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A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents

Sneyd, J. R.; Carr, A.; Byrom, W. D.*; Bilski, A. J. T.*

Author Information
European Journal of Anaesthesiology: July 1998 - Volume 15 - Issue 4 - p 433-445

Abstract

Introduction

Post-operative nausea and vomiting (PONV) are a relatively frequent cause of morbidity following general anaesthesia. Reduction of PONV has attracted considerable research, particularly because of the increase in day case surgery. Clinical anaesthesiologists and authors of research publications have frequently commented on an apparent reduction in PONV following maintenance of anaesthesia with propofol, however, few studies have addressed this question directly. Despite the modest numbers of studies directly investigating PONV, there exists a very large number of publications describing the clinical use of propofol and many of these were prospective randomized comparisons of maintenance of anaesthesia with propofol or inhalational agents. Meta-analysis allows the combination of multiple independent studies of low power to provide a pool of data from which, with appropriate caveats, general conclusions may be realized.

A previous report has described a meta-analysis of PONV with propofol; however, its author relied exclusively on a MEDLINE search and only identified 28 studies covering 1116 patients [1]. These authors concluded that the odds ratios for nausea and vomiting following maintenance with propofol compared with an inhalational agent were 0.29, 0.25 and 0.29 for vomiting, nausea and 'nausea and vomiting', respectively, indicating significant reductions with propofol treatment. A second meta-analysis [2] of 6069 patients from 84 studies compared the effects of either induction or maintenance with propofol and other anaesthetic agents on PONV. Comparator agents used for maintenance included propanidid, midazolam and alphaxalone. The study which divided PONV into early and late emetic events, suggested that the number-needed-to-treat [3] to prevent an early emetic event was 4.9. In contrast, prevention of a late event was not significantly different from control. In our analysis, we decided to use only inhalational agents as comparators for maintenance as this is probably more representative of clinical practice.

An unbiased and complete identification of as many studies as possible is of primary importance in preparing a meta-analysis [4]. Many pharmaceutical companies have databases on their products which are often more comprehensive than the standard commercial databases. This is because the data includes papers, abstracts or books written in foreign languages, many of which are identified by local personnel working in the country concerned. The research studies included in this meta-analysis were identified from the MEDLEY database of Zeneca Pharmaceuticals. The eligibility of the data for inclusion in the meta-analysis was determined independently of Zeneca by the two authors from Derriford Hospital who also extracted all the data for analysis in order to reduce the possibility of bias.

Methods

Identification of studies using the MEDLEY database

MEDLEY is a proprietary database which contains the most comprehensive and up-to-date collection of published literature on Zeneca's pharmaceutical products. Publications included on MEDLEY are derived from approximately 70 UK/European journals scanned in-house and approximately 6000 US and world-wide journals scanned by an external agency (1000 scanned manually and 5000 scanned electronically). Other sources of publications are world-wide company personnel who can supply published abstracts and papers from meetings, lectures and other functions. All publications included on MEDLEY are read and re-abstracted by medical information scientists who also assign keywords (descriptors) for subsequent database searches. By June 1995, MEDLEY included approximately 5300 publications on propofol, whereas a MEDLINE search revealed approximately 1700. MEDLEY therefore represents an exceptionally comprehensive research database and the abstracting and keywording process means that retrieval of information is considerably more efficient than would be possible by using standard library resources.

Our search strategy

Our search strategy covered the period from 1987 (clinical introduction of propofol) to June 1995 using PROPOFOL as a major descriptor with sub-headings INDUCTION or MAINTENANCE or both together with INHALATIONAL ANAESTHETICS as a major descriptor with sub-headings INDUCTION or MAINTENANCE or both together with the descriptors COMPARISON, NAUSEA and VOMITING. This search identified 169 publications. A second search also identified all papers comparing propofol with inhalational agents but excluded the above two side effect descriptors. This second search revealed a total of 192 publications. Eighty per cent (154/192) of these were addressing specific topics, such as EEG analysis, psychomotor and cognitive function. We also checked at random 10% of these 192 papers to determine the quality of indexing. From this, one paper was identified which did in fact include PONV data and this was included in our analysis.

