Anaesthesia 2014, 69, 1138–1150

doi:10.1111/anae.12713

Review Article A comparison of total intravenous anaesthesia using propofol with sevoflurane or desflurane in ambulatory surgery: systematic review and meta-analysis G. Kumar,1,2 C. Stendall,1 R. Mistry,2 K. Gurusamy3 and D. Walker4 1 Speciality Registrar, 4 Consultant, Department of Anaesthesia and Intensive Care, University College London Hospitals NHS Foundation Trust, London, UK 2 Research Fellow, Department of Peri-operative Medicine, 3 Lecturer, Division of Surgery, University College London, London, UK

Summary With the popularity of ambulatory surgery ever increasing, we carried out a systematic review and meta-analysis to determine whether the type of anaesthesia used had any bearing on patient outcomes. Total intravenous propofol anaesthesia was compared with two of the newer inhalational agents, sevoflurane and desflurane. In total, 18 trials were identified; only trials where nitrous oxide was administered to, or omitted from, both groups were included. A total of 1621 patients were randomly assigned to either propofol (685 patients) or inhalational anaesthesia (936 patients). If surgical causes of unplanned admissions were excluded, there was no difference in unplanned admission to hospital between propofol and inhalational anaesthesia (1.0% vs 2.9%, respectively; p = 0.13). The incidence of postoperative nausea and vomiting was lower with propofol than with inhalational agents (13.8% vs 29.2%, respectively; p < 0.001). However, no difference was noted in post-discharge nausea and vomiting (23.9% vs 20.8%, respectively; p = 0.26). Length of hospital stay was shorter with propofol, but the difference was only 14 min on average. The use of propofol was also more expensive, with a mean (95% CI) difference of £6.72 (£5.13–£8.31 (€8.16 (€6.23 €10.09); $11.29 ($8.62–$13.96))) per patient-anaesthetic episode (p < 0.001). Therefore, based on the published evidence to date, maintenance of anaesthesia using propofol appeared to have no bearing on the incidence of unplanned admission to hospital and was more expensive, but was associated with a decreased incidence of early postoperative nausea and vomiting compared with sevoflurane or desflurane in patients undergoing ambulatory surgery. .................................................................................................................................................................

Correspondence to: G. Kumar Email: [email protected] Accepted: 7 April 2014

Introduction The incidence and popularity of ambulatory surgery (also known as day-case or outpatient surgery) have increased rapidly over the last two decades, from over 500 000 cases annually in the UK in the 1990s to over 700 000 in 2005, and are continuing to rise [1]. This 1138

is related primarily to cost savings and enhanced convenience for patients [2, 3]. This proliferation has in part been made possible by the development of both intravenous and inhalational anaesthetic agents with improved pharmacokinetic profiles, favouring early recovery and reduced side-effects. So-called total © 2014 The Association of Anaesthetists of Great Britain and Ireland

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

intravenous anaesthesia (TIVA), with modern drugs like propofol administered by continuous infusion, is now commonplace in ambulatory surgical settings. However, the proposed advantages and propagation of the relatively new and less-soluble inhaled anaesthetics, sevoflurane and desflurane, have added a new dimension to patient care by rivalling propofol in ambulatory surgery. In theory, they allow faster recovery and earlier discharge home than the more traditional inhalational anaesthetic agents [4, 5]. A number of anaesthetic issues may delay discharge from hospital, including: cognitive recovery; cardiovascular recovery; pain; return to normal activity; and postoperative nausea and vomiting (PONV) [6]. Postoperative nausea and vomiting can be particularly problematic in ambulatory surgery as it may lead to delay in discharge or unscheduled admission to hospital [7]. Additionally, it has been reported as the anaesthetic complication that is of most concern to patients [8]. Multiple factors, including the anaesthetic agent delivered, are associated with an increased incidence of PONV and the optimal strategy for preventing PONV continues to be debated. Postoperative pain is also problematic, with over 30% of patients reporting moderate to severe pain following ambulatory surgery [9, 10]. We undertook a systematic review and metaanalysis to assess whether the maintenance of anaesthesia using propofol TIVA is associated with fewer unplanned hospital admissions than maintenance with the inhalational agents sevoflurane or desflurane.

Methods The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [11]. We designed a PICOS framework (Population, Intervention, Control, Outcome, Study design) to identify controlled studies, and used its elements as our primary selection criteria [12]. Articles were regarded as potentially eligible if they met all of the criteria depicted in Table 1. Also shown are the study’s primary and secondary endpoints. Only studies where the use of nitrous oxide was ‘matched’ (i.e. present or absent in both study groups) were included, as this was deemed a significant confounder having both analgesic properties and a higher incidence of PONV [13–15]. All studies were included © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2014, 69, 1138–1150

Table 1 Inclusion criteria according to the PICOS framework [12].

