# Meta-analysis of desflurane and propofol average times and variability in times to extubation and following commands

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DOI: 10.1007/s12630-011-9519-1

- Cite this article as:
- Wachtel, R.E., Dexter, F., Epstein, R.H. et al. Can J Anesth/J Can Anesth (2011) 58: 714. doi:10.1007/s12630-011-9519-1

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## Abstract

### Purpose

We performed a meta-analysis to compare the operating room recovery time of desflurane with that of propofol.

### Methods

Studies were included in which a) humans were assigned randomly to propofol or desflurane groups without other differences between groups (e.g., induction drugs) and b) mean and standard deviation were reported for extubation time and/or time to follow commands. Since there was heterogeneity of variance between treatment groups in the log-scale (i.e., unequal coefficients of variation of observations in the time scale), generalized pivotal methods for the lognormal distribution were used as inputs of the random effects meta-analyses.

### Results

Desflurane reduced the variability (i.e., standard deviation) in time to extubation by 26% relative to propofol (95% confidence interval [CI], 6% to 42%; *P* = 0.006) and reduced the variability in time to follow commands by 39% (95% CI, 25% to 51%; *P* < 0.001). Desflurane reduced the mean time to extubation by 21% (95% CI, 9% to 32%; *P* = 0.001) and reduced the mean time to follow commands by 23% (95% CI, 16% to 30%; *P* < 0.001).

### Conclusions

The mean reduction in operating room recovery time for desflurane relative to propofol was comparable with that shown previously for desflurane relative to sevoflurane. The reduction in variability exceeded that of sevoflurane. Facilities can use the percentage differences when making evidence-based pharmacoeconomic decisions.

# Méta-analyse des temps moyens du desflurane et du propofol et de leur variabilité au niveau des temps jusqu’à l’extubation et la réponse à un ordre

## Résumé

### Objectif

Nous avons réalisé une méta-analyse afin de comparer le temps de récupération en salle d’opération après une administration de desflurane par rapport au propofol.

### Méthode

Les études dans lesquelles a) des patients ont été randomisés en groupes recevant du propofol ou du desflurane sans autre différence entre les groupes (par ex. médicaments d’induction) et b) la moyenne et l’écart type étaient rapportés pour le temps jusqu’à extubation et/ou le temps nécessaire à la réponse à un ordre, ont été retenues. En raison de l’hétérogénéité du point de vue de la variance entre les groupes de traitement sur une échelle logarithmique (c.-à-d. des coefficients inégaux de variation des observations dans l’échelle de temps), des méthodes pivot généralisées pour la distribution log-normale ont été utilisées pour saisir les méta-analyses d’effets aléatoires.

### Résultats

Le desflurane a réduit la variabilité (c.-à-d. l’écart type) en matière de temps jusqu’à extubation de 26 % par rapport au propofol (intervalle de confiance [IC] 95 %, 6 % à 42 %; *P* = 0,006) et a réduit la variabilité en matière de temps jusqu’à la réponse à un ordre de 39 % (IC 95 %, 25 % à 51 %; *P* < 0,001). Le desflurane a réduit le temps moyen jusqu’à extubation de 21 % (IC 95 %, 9 % à 32 %; *P* = 0,001) et réduit le temps moyen jusqu’à la réponse à un ordre de 23 % (IC 95 %, 16 % à 30 %; *P* < 0,001).

### Conclusion

La réduction moyenne du temps de récupération en salle d’opération lors de l’administration de desflurane par rapport à du propofol était comparable à celle précédemment démontrée lors de la comparaison du desflurane au sévoflurane. La réduction de la variabilité a dépassé celle du sévoflurane. Les établissements peuvent utiliser les différences de pourcentage pour prendre des décisions pharmaco-économiques fondées sur des données probantes.