In total, we identified 170 studies in which patients were prospectively randomized to maintenance of anaesthesia with propofol or an inhalational agent and for which nausea, vomiting or 'nausea and vomiting' data were available. These publications were examined individually and independently by the two authors from Derriford Hospital. After exclusion of duplicates, which were mostly abstracts and full papers of the same data but also included other duplicate publications, a total of 96 publications remained. From each of these publications the induction agent, maintenance agent, analgesic, presence or absence of nitrous oxide, age (children/adults), type of surgery (arthroscopy/minor orthopaedic, breast, eye, facial/oral/dental/ENT, gynaecological laproscopy, other gynaecological, squint, and other/unspecified) and period of assessment for PONV were identified and the number of patients with nausea, vomiting or 'nausea and vomiting' recorded. Some studies contained more than two treatment arms. In these cases the two most appropriately matched treatment arms were selected for comparison (Table 1).

Table 1
Table 1:
Choice of treatment groups in studies with more than two treatment arms. The ideal comparison is group 1 vs. group 3 or 2 vs. 4 but this was not possible in many cases. We took only two treatment groups from each study and selected these to achieve the best balance. Thus if a study included group types 1, 2 and 3, we included 1 and 3 and excluded 2 to achieve the best possible match. Similarly, if there were group types 1, 2 and 4 we excluded group 1 for the same reason

Individual trials report nausea, vomiting or nausea and vomiting over different time periods. Thus a study might report data from 0-3 h and also from 3-6 h. It is usually not possible to determine from the publications whether the patients who experienced PONV in the second time period were different patients or the same ones having additional episodes. In addition, some studies report the cumulative incidence over a time period. It is therefore impossible, post-hoc to determine the distribution across time of different patients PONV. We have therefore analysed only the first time period for which PONV data were reported in each study. This approach imposes other limitations, as it merges patient populations who have been studied for different periods, although the influence of different observation periods was investigated graphically.

Foreign languages

In addition to English, we identified appropriate publications in French, German, Italian, Spanish, Japanese and Turkish.

Statistical analysis

For each dataset, and subsets of the vomiting dataset, log-odds ratios calculated from the incidence data of each individual trial were combined using the fixed-effects meta-analysis approach described by Whitehead [5]. Tests for a treatment effect (common odds ratio not equal to 1) were performed at the 5% level of significance. In the case of significant heterogeneity (P<0.05) the influence of covariates pertaining to whole trials (surgery type, comparator anaesthetic, observation period, opiate narcotic usage, nitrous oxide usage and patient age) on individual odds ratios was explored graphically. Because heterogeneity was detected in more than one dataset but no common explanatory covariate could be identified, all analyses were repeated using a random effects model [5]. The random effects model produced only marginally wider confidence intervals with similar mean odds ratio estimates to the fixed effects approach. For this reason, where heterogeneity was detected it was considered of minimal influence, and in all cases only the results of the fixed effects analyses were reported.

In addition, the number-needed-to-treat (the mean number of patients that if induced and maintained with propofol would save one incidence of PONV) was calculated by performing an additional meta-analysis using the probability difference approach [5]. This meta-analysis employed a random effects model because many of the sample sizes were small leading to a high degree of inter-trial variability in probability difference estimates.

Fail safe N[6] were calculated, representing the number of new, unpublished or un-retrieved null-result trials that would be required to exist to lower the significance of each meta-analysis to a non-significant level. All analyses were performed using statistical analysis system (SAS) [7].

Results

Eighty trials were performed on adult patients only, and 16 trials were performed on children only. Trials varied in the way PONV data were reported. Seventy trials comprising 4074 patients recorded vomiting incidence as an endpoint; 61 trials comprising 3516 patients recorded nausea incidence as an endpoint; and 17 trials totalling 742 patients recorded nausea and vomiting incidence as a single endpoint. This latter endpoint does not distinguish between incidences of nausea and incidences of vomiting, and so records all patients suffering from at least one of the two complaints. The percentage of patients in each trial recorded as vomiting or suffering from nausea, or suffering from nausea and vomiting are summarized by treatment group (Table 2).

