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A comparison of anesthetic regimens using etomidate and propofol in patients undergoing first-trimester abortions: double-blind, randomized clinical trial of safety and efficacy
Contraception 87 (2013) 55 – 62
Original research article
A comparison of anesthetic regimens using etomidate and propofol in patients undergoing first-trimester abortions: double-blind, randomized clinical trial of safety and efficacy☆,☆☆ Jing Wu a,⁎, Shanglong Yao a , Zhouyang Wu a , Zhiling Wu a , Shujuan Chu a , Geqing Xia b , Feitao Deng b a Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Received 7 May 2012; revised 31 July 2012; accepted 9 August 2012
b
Abstract Background: This prospective study compared the safety, recovery time and side effects of six distinct general anesthesia regimens for firsttrimester surgical abortion. Study Design: Two hundred forty women scheduled for surgical abortion at 6 to 8 weeks of gestation were randomized into three groups (n=40) of propofol: group P (2 mg/kg propofol alone), group PF (2 mg/kg propofol+1 mcg/kg fentanyl), group PMF (2 mg/kg propofol+1 mcg/kg fentanyl+0.02 mg/kg midazolam) and three groups (n=40) of etomidate: group E (0.2 mg/kg etomidate alone), group EF (0.2 mg/kg etomidate+1 mcg/kg fentanyl) and group EMF (0.2 mg/kg etomidate+1 mcg/kg fentanyl+0.02 mg/kg midazolam). Vital signs including pulse oxygen saturation (SpO2), mean arterial pressure (MAP) and heart rate were recorded as the primary outcomes. The recovery time and side effects were recorded as secondary outcomes. Results: During induction, SpO2 and MAP decreased significantly in all the three groups of propofol and were significantly lower than those in the groups of etomidate. Mean recovery times to both eye opening and to obeying commands were significantly shorter in group PF than those in groups P and PMF, while there were no significant differences among the three groups of etomidate. Compared with the etomidate groups, the incidence of injection-induced pain was significantly higher, while the scores of myoclonus and postoperative nausea and vomiting were lower, in the three propofol groups. Moreover, myoclonus scores as well as nausea and vomiting scores were lower in group EMF than in groups E and EF. Conclusions: The results of this study suggest that (a) etomidate is much safer than propofol for first-trimester surgical abortions and (b) using a lower dose of etomidate, supplemented with fentanyl and midazolam, is more beneficial than the use of etomidate with or without fentanyl in reducing adverse effects like myoclonus and postoperative nausea and vomiting. © 2013 Elsevier Inc. All rights reserved. Keywords: Analgesia, obstetrical; Abortion, induced; Propofol; Etomidate; Fentanyl; Midazolam
1. Introduction First-trimester surgical abortion is the outpatient surgical procedure most commonly performed in women [1]. While very safe, surgical abortion is still not completely risk-free ☆ Source of funding: This work was supported by Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. ☆☆ Registration: registration number: ChiCTR-TRC-12002115; name of trial registry: Chinese Clinical Trail Registry. ⁎ Corresponding author. Tel.: +86 02785351643. E-mail address: [email protected] (J. Wu).
0010-7824/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2012.08.014
from either a surgical or anesthetic perspective. With major complications occurring in less than 1% and a mortality of around 0.7 in 100,000, anesthesia-related events are the leading cause of morbidity for these procedures [2–4]. Nearly 68,000 women die every year from unsafe abortion, and millions are injured [5]. As a result of the large population in China and the emphasis upon abortion as a means of the family planning policy of China, safe and appropriate anesthesia regimens for surgical abortion have great public health importance. The anesthesia strategies for first-trimester surgical abortion have been explored for decades. As regards general
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anesthesia for these procedures, the use of inhalational anesthetics has largely been replaced by intravenous anesthesia for the numerous drawbacks associated with general anesthesia, such as the increased procedure-related blood loss and the obvious requirement of a vaporizer attached to the anesthesia machine [1]. Partially because of its rapid recovery profile, propofol is the most frequently used intravenous anesthetic today and has achieved widespread use in outpatient surgery [6,7]. However, the most prominent undesirable effect of propofol is its marked depression in respiratory and cardiovascular parameters. For instance, an induction dose of propofol results in a 25% to 30% incidence of apnea and a 25% to 40% reduction in systolic blood pressure [7]. Unlike propofol, etomidate administration results in minimal respiratory depression and more stable hemodynamics, and these properties set it apart from other rapid-onset induction agents, rendering it much safer [7,8]. However, due to side effects like myoclonus and postoperative nausea and vomiting, etomidate has seldom been used during surgical abortion. Since these side effects might be significantly reduced by using a combination of opioids (e.g., fentanyl) and benzodiazepines (e.g., midazolam) [9–14], which have also been found to be beneficial for preoperative anxiety and postoperative pain, the usage of etomidate in surgical abortion should be reassessed. It needs to be determined whether these adjunct agents have any impact on the safety of anesthesia or delay recovery. At present, there are too few convincing studies about the use of multiple anesthetic agents for surgical abortion. We undertook this study to evaluate the safety and performance of propofol and etomidate used alone or combined with fentanyl or fentanyl and midazolam to provide general anesthesia for surgical abortion.