Many hospitals strive to reduce their non-operative operating room (OR) time, i.e., time in the OR when surgery is not being performed. Reducing non-operative time can reduce labour costs for ORs with more than eight hours of cases.1-5

Many surgeons focus on non-operative time. Vitez and Macario asked surgeons to score the importance of particular attributes of anesthesia groups using a scale from 0 to 4; 0 = “no importance”, and 4 = “a factor that would make me switch groups/hospitals”.6 The mean score was 4.0 for “ability to calmly manage a crisis”. The mean score was only slightly less (3.9) for “patient quick to awaken”, demonstrating the importance surgeons place on promptly beginning the next case.

We previously used data from an anesthesia information management system to model the time from end of surgery to tracheal extubation.7 We applied that knowledge to perform meta-analyses of trials comparing extubation times following maintenance with desflurane and sevoflurane.7 Desflurane reduced the mean extubation time relative to sevoflurane by 25% and reduced the standard deviation by 21%.7 Desflurane reduced the mean extubation time relative to isoflurane by 34% and reduced the standard deviation by 36%.8

In our earlier analyses, we assumed that the coefficient of variation does not vary according to treatment, i.e., type of anesthetic. The assumption held for desflurane *vs* sevoflurane (see the Results section 2 and Fig. 5 of reference 7). However, we illustrate in the Appendix that the assumption does not hold true for desflurane *vs* propofol. We modified the statistical analysis by using generalized pivotal methods to account for differences in the coefficient of variation between groups. To explain the method, we use data from a small observational study of the times required to prepare propofol for the next case. In this article, we applied generalized pivotal methods to compare OR recovery times between desflurane and propofol.9-34

## Methods

^{1}seven because the articles did not report standard deviations or standard errors; and three because patients had not been randomized. There were two discrepancies in data extraction involving two of the remaining 26 articles. One discrepancy was an error by R.E.W. caught by F.D., and the other was an error by F.D. caught by R.E.W. For the first error, a weighted average was copied incorrectly from the preceding row, and for the second error, the author judged incorrectly that a target-controlled infusion had been used.

Characteristics of studies listed in sequence of increasing observed effect of desflurane *vs* propofol

Reference |
Propofol |
Desflurane | Sequence Generation | Remifentanil | Target Infusion | Titrated BIS or AEP | LMAD | Year | Mean Age (yr) | Mean Weight (kg) | Mean Duration (min) |
---|---|---|---|---|---|---|---|---|---|---|---|