Population

Interventions Controls (intervention) Outcomes

Study design

Adult (16 years or over), elective ambulatory surgery, undergoing general anaesthesia, non-sedation procedures Maintenance anaesthesia with propofol (total intravenous anaesthesia) Maintenance with desflurane and/or sevoflurane (inhalational anaesthesia) Primary: unplanned admission after planned day surgery Secondary: serious adverse events; postoperative and post-discharge nausea and vomiting; postoperative pain (4–8 h postoperatively); length of hospital stay; cost analysis; quality of life Randomised controlled studies in any language

PICOS, Population, Intervention, Control, Outcome, Study design.

irrespective of the method of induction of anaesthesia (intravenous or inhalational), and whether an antiemetic was used intra-operatively (provided that it was used in both groups). We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) in the COCHRANE Library, Science Citation Index Expanded and the meta-register of controlled trials were until November 2013 through a formal search strategy. The medical subject headings (MeSH) terms ‘anaesthesia, inhalational’, ‘anaesthesia, intravenous or TIVA’, and ‘ambulatory or day-case surgery’ were used along with equivalent free-text search terms as part of the search strategy. Additional studies were identified by review of the reference sections of all eligible studies. The decision to include a study was based on an independent review of each of the identified manuscripts by two study investigators (GK and CS) Potentially eligible studies (as determined by either reviewer) underwent review of the full-text manuscript by both reviewers working independently, who subsequently compared their judgements. Disagreements were harmonised by consensus and if necessary by arbitration by the senior researcher. Data extraction tables and an extraction form, including a set of parameters for relevant information on pre-operative testing, were created. 1139

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Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

The risk of bias was assessed according to the guidelines of the Cochrane Collaboration [16, 17], since there is a risk of overestimation of beneficial treatment effects in randomised clinical trials with a high risk of bias [18, 19]. The assessment of risk of bias was based on: sequence generation; allocation concealment; blinding (of patients, anaesthetists and outcome assessors); incomplete outcome data; selective outcome reporting; and source of funding [20]. Considering that follow-up was generally short (< 24 h after discharge), and the incidence of complications relatively low, trials that did not report the outcomes of all randomly assigned patients were considered to suffer from bias owing to incomplete outcome data. Exploration of bias using a funnel plot was performed when assessing PONV and length of stay in all trials, but was not possible for other outcomes because of the small number of trials included [21]. The software package RevMan 5 [22], provided by the Cochrane Collaboration, was used for analysis. For dichotomous data, the relative risk (RR) with the corresponding 95% confidence intervals (CI) was calculated for each study, and the results were pooled together using the Mantel–Haenszel method for combining trials. For continuous data, the mean difference and its corresponding 95% CI were calculated using the inverse variance method for meta-analysis. The individual effect sizes were weighted according to the reciprocal of their variance. If the standard deviation was not available for continuous outcomes, it was calculated according to the guidelines of the Cochrane Collaboration [20]. The outcomes from both fixed- and random-effects models were obtained in the meta-analysis; the model used did not influence the interpretation of effectiveness and the random-effects model is presented in the Results section as we included different types of ambulatory procedures. Heterogeneity (across-study inconsistency) was quantified using the I2 statistic, which estimates the percentage of variability across studies not due to chance [23, 24]. Values of I2 < 40% might not be important, 30–60% may represent moderate heterogeneity, 50–90% may represent high heterogeneity and values > 75% considerable heterogeneity. Subgroup analysis was performed where possible for each outcome to explore heterogeneity between 1140

propofol vs sevoflurane and propofol vs desflurane. Chi-squared tests for heterogeneity were performed to identify the differences between subgroups. A planned subgroup analysis of ASA status was not possible due to the relatively low anaesthetic risk of included patients, and a planned subgroup analysis comparing different types of surgery was also not possible due to there being too few trials in each category. Sensitivity analysis was performed excluding all trials where nitrous oxide was used. The impact of this on the primary outcome and PONV is presented in the results. Too few studies existed to perform it on other outcomes. All evidence were graded as low- or moderate-quality as per the GRADE approach [20], due to the limitations in trial design and implementation and/or the imprecision of the results due to small sample sizes.

Results After removing duplicates a, total of 347 references were identified from medical journal databases and the World Health Organization International Clinical Trials Registry Platform. One additional trial was identified by searching through references (Fig. 1). In total, 18 publications describing 18 completed randomised trials fulfilled the inclusion criteria. A total of 1621 patients were randomly assigned to either TIVA (685 patients) or inhalational anaesthesia (936 patients). All trials included adult patients (age 16 or above) who underwent ambulatory surgery and compared TIVA vs sevoflurane (1052 patients; 10 trials) and TIVA vs desflurane (569 patients; eight trials) (Table 2). Five trials included patients who did not receive nitrous oxide [27, 35, 39–41]. No serious adverse incidents attributable to any of the anaesthetic agents were reported. The majority of trials had a high risk of bias. Blinding was achieved in only one trial [38] as to whether TIVA or inhalational anaesthesia was used, and in most trials, details of the randomisation procedure or whether blinding of the outcome assessors took place was unclear (Table 3). Dropouts after randomisation were reported in only three studies [29, 37, 42]. Only 10 out of the 18 trials reported the primary outcome, thus raising the possibility of selective outcome reporting. It was unclear whether any trial was free from funding bias. © 2014 The Association of Anaesthetists of Great Britain and Ireland

