,随机分为6组。组1接受异丙酚靶控输注(targetcontrolled infusion,TCI)+5 mg托烷司琼；组2接受异丙酚TCI+10 mg地塞米松和1.25 mg氟派利多；组3接受异丙酚TCI+生理盐水；组4接受七氟醚+5 mg托烷司琼；组5接受七氟醚+10 mg地塞米松和1.25 mg氟派利多；组6接受七氟醚+生理盐水。研究终点是术后24 h内恶心呕吐发生的次数,采用盲法记录。结果各组患者的一般情况、麻醉时间、手术时间、拔管时间和术后24 h的痛觉模拟评分差异均无统计学意义。组2术后恶心呕吐的发生率显著低于组3(P=0.03),组5显著低于组6(P=0.01)。接受托烷司琼和异丙酚或七氟醚发生术后恶心呕吐的相对危险度分别为0.51或0.68；接受地塞米松联合氟哌利多和异丙酚或七氟醚发生术后恶心呕吐的相对危险度分别为0.40或0.39；相对于七氟醚,接受异丙酚麻醉发生术后恶心呕吐的相对危险度是0.80。1～6组每分钟的费用-效果比分别为1.07、0.88、1.14、1.05、0.74和1.06。结论异丙酚、托烷司琼、地塞米松和氟哌利多发生术后恶心呕吐的相对危险度不同。6种干预措施中,七氟醚结合地塞米松和氟哌利多具有最低的每分钟费用-效果比。

术后恶心呕吐(PONV)； 七氟醚 异丙酚； 托烷司琼； 地塞米松； 氟哌利多； 费用-效果

In recent years,new anesthetics,techniques and antiemetics have entered the market. Prophylactic antiemetics are useful in patients at risk of PONV［1］.Most previous studies have focused on the prophylaxis management for highrisk patients［2］.Researches on patients at relative low risk of PONV were rare.Nowadays,prevention of PONV should be examined not only for their clinical benefits but also their costs.

The aim of the present investigation was to compare 6 interventions for the prevention of PONV after LC in those at relative low risk of PONV,with the objective of looking at which combination is more economic and effective.

Materials and Methods

The local ethics committee approved the study protocol,and all patients gave informed consent to participate in the study.

SubjectsOne hundred and eithty male patients (ASA I-II)scheduled for elective LC were prospectively studied.Patients were enrolled from Jan.,2008 to Dec., 2008 in Zhongshan hospital.Inclusion criteria were nonsmoker status,no previous history of postoperative nausea and vomiting or motion sickness,and anticipated use of postoperative opioids［1］.Exclusion criteria were renal insufficiency(creatinine＞1.5 mg/d L),liver dysfunction(aspartate aminotransferase＞40 U/L, alanine aminotransferase＞40 U/L),abuse of alcohol and drugs,and documented coronary or valvular heart diseases.

proposalAll patients were instructed to refrain from food for 8 hours and not to drink for 3 houes before anaesthesia.There were no premedication.After a preoperative interview,by using computer-generated random numbers in sequentially numbered sealed envelopes,all patients fulfilling inclusion criteria were randomly separated into six groups：

In Group 1(n=30),anesthesia was induced by fentanyl 3μg/kg,lidocaine 20 mg, succinylcholine 1-2 mg/kg.target-controlled infusion (TCI)of pump using propofol(Diprivan 1%50 mL, DK550,AstraZeneca,UK)was initiated with the target plasma propofol concentration set at 6μg/ m L,and an endotracheal tube was inserted when the effect site concentration was above 3μg/m L.Vecuronium 0.08 mg/kg was used for the muscle relaxation.Anesthesia was maintained by a target plasma propofol concentration at 4μg/m L which was titrated to the clinical effects.Fentanyl and vecuronium were also added when anesthesia seemed inadequate.5 mg tropisetron(06070006, Southwest Pharmaceutical Co.,Ltd.)was given intravenously at the end of surgery.

Group 2(n=30)and group 3(n=30) received the same procedure for induction and maintenance of anesthesia,except that in group 2, 10 mg dexamethasone(060805,Shanghai General Pharmaceutical Co.,Ltd)and 1.25 mg droperidol (060501,Shanghai Xudong Pharmaceutical Co., Ltd)were given prior to induction while in group 3,no antiemetics were administration.

Group 4(n=30)received fentanyl 3μg/kg, lidocaine 20 mg,propofol 2 mg/kg(Diprivan 1%20 mL,DF483,AstraZeneca,UK)and succinylcholine 1-2 mg/kg to induce anesthesia.Sevoflurane(S005B602, Baxter,USA)was administered for the maintenance of anesthesia.Vecuronium 0.08 mg/kg was used for the muscle relaxation.Additional doses of fentanyl and vecuronium were given as necessary.5 mg tropisetron was given intravenously at the end of surgery.