30 | 30 | Yes | 2007 | 43 | 60 | 99 | |||||

30 | 30 | Yes | Yes | 2009 | 56 | 72 | 91 | ||||

20 | 20 | Yes | Yes | 2007 | 26 | 67 | 82 | ||||

23 | 22 | 1992 | 34 | 75 | 49 | ||||||

25 | 25 | Yes | 2001 | 48 | 75 | 141 | |||||

32 | 31 | Yes | Yes | 2001 | 18 | 59 | 75 | ||||

40 | 40 | Yes | Yes | 2003 | 46 | 66 | 96 | ||||

15 | 15 | 1991 | 37 | 74 | 31 | ||||||

13 | 15 | 1993 | 34 | 64 | 20 | ||||||

25 | 25 | Yes | Yes | Yes | Yes | 2006 | 42 | 79 | 51 | ||

35 | 35 | Yes | Yes | 2001 | 40 | 76 | 67 | ||||

40 | 40 | Yes | 2003 | 48 | 69 | 91 | |||||

30 | 30 | Yes | 1998 | 44 | 65 | 25 | |||||

23 | 23 | 1991 | 30 | 64 | 62 | ||||||

50 | 54 | Yes | 2002 | 35 | 66 | 32 | |||||

14 | 16 | 1993 | 28 | 78 | 91 | ||||||

30 | 30 | Yes | Yes | Yes | 2002 | 75 | 74 | 48 | |||

14 | 14 | 1997 | 77 | 67 | 201 | ||||||

20 | 20 | Yes | 1998 | 36 | 67 | 63 | |||||

35 | 40 | Yes | Yes | Yes | 2001 | 55 | 68 | 38 | |||

17 | 17 | Yes | Yes | 2001 | 30 | 70 | 79 | ||||

29 | 31 | Yes | 1998 | 27 | 66 | 68 | |||||

40 | 40 | Yes | 1998 | 29 | 71 | 71 | |||||

18 | 18 | Yes | Yes | 2004 | 50 | 76 | 342 | ||||

20 | 20 | 1996 | 24 | 79 | |||||||

11 | 12 | Yes | 2000 | 40 | 125 | 170 | |||||

100 | 100 | 2007 | 52 | 72 | 67 |

Percentage reductions in mean time and 95% confidence interval (CI) were calculated as described in the Appendix using Microsoft® Excel, Visual Basic for Applications.37 Percentage reductions in standard deviation and confidence interval were also calculated. The correlation between these two summary measures was studied, and the covariates were explored using Kendall’s rank correlation coefficient. Meta-regression was not used because the covariates that we expected to influence results (e.g., obese patients undergoing longer anesthetics would have larger differences) were not binary study characteristics but were measured variables with sampling error. The *P* values are two-sided and exact (StatXact® 9, Cytel Software Corporation, Cambridge, MA, USA). Fail-safe calculations assessed whether publication bias could have influenced conclusions.38

Economic interpretation of the meta-analysis results depends on the influence of time of emergence from general anesthesia on OR time. The Institutional Review Board at the University of Iowa approved observation of anesthesia providers at the ambulatory surgery centre. The times to prepare propofol for use in infusion syringe pumps were recorded by timing anesthesia providers as they drew up 50 mL of propofol and purged air from the attached extension tubing. Observational details and analyses of preparation times are described in the Appendix. In addition, activities of OR staff, including nurses, were observed from the time of end of surgery to tracheal extubation.

## Results

There were few substantive differences in quality among the studies. None of the studies were blinded for desflurane *vs* propofol, and all studies were randomized. All patients received the drugs to which they were randomized (Table 1). Nine of the 26 studies reported randomization using either a random number table or a computer random number generator.

*P*< 0.001) was unexplained by other measured variables (Table 4).

Times from end of surgery to extubation and from end of surgery to follow commands for each study in Table 1

Reference | Propofol (min) Mean (SD) | Desflurane (min) Mean (SD) | Desflurane Reduction in Mean | Desflurane Reduction in SD | ||||
---|---|---|---|---|---|---|---|---|

Extubation | Commands | Extubation | Commands | Extubation | Commands | Extubation | Commands | |