IdenƟficaƟon

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

Records idenƟfied through database searching n = 547

Anaesthesia 2014, 69, 1138–1150

AddiƟonal records idenƟfied through other sources n=1

Screening

Records screened n = 348

Eligibility

Records aŌer duplicates removed n = 348

Full text arƟcles screened for eligibility n = 37

Records excluded based on abstract screening n = 311

Included

Full text arƟcles excluded n = 19 Studies included in qualitaƟve synthesis n = 18

Studies Included in quanƟtaƟve synthesis n = 18

Figure 1 PRISMA flow-diagram. In total, 10 trials reported unplanned admission to hospital following ambulatory surgery. Four out of them detailed no admissions [25, 30, 34, 35], and one trial excluded inpatient admissions after randomisation [27]. The incidence of unplanned admission was lower with propofol compared with inhalational agents (1.3% vs 4.4%, respectively, RR 0.35 (95% CI 0.14–0.91), p = 0.03, Fig. 2). However, if surgical causes of admission were excluded and only anaesthetic reasons for admission included (pain, PONV, respiratory depression), there was no difference between propofol and inhalational anaesthesia (1.0% vs 2.9%, respectively, RR 0.44 (95% CI 0.15–1.27), p = 0.13; Fig. 3). No heterogeneity was noted (I2 = 0%). Sensitivity analysis excluding all trials involving nitrous oxide showed no difference in unplanned admission between the two anaesthetic techniques. All trials reported pre-discharge PONV. The incidence of PONV with propofol was lower compared © 2014 The Association of Anaesthetists of Great Britain and Ireland

with inhalational anaesthesia (13.8% vs 29.2%, respectively, RR 0.50 (95% CI 0.35–0.71, p < 0.001; Fig. 4). Similarly, PONV was lower comparing propofol with sevoflurane (15.1% vs 26.7%, respectively, RR 0.56 (95% CI 0.34–0.90); p = 0.02), and propofol with desflurane (10.9% vs 33.3%, respectively, RR 0.41 (95% CI 0.24–0.70); p = 0.001). There was moderate to high heterogeneity in these results (I2 = 52%). Sensitivity analysis excluding all trials involving nitrous oxide showed no difference in PONV (17% vs 20%, respectively, RR 0.87 (95% CI 0.51–1.47); p = 0.60). Seven trials reported PONV up to 24 h after discharge (Fig. 5). There was no difference between propofol and inhalational anaesthesia (23.9% vs 20.8%, respectively, RR 1.17 (95% CI 0.89–1.55; p = 0.26). Analogous results were seen when comparing propofol with sevoflurane (27.7% vs 23.6%, respectively, RR 1.22 (95% CI 0.89–1.67; p = 0.22) [27, 33, 34, 42], and propofol with desflurane (15.8% vs 15.0%; respectively, 1141

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Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

Table 2 Studies included in the meta-analysis and their characteristics.

Type of surgery

Total number of patients

Mean age; years

Was N2O used?

Induction of anaesthesia

Documented pre- or intra-operative anti-emetic

Study

Comparison

Ashworth and Smith [25] Chen et al. [26]

Propofol vs desflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs desflurane Propofol vs desflurane Propofol vs desflurane Propofol vs desflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs desflurane Propofol vs desflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs sevoflurane Propofol vs desflurane

Body surface

60

44

Yes

Propofol

No

Gynaecology

80

29

Yes

Propofol

No

Urology

71

63

No

No

146

35

Yes

Gynaecology

90

30

Yes

Orthopaedic

80

35

Yes

Propofol or sevoflurane Propofol or sevoflurane Propofol or desflurane Propofol

Not stated

53

40

Yes

Propofol

No

Orthopaedic

60

29

Yes

No

Gynaecology

52

?

Yes

Orthopaedic

169

33

Yes

Propofol or desflurane Propofol or sevoflurane Propofol

General surgery Orthopaedic

60

?