2. Materials and methods 2.1. Patients and group assignment A double-blind, randomized clinical trial was conducted at the Union Hospital in Wuhan City, Hubei, P.R. China. The study protocol was approved by institutional review board (Tongji Medical College, Huazhong University of Science and Technology, China). After written informed patient consent, 240 healthy women, who were at 6 to 8 weeks of gestation as confirmed by an ultrasound examination, without a history of vaginal deliveries and with no psychiatric disorders, uterine anomaly or any other severe medical
conditions, were scheduled for surgical abortion between August 2010 and January 2011. Patients (The American Society of Anesthesiologists physical status I–II, age 18–35 years, body weight 45–65 kg and height 150–170 cm) were assigned to one of six groups to receive general anesthesia (40 patients per group). Women had an equal probability of assignment to the groups. The randomization code was developed using a computer random number generator to select random permuted blocks. Only one anesthetist and one surgeon were involved in each of the procedures. The anesthetist, the surgeon, the nurses, the recorders as well as the patients, except for the researcher who concealed assignments using sequentially numbered, opaque, sealed envelopes and prepared the medicine, were blinded to the group assignment. 2.2. Methods of anesthesia and operation No local anesthesia or premedication was used. After venipuncture in the dorsum of the right or left hand, a standard intravenous bolus induction dose was used for every patient as follows: 1% midazolam (Jiangsu Nhwa Pharmaceutical Co., China) or normal saline was first administered as 0.02 mL/kg; 2 min later, 0.5% fentanyl (Yichang Humanwell Pharmaceutical Co., China) or normal saline was given as 0.01 mL/kg over a period of 30 s; another 2 min later, 2% propofol (Zeneca Pharmaceuticals, Wilmington, DE, USA) or 0.2% etomidate (Jiangsu Nhwa Pharmaceutical Co., China) was administered as 0.1 mL/kg over a period of 60 s (Table 1). At the end of induction, the abortions were immediately performed by vacuum aspiration. If the patient had spontaneous movement that hampered the conduct of the procedure, as per group allocation, either 2% propofol (Zeneca Pharmaceuticals, Wilmington, DE, USA) or 0.2% etomidate (Jiangsu Nhwa Pharmaceutical Co., China) was supplemented as a 1–2-mL bolus. As regards the procedure, if needed, cervical dilation was serially performed with metal dilators. Each patient received intravenously approximately 250 mL lactated Ringer's solution during the operation and 20 U of oxytocin after the procedure for routine uterotonic therapy. After completion of the abortion, patients were monitored in the recovery room for 2 h. 2.3. Evaluation of parameters Patients were monitored by electrocardiogram, noninvasive blood pressure and pulse oximetry throughout the entire operation. Vital signs including mean arterial pressure
Table 1 Anesthesia regimens of the study Drugs
Dose
Method
Time
Midazolam (2 mg/2 mL) or NS (2 mL) Fentanyl (0.1 mg/2 mL) or NS (2 mL) Propofol (200 mg/10 mL) or etomidate (20 mg/10 mL)
0.02 mL/kg 0.01 mL/kg 0.1 mL/kg
Given slowly Given over a period of 30 s Given over a period of 60 s
Initially 2 min later Another 2 min later
Abbreviation: NS, normal saline.