8.2 (3.0) | 13.7 (5.0) | −68% | −67% | |||||

6.4 (4.2) | 8.0 (0.8) | 7.6 (0.7) | 9.2 (0.7) | −14% | −15% | 84% | 14% | |

6.8 (3.7) | 7.8 (3.7) | 7.3 (3.4) | 8.7 (3.3) | −8% | −12% | 9% | 11% | |

10.6 (6.3) | 11.0 (5.5) | −4% | 13% | |||||

5.5 (3.3) | 5.7 (2.5) | −3% | 25% | |||||

10.4 (3.0) | 10.2 (5.1) | 0% | −71% | |||||

6.8 (4.6) | 6.5 (4.1) | 5% | 11% | |||||

10.0 (4.8) | 9.4 (4.4) | 4% | 9% | |||||

5.3 (2.3) | 5.0 (0.9) | 6% | 62% | |||||

6.9 (2.6) | 6.6 (2.8) | 6.4 (2.6) | 6.0 (2.2) | 6% | 9% | 0% | 22% | |

6.3 (2.1) | 8.7 (2.9) | 5.3 (2.5) | 7.3 (1.9) | 15% | 16% | −20% | 35% | |

10.5 (5.9) | 8.3 (6.1) | 21% | −4% | |||||

5.6 (2.9) | 6.6 (3.0) | 4.4 (1.5) | 5.1 (1.5) | 22% | 23% | 49% | 50% | |

8.3 (3.9) | 6.4 (2.4) | 23% | 39% | |||||

4.6 (2.2) | 3.5 (1.8) | 23% | 18% | |||||

12.2 (15.5) | 9.1 (3.1) | 26% | 83% | |||||

8.7 (3.8) | 10.5 (3.9) | 6.1 (3.1) | 7.7 (3.0) | 29% | 26% | 18% | 23% | |

9.9 (6.5) | 14.3 (8.0) | 6.9 (3.0) | 7.4 (3.2) | 32% | 48% | 55% | 61% | |

9.8 (4.0) | 10.6 (4.5) | 6.7 (2.8) | 7.2 (2.8) | 31% | 32% | 30% | 38% | |

6.0 (2.0) | 4.0 (2.0) | 32% | 0% | |||||

8.0 (4.0) | 5.0 (4.0) | 35% | −3% | |||||

7.0 (6.0) | 4.0 (2.0) | 42% | 67% | |||||

8.9 (5.3) | 8.3 (6.9) | 5.1 (3.3) | 4.7 (2.6) | 41% | 42% | 38% | 63% | |

13.2 (2.3) | 7.5 (1.3) | 43% | 43% | |||||

15.1 (1.8) | 6.4 (0.4) | 58% | 78% | |||||

13.2 (7.6) | 5.6 (1.4) | 58% | 82% | |||||

6.2 (3.2) | 2.3 (1.6) | 64% | 49% |

Desflurane reductions in operating room recovery times relative to propofol

All Studies | Excluding the studies with the largest and smallest reductions | |
---|---|---|

Mean time to extubation | 21% (95% CI, 4% to 36%; | 21% (95% CI, 9% to 32%; |

Mean time to follow commands | 25% (95% CI, 5% to 41%; | 23% (95% CI, 16% to 30%; |

Standard deviation of time to extubation | 30% (95% CI, 6% to 48%; | 26% (95% CI, 6% to 42%; |

Standard deviation of time to follow commands | 40% (95% CI, 26% to 52%; | 39% (95% CI, 25% to 51%; |

Mean Extubation | Mean Commands | SD Extubation | SD Commands | |||||
---|---|---|---|---|---|---|---|---|

Kendall’s Correlation | Uncorrected | Kendall’s Correlation | Uncorrected | Kendall’s Correlation | Uncorrected | Kendall’s Correlation | Uncorrected | |

| ||||||||

Total sample size | −0.07 | 0.74 | 0.02 | 0.92 | −0.25 | 0.18 | −0.06 | 0.75 |

Sequence generation | −0.18 | 0.44 | 0.03 | 0.90 | 0.04 | 0.88 | −0.32 | 0.11 |

Remifentanil | −0.24 | 0.28 | −0.24 | 0.26 | −0.48 | 0.02 | −0.14 | 0.53 |

Target infusion | −0.14 | 0.55 | −0.31 | 0.14 | −0.07 | 0.78 | −0.10 | 0.66 |

Titrated BIS or AEP | −0.09 | 0.72 | 0.12 | 0.60 | −0.16 | 0.51 | −0.39 | 0.05 |

LMAD | 0.03 | 0.95 | −0.02 | 0.96 | −0.03 | 0.95 | −0.16 | 0.47 |

Year | −0.34 | 0.07 | −0.18 | 0.33 | −0.15 | 0.44 | −0.33 | 0.06 |

Mean age (yr) | 0.12 | 0.54 | −0.13 | 0.45 | 0.34 | 0.06 | −0.24 | 0.16 |

Mean weight (kg) | 0.25 | 0.18 | 0.03 | 0.89 | 0.21 | 0.27 | −0.03 | 0.89 |

Mean duration (min) | −0.06 | 0.78 | 0.22 | 0.23 | 0.13 | 0.49 | 0.14 | 0.45 |

| ||||||||

Propofol value (min) | 0.30 | 0.11 | 0.21 | 0.24 | 0.30 | 0.10 | 0.20 | 0.25 |

We observed seven cases in which a propofol anesthetic was used. In all cases, at least one OR nurse or surgical technologist was performing no discernable activity for at least 100 sec prior to tracheal extubation (95% CI > 66% of cases). The time to draw up propofol and set up an infusion pump averaged one minute (see Appendix).