No

Propofol

91

34

Yes

Mixed

211

39

Yes

Mixed

61

38

Yes

General surgery Gynaecology

60

48

No

Propofol or desflurane Propofol or sevoflurane Propofol or sevoflurane Propofol

Ondansetron or droperidol No

80

34

No

Mixed

75

55

Yes

Propofol or sevoflurane Propofol

Propofol vs sevoflurane

Gynaecology

122

38

No

Propofol

Fish et al. [27] Fredman et al. [28] van Hemelrijk et al. [29] Jakobsson et al. [30] Kurpiers et al. [31] Lebenbom-Mansour et al. [32] Nathan et al. [33] Raeder et al. [34] Raeder et al. [35] Rapp et al. [36] Smith et al. [37] Smith and Thwaites [38] Stevanovic et al. [39] Tan et al. [40] Tang et al. [41]

White et al. [42]

Mixed

RR 1.03 (95% CI 0.56–1.87); p = 0.93) [25, 35, 41]. Overall, heterogeneity was high (I2 = 76%). In total, nine trials reported postoperative pain; in all these trials, there was no difference between propofol and inhalational anaesthesia. Eleven trials reported either the total hospital stay or ‘fit-for-discharge’ time (Fig. 6). These times were shorter in patients receiving propofol compared with those receiving inhalational anaesthesia; mean (95% CI) difference was 14 ( 21 to 8) min, p < 0.001. Hospital stay was also shorter comparing propofol with sevoflurane ( 14 ( 21 to 6) min, p < 0.001), but not when comparing propofol with desflurane ( 15 ( 30 to 1) min, p = 0.06). 1142

No No No

No No

No No Metoclopramide Dexamethasone Metoclopramide, ondansetron, droperidol Dolasteron

The chi-squared test for subgroup differences was not significant (p = 0.92), and heterogeneity was moderate. Five trials reported a cost analysis (Fig. 7). Three included the cost of maintenance anaesthesia only (i.e. the cost of the propofol or desflurane/sevoflurane used) [30, 38, 39], and two included the cost of all ancillary drugs (induction agents, neuromuscular blockers, analgesics and anti-emetics) [31, 37]. Total costs were significantly higher with propofol compared with inhalational anaesthesia in each individual trial and in the meta-analysis. The mean (95% CI) difference was £6.72 (£5.13–£8.31 (€8.16 (€6.23 €10.09); $11.29 ($8.62 $13.96))) per patient anaesthetic © 2014 The Association of Anaesthetists of Great Britain and Ireland

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

Table 3 Risk of bias (?, unclear risk of bias;

Study Ashworth and Smith [25] Chen et al. [26] Fish et al. [27] Fredman et al. [28] van Hemelrijk et al. [29] Jakobsson et al. [30] Kurpiers et al. [31] LebenbomMansour et al. [32] Nathan et al. [33] Raeder et al. [34] Raeder et al. [35] Rapp et al. [36] Smith et al. [37] Smith and Thwaites [38] Stevanovic et al. [39] Tan et al. [40] Tang et al. [41] White et al. [42]

, high risk of bias; +, low risk of bias).

Sequence generation

Allocation concealment

? + ? ? ? ? ? ?

?

? ? ? ? + ? + + + +

+ ? ? ? + ? ? + ? +

Propofol Study or subgroup Ashworth 1998 Jakobssen 1997 Nathan 1998 Raeder 1997 Raeder 1998 Rapp 1992 Smith 1999 Tan 2010 White 2007

Events Total 0 30 40 0 26 1 85 0 0 30 23 0 72 0 40 1 55 3

+ ? ? ? ? ?

Incomplete outcome data addressed

Free from academic bias

Free from source of funding bias

+ + + ?

+

?

+

+ + + + + + + +

? ? ? ? ? ? ? ?

+ + + + + + + + + +

? ? ? ? ? ? ? ? ? ?

Blinding of outcome assessors

Blinding of anaesthetists

+ ? ? ? ? ? + ? + ? ?

Total 30 40 26 84 30 68 139 40 67

+ + + + +

+

+ +

Desflurane/Sevoflurane Events 0 0 6 0 0 4 1 4 6

Anaesthesia 2014, 69, 1138–1150

Odds ratio

Odds ratio

Weight M-H, Random, 95% Cl Not estimable Not estimable 0.13 [0.01, 1.20] 18.8% Not estimable Not estimable 10.3% 0.30 [0.02, 5.88] 8.8% 0.64 [0.03, 15.83] 18.1% 0.23 [0.02, 2.16] 44.0% 0.59 [0.14, 2.46]

524 100.0% 401 Total (95% Cl) 5 21 Total events Heterogeneity: Tau2 = 0.00; Chi2 = 1.53, df = 4 (p = 0.82); I2 = 0% Test for overall effect: Z = 2.14 (P = 0.03)

M-H, Random, 95% Cl

0.35 [0.14, 0.91] 10 100 0.01 0.1 1 Favours propofol Favours inhalational

Figure 2 Unplanned admissions comparing propofol vs inhalational anaesthesia; all causes. episode, and heterogeneity was high (I2 = 86%). No trial looked at long-term outcome or quality-adjusted life years. Bias exploration suggested that publication bias among the data (PONV and duration of hospital stay) was unlikely (Fig. 8). For PONV, Egger’s bias was 0.5 (95% CI 2.9 to 1.9, p = 0.67), and for duration of hospital stay it was 2.4 (95% CI 10.9 to 6.1, p = 0.54). It was not possible to assess publication bias for other outcomes because of the small number of trials included. © 2014 The Association of Anaesthetists of Great Britain and Ireland