Table 2
Table 2:
Median and range of percentages of patients recording vomiting, nausea or nausea and vomiting by treatment group in 96 randomized comparisons of maintenance of anaesthesia with propofol or an inhalational anaesthetic agent

Vomiting database

Seventy trials (4074 patients) reported vomiting incidence data (Fig. 1). The results of meta-analyses for each subset of the vomit database are summarized (Table 3).

Fig. 1
Fig. 1:
Relative risk of vomiting occurring in anaesthetized patients maintained with either propofol or inhalational agents. Odds ratio and 95% confidence intervals for 70 trials reporting vomiting. Eleven trials had zero events on each treatment and are not plotted. The common odds ratio was 0.267 (95% CI: 0.220, 0.325), the final point representing a 3.7-fold reduction in vomiting.
Table 3
Table 3:
Results of meta-analyses on subsets of the vomiting dataset

Full dataset

A significantly lower incidence of vomiting was observed amongst patients induced and maintained with propofol compared to other agents (P<0.0001). The common odds ratio was estimated to be 0.267 (95% CI: 0.220, 0.325) representing a 3.7-fold reduction in risk of vomiting in patients receiving propofol compared with other agents. Significant heterogeneity was detected (P=0.045). Box plots suggested that all comparator anaesthetics produced similar odds ratios in favour of propofol, even though some comparator groups included propofol as induction agent (Fig. 2). Similarly, surgery type, opiate narcotic usage, patient age, and nitrous oxide usage did not appear to influence the odds ratios obtained. However, trials in which patients were observed for PONV for 0-24 h following surgery appeared to produce higher odds ratios than other trials. In four of the five trials, the odds ratios were greater than 1, favouring comparator, although individually these were not significant. In one of the five trials the odds ratio was significantly lower than 1 favouring propofol. When these trials were removed from the dataset, the test for heterogeneity was not significant (P=0.57). However, because this covariate was not found to be the cause of heterogeneity in the nausea dataset, it is possible that it is a chance finding.

Fig. 2
Fig. 2:
Relative risk of vomiting occurring in anaesthetized patients induced and maintained with propofol by comparator anaesthetic. Box plots of log-odds ratios by comparator anaesthetic for 70 trials reporting vomiting. Plots are suggestive that relative reductions in vomiting under propofol induction and maintenance are consistently observed across all comparator anaesthetics studied.

The mean number-needed-to-treat was 7.1 (95% CI: 5.6, 9.7) indicating that on average approximately seven patients treated with propofol would save one incidence of post-operative vomiting compared to maintenance using inhalational anaesthetics. Fail safe N was calculated to be 3090 trials, indication that 3090 null result trials would have to exist to cause the above result to be not significant.

Adults and children subsets

Individual meta-analyses of the trials studying adults (n=57) and children (n=13) showed significant reductions in vomiting in both subgroups under propofol anaesthesia compared with other anaesthetics (P<0.0001 and P<0.0001, respectively). Odds ratios and confidence intervals calculated (Table 3) represent 3.5- and 5.7-fold reductions in risk of vomiting in adults and children respectively when propofol is used at induction and maintenance.

Comparison with isoflurane

Two meta-analyses of trials comparing propofol with isoflurane were performed. The first (n=42) included all trials with isoflurane as comparator maintenance agent independent of induction agent. The second (n=16) was limited to those trials in which the comparator group also included propofol at induction. In both cases, propofol at maintenance and induction significantly reduced vomiting (P<0.0001 and P<0.0001, respectively). Odds ratios and confidence intervals calculated (Table 3) represent 3.7- and 2.6-fold reductions in risk of vomiting when compared with maintenance using isoflurane, and induction with propofol followed by maintenance with isoflurane respectively.

Comparison with desflurane or sevoflurane

Six trials reported vomiting incidence data using desflurane or sevoflurane. Meta-analysis revealed a significant reduction in vomiting in patients maintained with propofol compared with desflurane or sevoflurane (P=0.003). The common odds ratio was 0.430 (Table 3) representing a 2.3-fold reduction in risk of vomiting using propofol. This result, however, is based upon a very small subgroup of the total number of trials identified and should be repeated when more experience with these agents is published.