J. Wu et al. / Contraception 87 (2013) 55–62
(MAP), heart rate (HR) and pulse oxygen saturation (SpO2) were recorded at baseline (T1), after the induction of anesthesia (T2), before adding anesthetics with etomidate or propofol (T3), after the procedure (T4) and before discharge (T5). The induction dose and any supplementary bolus doses of propofol or etomidate that were subsequently administered were recorded, and the addition of these values produced the total dose of propofol or etomidate administered. In addition, the ‘time until first top-up’ (time from the induction dose until administering the first supplementary dose of either propofol or etomidate) was recorded. Operative time, beginning with insertion of the speculum and ending with removal of the speculum, was recorded. Recovery was assessed by recording (a) time to eye opening (the time in minutes measured from end of anesthesia to eye opening, either spontaneously or to verbal commands), (b) time to obeying commands (the time in minutes measured from end of anesthesia to the recovery of the patients' ability to answer questions such as ‘What is your name?’ or ‘When is your birthday?’) and (c) postanesthesia care unit (PACU) recovery time (corresponding to the time in minutes from end of anesthesia to attain adequate recovery as denoted by a modified Aldrete score ≥9 [15]). Side effects, including injection-induced pain [pain at the injection site, assessed after injection of propofol, on a binary scale (yes/no)], myoclonus (a brief and involuntary twitching of a muscle or a group of muscles, recorded on a scale between 0 and 3[12]), and postoperative nausea and vomiting (using a 4-point scale, with 0=none, 1=mild, 2= moderate and 3=severe), were recorded by a trained nurse. The vital signs were recorded as the primary outcome. The doses of either propofol or etomidate and the times at which any supplementary boluses were given, recovery times and side effects were recorded as the secondary outcomes. 2.4. Statistical analysis Baseline characteristics were compared using Kruskal– Wallis H test for categorical variables and one-way analysis of variance (ANOVA) tests for continuous variables. Statistical analysis was performed using SPSS 15.0 software. A power analysis for the primary endpoint demonstrated that 34 patients were required in each group to demonstrate a significant difference of 30% in cardiovascular or respiratory parameters [6,7] based on a two-tailed p value of .05 with a 95% chance to find a true effect. ANOVA for repeated measurements was used in detecting changes in vital signs and other outcomes within each group. pb.05 was considered to represent statistical significance. All p values reported were two-tailed. 3. Results Two hundred ninety-three patients were assessed for study eligibility, 38 patients did not meet inclusion criteria, 12 patients declined to participate, and 3 patients were
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excluded for other reasons, so 240 patients were finally enrolled (Fig. 1). None of the women had excessive bleeding, so there was no need to change the pads for any patient, and all of them were discharged in good health after 2 h. There were no significant differences in groups as regards the mean age, height and weight (Table 2). 3.1. Primary outcomes: vital signs Fig. 2A shows that mean SpO2 values in the groups P, PF and PMF significantly decreased from 98.9%±1.3%, 98.9%±0.9% and 98.8%±1.2% at T1 (preanesthesia) to 94.7%±4.2%, 91.9%±9.2% and 93.7%±7.0% at T2 (during induction) (all pb.01), while they did not change significantly in groups E, EF and EMF (from 99.0%±0.6%, 98.6%±1.4% and 98.9%±1.2% at T1 to 97.4%±3.7%, 97.1%±2.8% and 97.3%±3.4% at T2, all pN.05); there were no significant differences amongst all groups at the three other time points (pN.05). At T2, mean SpO2 values in the three propofol groups were much lower than those in the three etomidate groups (pb.05). Fig. 2B shows that mean MAP significantly decreased from 89±10 mmHg, 88±9 mmHg, 85±11 mmHg, 88±7 mmHg, 89±7 mmHg and 87±11 mmHg in groups P, PF, PMF, E, EF and EMF at T1 to 75±8 mmHg, 73±9 mmHg, 73±8 mmHg, 82±8 mmHg, 79±8 mmHg and 75±8 mmHg at T2, respectively(pb.01), and then increased at T3 (during the addition of anesthetics) in groups E (97±14 mmHg, p=.007) and EF (95±10 mmHg, p=.049). However, the mean