Discussion We have shown that unplanned admission to hospital is less frequent when TIVA is used compared with inhalational anaesthesia, but importantly, this was not statistically significant when surgery-related complications were excluded from the analysis. Surgical complications such as bowel perforation and traumatic haemorrhage were unlikely to be related to the intervention and hence the interpretation is that there is no evidence to support a difference in unplanned admission between TIVA and inhalational anaesthesia. 1143

Anaesthesia 2014, 69, 1138–1150 Propofol Study or subgroup Ashworth 1998 Jakobssen 1997 Nathan 1998 Raeder 1997 Raeder 1998 Rapp 1992 Smith 1999 Tan 2010 White 2007

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery Desflurane/Sevoflurane

Odds ratio

Odds ratio

Events

Total

Events

Total

Weight M-H, Random, 95% Cl

0 0 0 0 0 0 0 1 3

30 40 26 85 30 23 72 40 55

0 0 0 0 0 4 1 4 6

30 40 26 84 30 68 139 40 67

Not estimable Not estimable Not estimable Not estimable Not estimable 0.30 [0.02, 5.88] 0.64 [0.03, 15.83] 0.23 [0.02, 2.16] 0.59 [0.14, 2.46]

12.7% 10.8% 22.3% 54.2%

Total (95% Cl) 401 524 100.0% Total events 4 15 Heterogeneity: Tau2 = 0.00; Chi2 = 1.59, df = 3 (p = 0.90); I2 = 0% Test for overall effect: Z = 1.51 (p = 0.13)

M-H, Random, 95% Cl

0.44 [0.15, 1.27]

0.01 0.1 1 10 100 Favours propofol Favours inhalational

Figure 3 Unplanned hospital admissions comparing propofol vs inhalational anaesthesia; anaesthetic causes. Inhalational Risk ratio Propofol Events Total Events Total Weight M-H, Random, 95% Cl Study or subgroup 10.1.1 Propofol vs Sevoflurane 0.20 [0.05, 0.86] 40 Chen 2006 40 10 4.2% 2 0.97 [0.06, 14.94] Fish 1999 1.6% 1 36 1 25 14 0.66 [0.40, 1.08] 96 10.7% 50 41 Fredman 1995 26 0.33 [0.16, 0.70] 8.6% Nathan 1998 6 18 26 9.5% 84 16 85 Raeder 1997 0.93 [0.49, 1.75] 15 6.6% Smith & Thwaites 1999 139 0.26 [0.09, 0.70] 72 30 4 2.7% 31 1 0.07 [0.01, 0.53] Smith 1999 14 30 3.6% Stevanovic 2008 30 0.50 [0.10, 2.53] 2 4 30 7.0% 1.00 [0.39, 2.59] 7 Tan 2010 40 7 40 1.37 [0.77, 2.43] 67 10.1% 18 16 55 White 2007 464 588 64.7% 0.56 [0.34, 0.90] Subtotal (95% CI) 70 157 Total events Heterogeneity: Tau2 = 0.31;Chi2 = 23.29, df = 9 (p = 0.006); I2 = 61% Test for overall effect: Z = 2.41 (p = 0.02) 10.1.2 Propofol vs Desflurane Ashworth 1998 Hemelrijk 1991 Jakobssen 1997 Kurpiers 1996 Lebenbom-Mansour 1993 Raeder 1998 Rapp 1992 Tang 2001 Subtotal (95% CI)

3 9 2 3 0 5 1 1

30 23 40 26 14 30 23 35 221

0 42 7 11 13 12 27 4

30 67 40 27 46 30 68 40 348

1.4% 10.4% 4.0% 5.7% 1.5% 7.3% 2.8% 2.4% 35.3%

Risk ratio M-H, Random, 95% Cl

7.00 [0.38, 129.93] 0.62 [0.36, 1.07] 0.29 [0.06, 1.29] 0.28 [0.09, 0.90] 0.12 [0.01, 1.84] 0.42 [0.17, 1.04] 0.11 [0.02, 0.76] 0.29 [0.03, 2.44] 0.41 [0.24, 0.70]

24 116 Total events Heterogeneity: Tau2 = 0.14; Chi2 = 9.40, df = 7 (p = 0.23); I2 = 25% Test for overall effect: Z = 3.28 (p = 0.001) 936 100.0% 685 Total (95% Cl) 94 273 Total events Heterogeneity: Tau2 = 0.25; Chi2 = 35.20, df = 17 (p = 0.006); I2 = 52% Test for overall effect: Z = 3.79 (p = 0.0001) Test for subgroup differences: Chi2 = 0.73, df = 1 (p = 0.39), I2 = 0%

0.50 [0.35,0.71]