The presence of opiate narcotics or nitrous oxide

Significant reductions in vomiting were maintained in the subsets of trials concomitantly employing an opiate narcotic in both treatment groups (n=45, P<0.0001), and in those using nitrous oxide with both anaesthetic treatments (n=51, P<0.0001). Odds ratios and confidence intervals calculated (Table 3) represent 3.6-fold and 4.0-fold reductions in risk of vomiting using propofol when concomitantly using an opiate narcotic or nitrous oxide, respectively.

Nausea dataset

Sixty-one trials (3516 patients) reported nausea incidence data. Meta-analysis revealed a significant reduction in nausea amongst patients induced and maintained with propofol compared with other anaesthetic agents (P<0.0001). The common odds ratio was 0.377 (95% CI: 0.316, 0.450) representing a 2.7-fold reduction in nausea incidence using propofol. The test for heterogeneity was significant (P=0.02) but graphical examination of the odds ratios did not suggest that the heterogeneity could be explained by any single trial-specific covariate.

The mean number-needed-to-treat was 8.1 (95% CI: 6.3, 11.1) indicating that on average approximately eight patients treated with propofol would save one incidence of post-operative nausea compared with maintenance using inhalational anaesthetics. Fail safe N was calculated to be 1804 trials.

Nausea and vomiting dataset

Seventeen trials (742 patients) reported incidence data in terms of nausea and/or vomiting. Meta-analysis revealed a significant reduction in nausea and/or vomiting amongst patients induced and maintained with propofol compared with those maintained with other anaesthetic agents (P<0.0001). The common odds ratio was 0.374 (95% CI: 0.262, 0.535) representing a 2.7-fold reduction in risk of nausea/vomiting using propofol. The test for heterogeneity was not significant (P=0.44).

The mean number-needed-to-treat was 6.6 (95% CI: 4.6, 11.9) indicating that on average approximately seven patients treated with propofol would save one incidence of post-operative nausea and vomiting compared with maintenance using inhalational anaesthetics. Fail safe N was calculated to be 112 trials.

Discussion

PONV is one of the most common side effects following general anaesthesia with a generally reported incidence of between 1 and 43% [8]. Higher values have been reported in a few studies including a number in our analysis. A large prospective study in 25 981 patients in 1722 hospitals revealed that the incidence of nausea and vomiting following propofol anaesthesia was low at 1.9% [9]. At the same time, a number of prospective randomized comparative studies suggested that there was a lower incidence of PONV following maintenance of anaesthesia with propofol than after inhalational agents. The relevance of this however to clinical practice could have been dependent upon a number of other factors such as type of surgical procedure, use of opiate narcotic and age of patient. The use of meta-analysis allowed us to provide an estimate of the relative risk of PONV occurring with propofol or an inhalational agent as well as providing us with a guide to the possible effects of some of the above contributory factors on this risk.

Our meta-analysis revealed that patients who received maintenance of anaesthesia with propofol had a significantly lower incidence of PONV, regardless of induction agent, choice of inhalation agent, presence/absence of nitrous oxide, age of patient or use of opiate. The mean number-needed-to-treat (NNTT) with propofol to save one incidence of nausea, vomiting and 'nausea and vomiting' was 7.1, 8.1 and 6.6, respectively. These numbers are small enough to be of clinical value, particularly in the context of day case surgery where PONV is the most common cause of costly unplanned admission [10,11]. A previous metaanalysis by Tramer et al.[2] reported more variable values of NNTT. These however were calculated using a naive pooling of the data which leads to biased estimates. We used a formal probability difference meta-analysis to estimate NNTT, which appropriately weights data from individual trials. In addition, Tramer et al.[2] included studies in which agents such as propanidid, midazolam and alphaxalone were used as comparators for maintenance. In our analysis, we used only inhalation agents as comparators for maintenance because this allowed us to examine the effects of other possible contributory factors. The analysis of Tramer et al.[2] also showed that propofol had a positive effect on the incidence of PONV but only in the short term (0-6 h). In our study, we were unable to divide PONV into early and late emetic events because there were insufficient data available.