MAP values showed significant decreases at T4 (after operation) in group P (77±13 mmHg, pb.01) and group E (79±12 mmHg, pb.01). These reductions were still lower at T5 (recovery) in groups P, PF, PMF and E (72±18 mmHg, 76±13 mmHg, 73±13 mmHg and 80±11 mmHg, pb.01 or .05). At T2, mean MAP values were higher in groups E and EF than in the three propofol groups (pb.01 or .05), while there were no significant differences in all groups at the other four time points (pN.05). Fig. 2C shows that mean HR significantly decreased from 84±14 bpm, 85±18 bpm, 91±20 bpm, 92±10 bpm and 85±13 bpm in groups P, PF, PMF, EF and EMF at T1 to 75±10 bpm, 73±12 bpm, 75±11 bpm, 76±16 bpm and 72±12 bpm at T2 (pb.01) except in group E, in which mean HR did not show any significant change (from 84±10 bpm at T1 to 77±11 bpm at T2, pN.05) but increased at T3 (94±16 bpm, p=.024) (Fig. 2). And there were no significant differences in all other groups at the five time points (pN.05). 3.2. Secondary outcomes: anesthetics use and recovery As regards operative time, no statistically significant differences in mean time (7.8±1.6 min, 8.2±2.5 min, 8.2±3.6 min, 7.9±2.1 min, 7.5±3.1 min and 7.8±2.9 min in groups P, PF, PMF, E, EF and EMF, p=.843) were noted between groups (Table 3). The mean time to eye opening in group PF was significantly shorter than that in group PMF (4.5±1.7 min vs. 6.0±2.5 min, p=.026). In addition, the mean time to
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J. Wu et al. / Contraception 87 (2013) 55–62
Enrollment
Assessed for eligibility (n=293)
Excluded (n=53) Not meeting inclusion criteria (n=38) Declined to participate (n=12) Other reasons (n=3)
Randomized (n=240)
Allocation Etomidate groups (group E, EF and EMF, n=40 in each group): Allocated to intervention (n=120)
Propofol groups (group P, PF and PMF, n=40 in each group): Allocated to intervention (n=120)
Follow-Up Follow-up (n=120)
Follow-up (n=120)
Analysis Analyzed (n=120)
Analyzed (n=120)
Fig 1. CONSORT flow diagram.
obeying commands achieved in group PF (4.6±1.7 min) was significantly shorter than that in groups P (5.7±1.6 min, p= .042) and PMF (6.2±2.4 min, p=.016). The mean PACU recovery time in group PF was significantly shorter than that in group P (11.8±2.7 min vs. 13.9±3.2 min, p=.047). The mean ‘time until first top-up’ (time from the induction dose until administering the first supplementary dose) was significantly shorter in group P than in group PF (4.2± 2.1 min vs. 5.7±3.1 min, p=.037, Table 4) but did not show any significant difference between groups P and PMF (4.2± 2.1 min vs. 5.5±4.0 min, p=.088), while those variables in group E (2.7±1.5 min) were significantly shorter than those variables in groups EF (6.2±3.3 min, pb.001, Table 5) and EMF (7.1±4.0 min, pb.001). The number of supplementary boluses of hypnotic given in group P (2.1±0.9 times) was significantly more than that in group PF (1.6±0.9 times, p= .033) and PMF (1.3±1.3 times, p=.002), while those variables in group E (2.0±1.0 times) were significantly
more than those in groups EF (1.2±1.3 times, p=.017) and EMF (1.3±1.2 times, p=.033). The total dose of propofol in group PMF (149.5±30.0 mg) was significantly less than those variables in groups P (186.4±31.5 mg, pb.001) and PF (175.6±28.0 mg, pb.001). Similarly, the total dose of etomidate in group EMF (15.8±4.2 mg) was significantly less than those variables in groups E (19.9±4.0 mg, pb.001) and EF (18.9±4.8 mg, p=.002). But the total dose did not show any significant difference between groups P and PF (p=.246) and between groups E and EF (p=.318). 3.3. Secondary outcomes: side effects As regards injection-induced pain, there was a significant difference between the propofol groups and the etomidate groups. Twenty-nine, 24 and 32 out of 40 patients in groups P, PF and PMF, respectively (72.5%, 60% and 80%), complained of injection-induced pain vs. 6, 0 and 6 out of 40 in
Table 2 Demographics of the study groups (each group n=40)
Age (years) Height (m) Weight (kg)
Group P
Group PF
Group PMF
Group E
Group EF
Group EMF
p value
27.1±4.0 1.61±0.05 52.2±7.9
28.4±6.2 1.62±0.04 53.7±4.8
28.2±5.0 1.62±0.06 53.8±4.3
27.1±5.0 1.61±0.04 51.5±8.7
29.5±6.3 1.61±0.04 52.6±7.9
27.7±5.8 1.61±0.04 53.2±6.2
.392 .379 .601
Data are mean±SD. There were no significant differences between groups with regards to mean age, height and weight.