0.01

0.1

Favours propofol

1

10

100

Favours inhalational

Figure 4 Postoperative nausea and vomiting in propofol vs inhalational anaesthesia. A total overall unplanned admission rate of 2.1% was identified in this review, which is comparable with several clinical studies that have reported rates ranging 1144

from 0.5% to 10% [43, 44], with an ideal standard of under 2% [45]. We have also shown that the incidence of PONV was lower when propofol was used © 2014 The Association of Anaesthetists of Great Britain and Ireland

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

Study or subgroup

Propofol Events Total

Inhalational Events Total

Anaesthesia 2014, 69, 1138–1150

Risk ratio M-H, Random, 95% Cl

Weight

Risk ratio M-H, Random, 95% Cl

10.2.1 Propofol vs Sevoflurane Fish 1999 1 36 0 35 4.5% 2.92 [0.12, 69.32] 26 19.5% 0.33 [0.16, 0.70] Nathan 1998 6 26 18 84 20.6% 0.93 [0.49, 1.75] Raeder 1997 15 16 85 67 22.1% 2.59[1.61, 4.16] White 2007 34 16 55 212 66.8% Subtotal (95% CI) 202 1.05 [0.36, 3.13] Total events 56 50 Heterogeneity: Tau2 = 0.91; Chi2 = 22.22, df = 3 (p < 0.0001); I2 = 87% Test for overall effect: Z = 0.09 (p = 0.92) 10.2.2 Propofol vs Desflurane 30 0 Ashworth 1998 1 30 4.5% 30 20.5% Raeder 1998 30 13 10 8.3% 5 Tang 2001 1 35 40 95 Subtotal (95% CI) 100 33.2% 15 Total events 15 Heterogeneity: Tau2 = 0.40; Chi2 = 2.92, df = 2 (p = 0.23); I2 = 31% Test for overall effect: Z = 0.04 (p = 0.96)

3.00 [0.13, 70.83] 1.30 [0.68, 2.49] 0.23 [0.03, 1.86] 0.97 [0.31, 3.06]

Total (95% CI)

297 1.01 [0.48, 2.12] 312 100.0% 71 Total events 65 Heterogeneity: Tau2 = 0.59; Chi2 = 25.16, df = 6 (p = 0.0003); I2 = 76% 10 1 50 0.1 0.02 Test for overall effect: Z = 0.02 (p = 0.98) Favours propofol Favours inhalational Test for subgroup differences: Chi2 = 0.01, df = 1 (p = 0.92); I2 = 0%

Figure 5 Post-discharge nausea and vomiting in propofol vs inhalational anaesthesia. Propofol Inhalational Mean Difference Study or subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% Cl 10.3.1 Propofol versus Sevoflurane 196 75 183 82 50 5.1% –13.00 [–40.23,14.23] 96 Fredman 1995 85 155 12 143 11 84 29.2% –12.00 [–15.47, –8.53] Raeder 1997 72 195 145 189 133 139 Smith 1999 2.5% 6.00 [–34.13, 46.13] 40 40 28.2% –20.00 [–24.17, –15.83] Tan 2010 235 10 255 9 55 White 2007 23.00 [–17.26, 63.26] 179 109 202 116 67 2.5% 426 67.6% 302 Subtotal (95% CI) Heterogeneity: Tau2 = 32.21; Chi2 = 12.89, df = 4 (p = 0.01); I2 = 69% Test for overall effect: Z = 3.46 (p = 0.0005) 10.3.2 Propofol versus Desflurane Ashworth 1998 Jakobssen 1997 Kurpiers 1996 Lebenbom-Mansour 1993 Raeder 1998 Rapp 1992

156 254 176 110 287 130

49 79 0 22 63 26

30 40 26 14 30 23

166 255 184 147 278 150

50 60 0 59 54 57

30 40 27 46 30 68

–13.64 [–21.36, –5.91]

5.8% 4.1%

–10.00 [–35.05, 15.05] –1.00 [–31.74, 29.74] Not estimable 7.9% –37.00 [–57.58, –16.42] 4.4% 9.00 [–20.69 ,38.69] 10.2% –20.00 [–37.22, –2.78]

163 Subtotal (95% CI) 241 32.4% Heterogeneity: Tau2 = 145.33; Chi2 = 8.03, df = 4 (p = 0.09); I2 = 50% Test for overall effect: Z = 1.89 (p = 0.06)

–14.56 [–29.65, 0.53]

Total (95% Cl)

–14.27 [–20.95, 7.59]

465

Mean Difference IV, Random, 95% Cl

667 100.0%

Heterogeneity: Tau2 = 36.63; Chi2 = 21.05, df = 9 (p = 0.01); I2 = 57% Test for overall effect: Z = 4.19 (p < 0.0001) Test for subgroup differences: Chi2 = 0.01, df = 1 (p = 0.92), I2 = 0%