Group 5(n=30)and group 6(n=30) underwent the same protocol as group 4.But in group 5,10 mg dexamethasone and 1.25 mg droperidol were given prior to induction,while in group 6 no antiemetics were administratied.

At arrival in the operating theatre,an intravenous cannula was inserted into the patientˊs nondominant hand and all patients received a Lactated Ringerˊs solution at a rate of 10 m L/kg per hour.The designed patientsˊage and weight were entered into the TCI pump(Diprifusor,Graseby, UK)and the infusion line was attached to the intravenous cannula.All patients breathed O2at 5 L/min from a clear plastic mask attached to a circle absorber system during induction,the TCI pump was initiated with the target plasma propofol concentration set at 6μg/m L in group 1,2 and 3. When the effect site concentration was above 3μg/ m L,an endotracheal tube was inserted.After the insertion of the endotracheal tube,the vaporiser was opened to 2.5%and the TCI target reduced to 4μg/m L in the designed groups.A constant fresh gas flow of 1 L/min was used during maintenance (steady state)of anesthesia.Ventilation patterns were adjusted to keep end-expiratory CO2between 35 and 40 mm Hg(1 mm Hg=0.133 k Pa,the same below,continuous capnography).Concentrations of volatile anesthetics was measured by using a solor 8 000 monitor.

Each patient was inserted a nasogastric tube upon intubation and suction applied to empty the stomach of air and gastric contents.During surgery,the pneumo-peritoneum was insufflated with CO2,with an intra-abdominal pressure of 15 mm Hg.Prior to endotracheal extubation,the nasogastric tube was suctioned again and then removed.When reaching the extubation criteria, the trachea was extubated.In the operating theater,patients were monitored continuously with electrocardiography,pulse oximetry,capnography, and noninvasive blood pressure measurements.

Depth of anaesthesia was adjusted in all 6 groups in order to maintain heart rate and blood pressure within 15%-20%from baseline,the vaporiser or TCI pump and fentanyl were adjusted as necessary to maintain adequate anaesthesia according to clinical signs.5 mg tropistron were given at the end of surgery in group 1 and 4.10 mg dexamethasone and 1.25 mg droperidol were given prior to induction in group 2 and 5.Saline was given in group 3 and 6.Anesthesia and the administration of antiemetic drugs were provided by anesthesiologists who were not involved in the study and who were experienced in both techniques.

ObservationindexPatients were monitored for 24 hours postoperatively.Our primary outcome measure was the incidence of any nausea,emetic episodes(retching or vomiting),or both(i.e. postoperative nausea and vomiting).Trained investigators who were fully blinded to the intraoperative management and random treatment assignments recorded the number of emetic episodes.

Postoperative pain was noted using the visual analog scale(VAS,0：no pain,10：the most pain). Patients were also asked to assess their postoperative state as satisfactory score with regard to the incidence of nausea,vomiting,pain, and adverse events(0：the worst satisfaction, 10Lthe most satisfaction).

The expense of sevoflurane was calculated by the following formula［3］：

The volume of vapour produced from 1 m L of liquid for sevoflurane at 20℃and 1 atmosphere pressure is 182.7 m L/min［4］.

Prices for all used substances were taken from our hospital pharmacy list.The costs of stuff and fixed costs such as monitoring equipment or other overhead costs(e.g.hospital overheads)and the social costs were not taken into consideration.

StatisticalanalysisStatistical analyses were carried out by Stata 7.0.The continuous data were represented as x—±s and compared by the analysis of variance(ANOVA).Non-parametric data were analyzed by the Kruskal-Wallis rank sum test and categorical data were analyzed by the Pearsonˊs Chi-square test.Theαerror was set at 0.05,andβ error at 0.2.P＜0.05 was considered to indicate statistical significance.

Results

All the 180 patients completed the study and no major events were noticed during anesthesia. The patient characteristics were given in Tab 1. There was no significant difference among all 6 groups according to the age and weight.

Tab 1 patient characteristics(±s,n=30)

Data were compared by the analysis of variance(ANOVA).

Preoperative observations and the amount of anaesthetics used were given in Tab 2.Postoperative observations were described in Tab 3.Time of surgery and time of anesthesia(start of induction of anesthesia until extubation)were similar in all groups.Time of extubation(end of surgery until extubation)and VAS for 24 hours postoperation were not significantly different in six groups.The satisfactory score in group 6 was significantly lower than the other groups(P＜0.05).