J. Wu et al. / Contraception 87 (2013) 55–62
Group P
A
Group PF
Group PMF
Group E
59
Group EF
Group EMF
100 98
abc abc ab **
SPO2(%)
96 94
**
92
**
**
90 88 86 84 82 80 T1
T2 Group P
B
T3
Group PF
T4
Group PMF
Group E
T5
Group EF
Group EMF
120
MAP(mmHg)
110 100 ** *
90 **
**aabbcc **abbcc
80 70
* * ** **
**
** ** **
60 T1
C
T2 Group P
T3
Group PF
T4
Group PMF
Group E
Group EF
T5 Group EMF
120 110
HR(bpm)
100 *
*
90 80 ** ** ** ** **
70 60 T1
T2
T3
T4
T5
Fig 2. Mean SPO2 (A), MAP (B) and HR (C) levels of six study groups (each group n=40). Data are mean±SD. Two-way ANOVA determined significant differences. a or aa: pb.05 or .01 differences between group P and each of the other groups. b or bb: pb.05 or .01 differences between group PF and each of the other groups. c or cc: pb.05 or .01 differences between group PMF and each of the other groups. ⁎ or ⁎⁎: pb.05 or .01 differences between the values at T1 and each of the four other time points. Abbreviations: T1, preanesthesia; T2, induction; T3, adding anesthetics; T4, after operation; T5, recovery.
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J. Wu et al. / Contraception 87 (2013) 55–62
Table 3 Operative and recovery times of study groups (each group n=40) Group P Operative time (min) Recovery time (min) Time to eye opening Time to obeying commands PACU recovery time
Group PF
Group PMF
Group E
Group EF
Group EMF
F
p value
7.8±1.6
8.2±2.5
8.2±3.6
7.9±2.1
7.5±3.1
7.8±2.9
.408
.843
4.7±1.2 5.7±1.6 b 13.9±3.2 b
4.5±1.7 4.6±1.7 a 11.8±2.7a
6.0±2.5 b 6.2±2.4 b 12.7±4.3
5.2±5.1 5.1±3.1 12.0±5.7
5.4±2.1 5.8±2.3 13.6±5.0
4.6±2.1 4.7±2.2 12.8±5.0
1.709 3.372 1.264
.133 .006 .281
Data are mean±SD. One-way ANOVA determined significant differences. a: pb.05 differences between groups P and PF. b: pb.05 differences between groups PF and P, and between groups PF and PMF. Time to eye opening (the time in minutes measured from end of anesthesia to eye opening, either spontaneously or to verbal commands). Time to obeying commands (the time in minutes measured from end of anesthesia to the recovery of the patients' ability to answer questions such as ‘What is your name?’ or ‘When is your birthday?’). PACU recovery time (the time in minutes from end of anesthesia to attain adequate recovery as denoted by a modified Aldrete score ≥9).
the E, EF and EMF groups, respectively (12.5%, 0% and 12.5%). There were no significant differences in pain levels amongst the three groups of propofol or etomidate. As concerns myoclonus and postoperative nausea and vomiting, these two side effects in the propofol groups were lower than in the etomidate groups. Three, 1 and 1 out of 40 patients in groups P, PF and PMF, respectively (7.5%, 2.5% and 2.5%), recorded myoclonus vs. 18, 24 and 13 out of 40 in the E, EF and EMF groups, respectively (45%, 60% and 32.5%). Zero, 1 and 0 out of 40 patients in groups P, PF and PMF, respectively (0%, 2.5% and 0%), recorded myoclonus vs. 23, 20 and 9 out of 40 in the E, EF and EMF groups, respectively (57.5%, 50% and 22.5%). There were no significant differences in incidence of myoclonus and postoperative nausea and vomiting amongst the three groups of propofol. But the incidences of myoclonus and postoperative nausea and vomiting in group EMF (32.5% and 22.5%) were lower than those in groups E (45.0% and 57.5%) and EF (60% and 50%) (Table 6).