–50 –25 0 25 50 Favours propofol Favours inhalational

Figure 6 Length of hospital stay in propofol vs inhalational anaesthesia. compared with inhalational anaesthesia, but no difference was noted in the incidence of nausea and vomiting after discharge. Length of hospital stay also was © 2014 The Association of Anaesthetists of Great Britain and Ireland

shorter with propofol but it is arguable whether the small difference found is likely to be clinically relevant. Additionally, no difference was noted in the incidence 1145

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Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

Propofol Inhalational Mean SD Total Mean SD Total

Study or subgroup

10.4.1 Propofol vs Sevoflurane 8.84 Smith & Thwaites 1999 19.52 Smith 1999 12.56 Stevanovic 2008

4.49 4.67 1.32

30 5.91 1.5 72 11.81 4.51 30 5.56 0.87 132

Subtotal (95% Cl)

Mean difference Weight IV, Random, 95% Cl

31 139 30

20.8% 23.0% 26.3%

2.93 [1.24, 4.62] 7.71 [6.40, 9.02] 7.00 [6.43, 7.57]

200

70.1%

5.99 [3.76, 8.21]

Mean difference IV, Random, 95% Cl

Heterogeneity: Tau2 = 3.47; Chi2 = 22.40, df = 2 (p < 0.0001); I2 = 91% Test for overall effect: Z = 5.27 (p < 0.00001) 10.4.2 Propofol vs Desflurane 10.72 Jakobssen 1997 35.47 Kurpiers 1996

3.2 12.37

40 3.81 1.69 26 21.33 8.65

40 27

24.0% 5.9%

6.91 [5.79, 8.03] 14.14 [8.37, 19.91]

66

67

29.9%

9.95 [2.95, 16.94]

198 267 100.0% Total (95% Cl) Heterogeneity: Tau2 = 2.42; Chi2 = 28.69, df = 4 (p < 0.00001); I2 = 86%

6.72 [5.13, 8.31]

Subtotal (95% Cl)

Heterogeneity: Tau2 = 21.64; Chi2 = 5.82, df = 1 (p = 0.02); I2 = 83% Test for overall effect: Z = 2.79 (p = 0.005)

–20 –10 0 10 20 Favours propofol Favours inhalational

Test for overall effect: Z = 8.28 (p < 0.00001) Test for subgroup difference: Chi2 = 1.12, df = 1 (p = 0.29), l2 = 10.7%

Figure 7 Cost analysis of propofol vs inhalational anaesthesia.

SE(log[RRI)

0

SE(MD) 0

(b)

(a)

10

0.5 20

1 30

1.5 40

2

RR 0.01

0.1

1

10

100

50

MD –50

–25

0

25

50

Figure 8 Funnel plot for propofol vs inhalational anaesthesia, for (a) postoperative nausea and vomiting and (b) length of hospital stay. The vertical axis shows the precision of the estimate of the treatment effect (the smaller the confidence interval, the more precise the study, and the further up the study is placed). The horizontal axis measures the treatment effect (relative risk or mean difference.) The data points are from each study and the vertical line shows where the pooled estimate from the meta-analysis lies. of postoperative pain but maintenance anaesthesia with propofol was more expensive than with sevoflurane or desflurane. No serious anaesthetic adverse events were reported in any of the selected studies, and this was as 1146

expected, since major morbidity and mortality directly attributed to anaesthesia now occur extremely rarely [46]. Likewise, no studies reported quality of life, and this was expected due to the nature of surgery, with no difference in quality of life resulting from different © 2014 The Association of Anaesthetists of Great Britain and Ireland

Kumar et al. | Systematic review of maintenance anaesthesia in day surgery

methods of anaesthesia anticipated several days following discharge. Considering that mortality and quality of life contribute to the quality-adjusted life year, which is the main measure used to assess benefits in cost-effectiveness analyses, the choice of anaesthetic agent will depend on re-admission to hospital, costs, PONV and pain. We have shown that PONV was less common when TIVA was used – this correlates with extensive evidence that propofol is the best anaesthetic agent for preventing PONV [47–49], and is of particular importance since it is the postoperative anaesthetic complication that is of most concern to patients [8]. It is also significant because of the potential association with delayed discharge and unplanned admissions, and related cost implications [6, 50]. This may be supported by the fact that hospital admission was lower with TIVA in all the selected studies, although this did not reach statistical significance. The distinction between pre- and post-discharge nausea and vomiting has not been well investigated [42]. After discharge, PONV has been reported to have an incidence of 30– 50%, and we have reported an incidence of 22% in this meta-analysis. Many patients experience PONV for the first time only after leaving hospital [50, 51]. Interestingly, despite propofol’s being associated with significantly less in-hospital PONV, our analysis shows it provides no benefit in the first 24 h after discharge. This may be explained by propofol’s pharmacokinetic profile. A minimum plasma concentration of propofol (mean 343 ng.ml 1 [52]) is necessary to produce an anti-emetic effect; this is lower than that required to produce an anaesthetic effect (approximately 500 ng.l 1), and since it has a short half-life, therapeutic anti-emetic plasma levels are unlikely to persist after several hours [53]. Propofol may provide prophylaxis against early PONV only, and suitable strategies should be planned for patients after discharge. Although not having a direct cost implication to the hospital, preventing PONV once the patient has returned home is still important as it may delay resumption of normal activities and readiness for work, and negatively impact on patient experience. The reduction in the incidence of PONV may be the reason why our analysis demonstrated that propofol was associated with earlier readiness for discharge © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2014, 69, 1138–1150