Meta-analysis allows the pooling of results of clinical trials which individually have insufficient power to investigate a therapeutic issue. In this case the alternative, a large randomized trial, would have been costly, impractical and unnecessary. By investigating the influence of trial-specific covariates we were able to generalize the overall results across a wide number of comparator induction and maintenance combinations, and a range of surgical procedures. This would have been beyond the scope of a single large study. Although some evidence of heterogeneity was detected the results of the fixed effects analyses were closely supported by the corresponding random effects models.

Meta-analysis is limited by the representativeness of the individual trials included. The MEDLEY database contains the most comprehensive collection of published literature on propofol. Our meta-analysis contained more studies than similar previously reported analyses [1,2]. In addition, we kept distinct the endpoints nausea, vomiting and 'nausea and vomiting' but found consistent results across the three datasets. Because measurement of PONV was not a primary aim of the majority of publications included, any bias to publish onlypositive studies is of limited influence on our results. However, alongside each meta-analysis we calculated the number of null-result trials that would be required to exist to lower the significance of our analysis to a non-significant level (the fail safe N). We consider it unlikely that significant numbers of studies exist in which propofol actually increased the incidence of nausea and vomiting as these would have been published, but fully accept that a significant number may exist which were not published because no difference was shown between the two groups. The technique of 'fail-safe N would therefore seem appropriate as an adjunct to our analysis indicating the strength of the results presented.

Early studies suggested that there were differences in the incidences of PONV between the established volatile agents in current use [12,13]. However a more recent retrospective analysis of data from a large prospective randomized clinical study in 17 201 patients undertaken by Forrest et al.[14] revealed a similar incidence of emetic symptoms for halothane, enflurane and isoflurane. The incidence values for nausea were 18.3, 18.5 and 19.1% and for vomiting were 12.6, 11.9 and 11.5%, respectively. The median incidence values for all volatile agents in our meta-analysis was similar to those found by Forrest et al.: namely for nausea 23.5% and for vomiting 13.5%. It is of interest that our median incidence values for propofol at 8.2 and 4.2%, respectively, were slightly higher than those found by McLeskey et al.[9].

Nitrous oxide is believed to be an emetic agent which can be associated with PONV. This property can be initiated by a number of mechanisms [15-17] and therefore it is possible that it may exhibit different emetic activity depending on whether an inhalational agent or propofol were used for anaesthesia. No such differential effect was observed in our meta-analysis.

Our meta-analysis showed that vomiting incidence was significantly reduced in both adults and children maintained with propofol compared with other anaesthetics. In fact the odds ratio obtained from the children dataset was lower than that of the adults dataset indicating that propofol is highly effective in the surgical procedures undertaken in this age group which generally have a higher risk of post-operative emesis e.g. tonsillectomy, adenoidectomy and strabismus surgery.

All clinically useful agonists acting at μ opioid receptor such as morphine, fentanyl and alfentanil can induce nausea and vomiting. In theory this emetic stimulus could oppose the antiemetic effects of propofol when the two drugs are used together. Our meta-analysis revealed no reduction in the odds ratio with propofol compared with other agents when opiate narcotics were used concomitantly.

In conclusion, patients who received maintenance of anaesthesia with propofol had a significantly lower incidence of PONV in comparison with inhalational agents regardless of induction agent, choice of inhalation agent, presence/absence of nitrous oxide, age of patient or use of opiate.

Acknowledgment

We thank Frances Moore who undertook the search of the MEDLEY database.

References

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Appendix

References used in the meta-analysis

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Bennett MWR, Bembridge JL, Shah MV. A comparison of the effect on gastric emptying of either enflurane or propofol given during maintenance of anaesthesia for minor surgery. Anaesthesia 1994; 49 (8): 675-677.

Blanco E, Blanco J, Vidal MI, Molins N, Freire J, Alvarez J. (Estudio comparativo entre propofol e isoflurano para el mantenimiento de la anestesia en cirugia de abdomen superior.) Comparative study between propofol and isoflurane for maintenance of anaesthesia in surgery of the upper abdomen. Revista Espanola de Anestesiologia y Reanimacion 1992; 39 (Suppl 1): 9.