4. Discussion The results of this study suggest that etomidate is much safer than propofol for surgical abortion and that the adjuncts (fentanyl and midazolam) reduce its dose and side effects with minimal effects on safety and recovery. Intravenous anesthetics are associated with some adverse effects, including decreases in arterial blood pressure, apnea, injection-induced pain, nausea and vomiting, and myoclonus [6,7]. As a profound cardiovascular depressant, propofol often decreases systemic blood pressure during induction
and produces a high incidence of apnea, lasting longer than 30 s, which exposes the patient to the risks of a decrease in SPO2 [6,7]. As brain damage related to respiratory events is the leading cause of morbidity in anesthesia-related events, the safety of anesthesia is of primary importance [16]. In contrast, the hemodynamic stability and minimal respiratory depression following the use of etomidate are unique characteristics among the rapid-onset induction agents, so etomidate provides a wider margin of safety than barbiturates or propofol [8]. Our study found similar results; during induction, mean SPO2 values were higher in the three etomidate groups than in the three propofol groups, with significant decreases in the propofol groups but not in the etomidate groups. As for mean MAP values, they were higher in groups E and EF than those in the three propofol groups. However, there was no significant difference in recovery times between etomidate and propofol. Injectioninduced pain at the injection site is cited as a frequent side effect of propofol and etomidate [6–8]. Our study found a higher incidence of injection-induced pain in the propofol groups (60% to 80%) than in the etomidate groups (0% to 12.5%) which may be partly because of the high concentration (2%) of propofol in our study and the differences in lipid emulsion. At high concentrations, both propofol and etomidate activate transient receptor potential type A1 cation channels, a mechanism that may underlie injection-induced pain [17]. In regards to other side effects, in agreement with many studies, etomidate has been found to be associated with a high incidence of nausea and vomiting (30% to 40%), which is higher than that following propofol administration [18]. The incidence of myoclonus following etomidate is also highly variable (0% to 70%) [8,19]. Our study found
Table 4 Requirement of propofol: a group-wise comparison (each group n=40)
Time until first top-up (min) Number of supplementary boluses (times) Total dose (mg)
Group P
Group PF
Group PMF
F
p value
4.2±2.1 b 2.1±0.9 b 186.4±31.5
5.7±3.1 a 1.6±0.9 a 175.6±28.0
5.5±4.0 1.3±1.3 aa 149.5±30.0 aabb
2.569 5.446 16.122
.081 .005 b.001
Data are mean±SD. One-way ANOVA determined significant differences. a or aa: pb.05 or .01 differences between groups P and PF, and between groups P and PMF. b or bb: pb.05 or .01 differences between groups PF and P, and between groups PF and PMF. Time until first top-up (time from the induction dose until administering the first supplementary dose of either propofol or etomidate).
J. Wu et al. / Contraception 87 (2013) 55–62 Table 5 Requirement of etomidate: a group-wise comparison (each group n=40) Group E
Group EF ee
Time until first 2.7±1.5 top-up (min) Number of 2.0±1.0 e supplementary boluses (times) Total dose (mg) 19.9±4.0
6.2±3.3
dd
1.2±1.3 d
18.9±4.8
Group EMF F 7.1±4.0
dd
1.3±1.2 d
15.8±4.2 ddee
p value
21.372 b.001 4.634
.012
9.830 b.001
Data are mean±SD. One-way ANOVA determined significant differences. d or dd: pb.05 or .01 differences between groups E and EF, and between groups E and EMF. e or ee: pb.05 or .01 differences between groups EF and E, and between groups EF and EMF. Time until first top-up (time from the induction dose until administering the first supplementary dose of either propofol or etomidate).