home compared with inhalational anaesthesia, supported by a previous study that concluded that nausea was the single most important factor which affected discharge following ambulatory surgery [7]. However, although statistically significantly different, the clinical significance of the difference in hospital readiness is very minimal, as the average difference was only about 10–15 min between the two techniques. None of the trials reported any significant difference in postoperative pain or opioid use. This may be because the analgesic properties of propofol have been well reported, and so this was not investigated [54– 56]. Alternatively, it may be that there was no significant difference in pain between TIVA and inhalatational anaesthesia because of the nature of the procedures carried out. In interpreting differences in actual discharge and fit-for-discharge times, it is critical to understand that other co-factors influencing the interpretation of each outcome may be relevant. Being ready for discharge is usually assessed using standardised recovery protocols, whereas discharge time is the actual time when the patient leaves hospital. The latter is affected by many factors such as local guidelines, delay in transport, or needing to pass urine, although type of anaesthetic should not affect this. Unfortunately, many authors have not made a distinction between these variables. In our study, the cost of propofol as a maintenance anaesthetic was significantly higher than that of desflurane or sevoflurane. No trials calculated the total cost including ancillary equipment or wastage. It has been recommended that drug wastage should be included in the total cost [57]. If this was the case, propofol may cost even more, in part, because it is packaged as a preservative-free, single-patient-use agent [58]. Therefore, any opened propofol remaining at the end of surgery would have been wasted. Although the saving per patient was small, the potential for savings over the course of a year would be large. Whether this saving would be negated by the potential extra need for anti-emetics with inhalational anaesthesia, or the need for different equipment such as infusion pumps [59], has not been analysed. There are a number of limitations to our metaanalysis. Although we conducted a thorough review of work published in all languages, one trial was 1147

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excluded due to being untraceable [60]. Many authors did not differentiate between nausea and vomiting or did not state whether it was counted twice as two pathologies. We included patients who were administered nitrous oxide; although it is less commonly used in the UK [61–63], it may be used in other countries. However, our sensitivity analysis showed nitrous oxide had no impact on hospital admission, but may have affected PONV. Patients undergoing inducution of anaesthesia with inhalational agents were included, and this could affect the primary endpoints since in a few patients, induction was with desflurane, an airway irritant and hence potentially emetogenic [64, 65]. This could have decreased the effect of propofol on PONV. However, we have presented the results from pragmatic trials that reflect real-life situations and the influence of the induction method on the ability of propofol to reduce PONV should be further investigated. Perhaps the biggest limitation is the fact that only three of the included trials were conducted within the past 10 years, with the majority in the 1990s. These older trials may have more influence on outcomes since they were conducted at a time when sevoflurane, desflurane and TIVA were relatively new and thus less refined, potentially producing more adverse outcomes than may be expected in the modern era. However, it was necessary to include all these trials due to their abundance and large trial numbers, increasing the likelihood of producing significant results. There was no evidence of heterogeneity in the primary outcome of unplanned hospital admission, but for all other outcomes significant heterogeneity was detected, with poor overlapping of confidence intervals even within the subgroups, decreasing confidence in the effect estimate. A potential reason could be the type of surgery, but there were not enough trials to investigate the influence of each surgical specialty on the effectiveness of TIVA. There was no evidence of publication bias for the two outcomes where we could explore them. The majority of trials in this analysis are relatively small. A power calculation has identified that a large, double-blinded randomised controlled trial of at least 820 participants in each of the TIVA and inhalational groups would be needed to corroborate the results found here with a confidence of 95%. This is the first 1148

meta-analysis of this nature and the results are comparable with a previous systematic review that included seven of the trials we analysed and included comparison with isoflurane, but did not differentiate use of nitrous oxide [4]. Although the evidence was of low quality overall, based on the literature, TIVA appears to be preferable to inhalational anaesthesia in patients undergoing ambulatory surgery with regards to preventing PONV, but no other major advantages were discovered. When hospital admissions due to surgical causes were excluded, there was no evidence of a difference in hospital admission between TIVA and inhalational anaesthesia. However, given that there was an almost threefold difference in unplanned hospital admissions between TIVA and inhalational anaesthesia (1.0% vs 2.9%, respectively) further robust randomised controlled trials are needed to identify whether a truly significant difference exists.

Competing interests No competing interests declared.

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