Tab 2 Intraoperative observations(±s,n=30)

Data were compared by the Kruskal-Wallis rank sum test.″-″：Not administrated.

Tab 3 postoperative observations(±s,n=30)

VAS：Visual analog scale；PONV.Postoperative nausea and vomiting；Health effect：No.of patients without PONV.VAS and Satisfactory Score were compared by the Kruskal-Wallis rank sum test,(1)P＜0.05,vs.the other groups.

The incidence of PONV in group 2 was significantly lower than that in group 3(P=0.03), and in group 5 was significantly lower than that in group 6(P=0.01).Compared with those received only anesthetics,the relative risk of PONV for patients who received anesthetics combined with antiemetics was reduced to 0.62(95%CI：0.47-0.88).The relative risk of PONV for those received tropisetron and propofol or sevoflurane were 0.51(95%CI：0.21 -1.2)or 0.68(95%CI：0.37-1.24),for those received dexamethasone,droperidol and propfol or sevoflurane were 0.40(95%CI：0.14-1.12)or 0.39 (95%CI：0.16-0.95),for those received propofol was 0.80(95%CI：0.46-1.4)(Tab 4 to Tab 6). Cost associated with each group was shown in Tab 7. Cost-effectiveness ratio was defined as“The total anesthesia cost/The number of patients without PONV”.Patients based on sevoflurane combined with dexamethasone and droperidol had the lowest costeffectiveness ratio per minute in all 6 groups.

Tab 4 Risk of p ONV according to patientsˊrandomly assigned antiemetics(±s)

CI：Confidence interval.Data were compared by the Pearsonˊs Chi-square test.

Tab 7 The primary drug cost and total anesthetic cost associated in each group(RMB,±s)

Total anesthetic cost referred all anesthesia associated cost during the operation,including drug cost,material cost,operating cost and monitor cost.

Discussion

Today,the financial consequences of treating patients seem to be as important as the medical consequences.It is challenging to reduce the cost of anesthesia while maintaining or even improving quality［5］.

PONV is one of the most common complications following surgery.Better anesthetic techniques,along with a new generation of antiemetics,reduced the incidence of PONV in todayˊs practice.Nevertheless,PONV still occurs, with an incidence up to 75%in some high-risk patients［6］.It is reported that PONV is one of the most unpleasant postoperative symptoms so that avoiding PONV is as important as avoiding pain postoperatively［7］.Patients are willing to spend up to 100 US dollars out of their pocket for an effective antiemetic［8］.

It is well known that the incidence of PONV varies considerably according to the basic risk factors of patients and type of surgery conducted. Those who were of at least two of the following risk factors：female sex,nonsmoker status,previous history of postoperative nausea and vomiting or motion sickness,and anticipated use of postoperative opioids,when underwent laparoscopic cholecystectomy,they are defined as high-risk patients［9］.But,in those relative low-risk patients,the most cost-effective way for preventing PONV remains unknown.

One of the most important way to prevent PONV is to use antiemetics.All the tested antiemetics are proved to be safe.Droperidol is one of the most widely used drugs.A quantitative systematic review showed that for prevention of early nausea(within 6 h postoperatively),relative risk(RR)of droperidol was 0.45 and for prevention of early vomiting,RR was 0.65［10］.It may have an effect on dopamine receptor D2. However,low-dose droperidol can cause dysphoria. In Dec.,2001,the FDA issued a new“black box”warning on droperidol because of concerns of serious cardiac arrhythmias secondary to QT prolongation［11］.However,there is little evidence that antiemetic doses trigger this condition［12］. None of the patients who received droperidol showed side effects in our study.

Intravenous dexamethasone generally requires a longer period of time to take effect and a time lag of 12-24 hours to achieve maximal result. Dexamethasone should be given before or immediately after induction of anesthesia rather than waiting until the surgery is nearly completed,probably by reducing surgery-induced inflammation［13］.Specific guidelines have been issued on the prevention and management of nausea and vomiting［14］.According to theseguidelines,a combination of droperidol 1.25 mg with dexamethasone 10 mg is recommended for operative procedures associated with a high risk of nausea and vomiting,including laparoscopic procedures.We used a combination of droperidol and dexamethasone based on this recommendation and low cost of these agents.In our study,we found that the relative risk of PONV for those received dexamethasone,droperidol and propfol was 0.40 while for those received dexamethasone, droperidol and sevoflurane was 0.39.