## Discussion

Desflurane proportionally reduces the mean time to extubation and time to follow commands relative to propofol (21% and 23%), approximately the same as sevoflurane (25% and 19%)7 but less than isoflurane (34% and 34%).8 Clinicians provide anesthesia care in heterogeneous ways (Table 1) and meta-analysis of economic endpoints provides managerial insight into overall (pooled) effect (Table 3).39 The principal limitation is that since drug (treatment) effect is proportional,7 for results to be useful economically to a facility, results need to be converted to absolute reductions in time using the facility’s patients’ typical OR recovery times. For example, a 20% reduction in the mean time represents 1.5 min for patients with the brief mean interval of 7.5 min *vs* 2.5 min for patients with the long mean interval of 12.5 min.7 Differences between anesthetic agents in OR recovery times are studied since they can limit OR throughput, based on non-anesthesia OR personnel waiting for the patient to be extubated during emergence for most (> 66%) cases. Outside of ORs there typically are additional personnel (e.g., housekeepers and post-anesthesia care unit nurses) waiting for the end of cases, since surgical suites appropriately staff for multiple ORs in which cases end simultaneously.40,41 Additional personnel (e.g., housekeepers and postanesthesia care unit nurses) are typically outside of ORs waiting for cases to end, since surgical suites are appropriately staffed for multiple ORs on the basis of cases that end simultaneously.40,41

Achievable reductions in direct OR costs resulting from time savings in the OR can be calculated as described in the Discussion of reference 7. Specific values are unique to each facility (e.g., application of our results depends on the number of ORs with more than eight hours of cases daily). Other endpoints, such as time to home discharge and nausea, have previously undergone meta-analysis42-44 and are also of value when comparing the overall impact of the selection of anesthetic drugs. Selection of propofol adds approximately one minute to fill a syringe for infusion and to set up the infusion pump (see Appendix).

The novel findings of our study are twofold. First, as shown in the Figure, the reductions in the variabilities in OR recovery time are larger when desflurane is compared with propofol (26%, time to extubation and 39%, time to follow commands) than when desflurane is compared with sevoflurane (21% and 22%, respectively).7 Second, as is the focus of the Appendix, the reductions in the variabilities relative to propofol (26% and 39%) are larger than the corresponding mean reductions (21% and 23%). Such results are striking when considered in light of the traditional weighted mean difference meta-analysis that assumes a 0% reduction in variability. The pharmacokinetic/dynamic basis for the difference between reductions in standard deviation and mean is unknown. Variability matters clinically, as it contributes to the incidence of prolonged extubation times (e.g., > 15 min). Anesthesiologists rate recovery from propofol as poor when such prolonged extubations occur.45 Resulting intangible OR costs include significantly longer times to incision of to-follow cases7 (e.g., from surgeons leaving surgical suite46). The methods described in the Appendix and summarized in the Figure can be used in future clinical trials and meta-analyses of such trials with the reduction in variability of task duration as a primary study endpoint.

In conclusion, the mean reduction in OR recovery times for desflurane relative to propofol was comparable with that shown previously for desflurane relative to sevoflurane. The reduction in variability with propofol exceeded that compared with sevoflurane. Facilities can use the percentage differences when making evidence-based pharmacoeconomic decisions.

One article was unclear about whether the desflurane and propofol groups had both received nitrous oxide. An e-mail to the author clarified the protocol.

## Acknowledgements

We appreciate the assistance of Emine Bayman PhD who used WinBUGS code to perform another analysis of the standard deviations. We thank Martin Mueller MD for reviewing the articles written in German.

### Competing interests

This research was supported by Baxter Healthcare Corporation. Baxter Healthcare Corporations’ physicians and scientists made recommendations about the study design prior to providing funding, and they reviewed the manuscript once written. They were not involved in the conduct of the study; collection, analysis, or interpretation of the data; or preparation of the manuscript. Drs. Dexter and Epstein have previously performed research funded by Abbott Laboratories, and they previously performed research funded by Baxter Healthcare Corporation. Drs. Wachtel and Dexter receive no funds personally, other than their salaries from the University of Iowa. They do not receive travel expenses or honoraria from any source other than the University, and they have tenure with no incentive program.