Blobner M, Schneck HJ, Felber AR, Goegler S, Feussner H, Jelen-Esselborn S. (Vergleichende Untersuchungen der Aufwachphase: Laparoskopische Cholezystektomie nach Isofluran-, Methohexital- und Propofolanaesthesie.) Comparison of recovery from anaesthesia with isoflurane, methohexitone, and propofol for laparoscopic cholecystectomy. Anaesthesist 1994; 43 (9): 573-581.

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Ann Francaises d'Anesthesie et de Reanimation 1987; 6 (4): 324-326.

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Bonilauri M, Riverso P, Faraldi C, Mazzarello L, Merli L, Vallebona C. (Anestesia endovenosa con propofol negli interventi chirurgici in regime di day hospital.) Endovenous anesthesia using propofol in surgical interventions performed in a day hospital situation. Minerva Medica 1990; 81 (7-8 suppl): 39-43.

Borgeat A, Popovic V, Meier D, Schwander D. Comparison of propofol and thiopental/halothane for short-duration ENT surgical procedures in children. Anesth Analg 1990; 71 (5): 511-515.

Candela-Toha AM, Benatar-Hasserfaty J, Ascorve-Dominguez A. (Induccion y mantenimiento de la anestesia con propofol y con tiopental-isoflurano. Estudio comparativo.) Induction and maintenance of anesthesia with propofol and thiopental-isoflurane. Comparative study. Revista Espanola de Anestesiologia y Reanimacion 1991; 38 (4): 218-221.

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Deramoudt V, Gaudon M, Malledant Y, Chatellier A, Saint-Marc C, Lecallonnec A. (Effects du propofol sur la pression intraoculaire dans la chirurgie de strabisme de l'enfant.) Effect of propofol on intraocular pressure during paediatric squint surgery. Ann Francaises d'Anesthesie et de Reanimation 1990; 9 (1): 1-5.

DiLuciano ME, Vetter TR, Burnstine RA. Vomiting after pediatric strabismus surgery with a propofol infusion versus a balanced potent inhalation technique. Anesthesiology 1992; 77 (3A) Sep: A13.

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Eberhart LHJ, Kumm M, Seeling W. (Keine bessere Vigilanz nach Allgemeinanaesthesie mit Propofol bei Koloneingriffen: Vergleich von drei Verfahren der Allgemeinanaesthesie (Propofol, Halothan und Midazolam/Fentanyl) in Kombination mit einer Katheter-epiduralanaesthesie.) General anaesthesia with propofol offers no advantage in early recovery to halothane and midazolam/fentanyl after colon surgery with epidural anaesthesia. Anaesthesist 1994; 43 (3): 159-167.

Glass P, Ginsberg B, Hawkins ED, Markham K, Jacobs JR. Comparison of sodium thiopental/isoflurane to propofol (delivered by means of a pharmacokinetic model-driven device) for the induction, maintenance, and recovery from anesthesia. Anesthesiology 1988; 69 (3A): A575.

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Graham SG, Aitkenhead AR. A comparison between propofol and desflurane anaesthesia for minor gynaecological laparoscopic surgery. Anaesthesia 1993; 48 (6): 471-475.

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Harbers JBM, De-Grood PMRM. Comparison of propofol, etomidate and isoflurane for day surgery. 5th International Congress Belgian Society of Anesthesia and Reanimation, 1988: 20.

Hendolin H, Kansanen M, Koski E, Nuutinen J. Propofol-nitrous oxide versus thiopentone-isoflurane-nitrous oxide anaesthesia for uvulopalatopharyngoplasty in patients with sleep apnea. Acta Anaesthesiol Scand 1994; 38 (7): 694-698.

Herregods L, Capiau P, Rolly G, De-Sommer M, Donadoni R. Propofol for arthroscopy in outpatients. Comparison of three anaesthetic techniques. Br J Anaesth 1988; 60 (5): 565-569.

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Keywords:

INHALATIONAL AGENTS, propofol; NAUSEA, vomiting; META-ANALYSIS

© 1998 European Academy of Anaesthesiology