Tropisetron is a new generation of 5-hydroxytryptamine type 3 antagonists.It is metabolized by the liver cytochrome P-450 2D5system,and due to the polymorphism of this system,it metabolizes faster in some individuals. The mean elimination half-life is 8 hours in individuals with fast metabolism and 30 to 40 hours in those with slow metabolism,which could make tropisetron suitable for prevention of PONV in a single dose.Tropisetron is considered relatively safe but more expensive than droperidol and dexamethasone.In our study,the relative risk of PONV for those received tropisetron and propofol or sevoflurane were 0.51 or 0.68.

We chose target-controlled infusion of propofol and sevoflurane as two of the anesthesia techniques because both of them are reported to provide stable hemodynamics during anesthesia and are used more and more widely for recent years.

The TCI system was as simple to use as a vaporiser,in that adequate anaesthetic conditions it could always be restored by adjusting the target concentration and no patient required an additional manual bolus of propofol or other intervention. Though it was said that use of sevoflurane as a maintenance anesthesia allowed rapid recovery［15］, the extubing time in TCI groups and sevoflurane groups were similar according to our data.This may be explained by using current Diprifusor software in TCI pump which showed the effect site (brain)concentration as a sign of anesthesia recovery.

It has been reported that PONV occurs less frequently after a propofol-based anesthetic compared with other methods［16］.The possible effects of propofol are its interactions with the dopaminergic and the serotoninergic systems. Propofol may depress the synaptic transmissionin cortex region olfactory and decrease the release of excitatory amino acids［17］.According to our data, the relative risk of PONV for those who received propofol was 0.80 compared with sevoflurane.

In our study,the relative risk of PONV for those received anesthetics combined with antiemetics was 0.62 compared with those only received anesthetics. Since propofol is more expensive than sevoflurane and patients usually have to afford the cost of waste drug, the combination of sevoflurane and 10mg dexamethason plus 1.25mg droperidol has the lowest cost-effective ratio per minute for relatively low-risk patients undergoing LC.

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Cost-effectiveness comparison between 6 interventions for the prevention of postoperative nausea and vomiting（p ONV）on low-risk patients

WANG Li-jun1,CANG Jing2△,XUE Zhang-gang2
(1Department of Anesthesiology,Ear Eye Nose and Throat Hospital,Fudan University,Shanghai 200031,China；2Department of Anesthesiology,Zhongshan Hospital,Fudan University,Shanghai 200032,China)

Objective We conducted this study to compare the cost and effectiveness of prophylactic antiemetic interventions combined with different anesthetic techniques on those relative low-risk patients received laparoscopic oholcystectomy(LC).MethodsOne hundred and eighty male patients fulfilling inclusion criteria scheduled for LC were randomized divided into 6 groups,with 30 patients in each group.Group 1 received target-controlled infusion(TCI)of propofol+5 mg tropisetron.Group 2 received TCI propofol+10 mg dexamethasone+1.25 mg droperidol.Group 3 received TCI propofol without antiemetics.Group 4 received sevoflurane+5 mg tropisetron.Group 5 received sevoflurane +10 mg dexamethasone+1.25 mg droperidol.Group 6 received sevoflurane without antiemetic.Theprimary outcome was nausea and vomiting within 24 hours after surgery,which was evaluated blindly.ResultsNo difference was seen with regard to patient characteristics,time of surgery,anesthesia and extubation and visual analogue score(VAS)for 24 hours after surgery.The incidence of postoperative nausea and vomiting(PONV)in group 2 was significantly lower than in group 3(P=0.03),and in group 5 was significantly lower than that in group 6(P=0.01).The relative risk of PONV for those received tropisetron and propofol or sevoflurane were 0.51 or 0.68,for those received dexamethasone,droperidol and propfol or sevoflurane were 0.40 or 0.39,for those received propofol was 0.80.The relative risk of PONV for those received antiemetics were 0.62 compared with those received only anesthetics.Looking at the total cost including waste,the cost-effectiveness ratio per minute was 1.07,0.88,1.14,1.05,0.74 and 1.06 respectively in group 1 to 6.ConclusionsPropofol,tropisetron,dexamethasone and droperidol had different relative risk of PONV.Dexamethasone plus droperidol and sevoflurane had the lowest cost-effectiveness ratio per minute.

postoperative nausea and vomiting(PONV)； propofol； sevoflurane； tropisetron；dexamethasone； droperidol； cost-effectiveness Postoperative nausea and vomiting(PONV)is one of the most common complications after laparoscopic cholecystectomy(LC).It is associated with the high risk of suture dehiscence,aspirated pneumonia,respiratory tract obstruction and so on, therefore it delays discharge time and increases medical cost.

R 656

B

10.3969/j.issn.1672-8467.2014.01.012

2013-02-12；编辑：张秀峰)

△Corresponding author E-mail：cjj286@126.com