that the incidences of nausea and vomiting and myoclonus in the three etomidate groups (32.5% to 60%, 22.5% to 57.5%) are much higher than those in the three propofol groups (2.5% to 7.5%, 0% to 2.25%). Addition of opioids to the general anesthesia regimen has been found to be beneficial for postoperative pain and myoclonus [1,8–10,20]. However, the use of an opiate alongside propofol increases the incidence of apnea, especially prolonged apnea, and appears to augment the decrease in arterial blood pressure [6,7,18,21], as well as further increasing the incidence of nausea and vomiting related to etomidate [12,13]. However, our study did not find any significant differences in these adverse effects between the fentanyl-treated groups and the nonopioids groups. This may be due partly to the dose of fentanyl used in our study (on average, a dose of around 0.05 mg), which is much less than that in other studies (0.1 mg) [9,10]. Our results showed that vital signs, total dose and side effects did not show significant differences between groups P and PF and between groups E and EF, but the time until obeying commands and the PACU recovery time in group PF are significantly shorter than those in group P. The addition of midazolam has been advocated for reducing the incidence of myoclonus and postoperative nausea and vomiting related to intravenous anesthetics [11–14]. Table 6 Incidence in the severity of myoclonus and nausea and vomiting in the study groups (each group n=40) Side effects Myoclonus
Nausea and vomiting
0 1 2 3 0 1 2 3
Group E
Group EF
Group EMF
H
p value
22 (55.0) 12 (30.0) 0 (0.0) 6 (15.0) 17 (42.5) 2 (5.0) 3 (7.5) 18 (45.0)
16 (40.0) 10 (25.0) 8 (20.0) 6 (15.0) 20 (50.0) 6 (15.0) 4 (10.0) 10 (25.0)
27 (67.5) 8 (20.0) 2 (5.0) 3 (7.5) 31 (77.5) 3 (7.5) 2 (5.0) 4 (10.0)
6.928
.001
5.138
.007
Data are presented as n (%) with p value from Kruskal–Wallis H test. For all variables, missing data were ≤0.05%. Grade of severity or score of myoclonus and nausea and vomiting as assessed on a 4-point scale, with 0= none, 1=mild, 2=moderate and 3=severe.
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Low-dose intravenous midazolam (0.015 mg/kg) reduces etomidate-induced myoclonus and does not prolong recovery in unpremedicated patients undergoing short procedures [12]. Furthermore, midazolam 0.05 mg/kg is effective in the prevention of postoperative vomiting after anesthesia in patients undergoing thyroidectomy [14]. Our study found similar results; both myoclonus and nausea and vomiting were less frequent in group EMF (0.2 mg/kg etomidate+1 mcg/kg fentanyl+0.02 mg/kg midazolam) than in groups E and EF. In contrast, there were no differences in the propofol groups because of the antiemetic effect of propofol. We also found that propofol or etomidate, combined with fentanyl and midazolam, showed similar vital signs and recovery times with much fewer total doses, but the times until eye opening and until following commands in group PMF were significantly longer than those in group PF. These results suggest that midazolam is more appropriate to combine with etomidate than with propofol because the combination with etomidate shows fewer side effects coupled with shorter recovery times. A possible limitation of the current study is the lack of additional data about patients’ satisfaction and postabortion pain. Although this study gives credence to the hypothesis that low-dose fentanyl and midazolam reduce the dose and side effects of etomidate with minimal effects on safety and recovery, a larger trial powered to detect differences is needed to confirm these findings before we recommend a change in clinical practice as regards the use of multiple anesthetic agents for surgical abortion. In conclusion, the administration of etomidate is much safer than that of propofol for first-trimester surgical abortions, and etomidate combined with low doses of fentanyl and midazolam is more beneficial than etomidate alone for reducing myoclonus, nausea and vomiting. Acknowledgments We thank all the patients, doctors and nurses who participated in this study. And we also thank Gunsham Purusram for suggestions and revision. References [1] Renner RM, Jensen JT, Nichols MD, Edelman AB. Pain control in first-trimester surgical abortion: a systematic review of randomized controlled trials. Contraception 2010;81:372–88. [2] Bartlett LA, Berg CJ, Shulman HB, et al. Risk factors for legal induced abortion-related mortality in the United States. Obstet Gynecol 2004;103:729–37. [3] Hakim-Elahi E, Tovell HM, Burnhill MS. Complications of firsttrimester abortion: a report of 170,000 cases. Obstet Gynecol 1990;76: 129–35. [4] Lawson HW, Frye A, Atrash HK, Smith JC, Shulman HB, Ramick M. Abortion mortality, United States, 1972 through 1987. Am J Obstet Gynecol 1994;171:1365–72. [5] World Health Organization. Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2000. 4th ed. Geneva, Switzerland: World Health Organization; 2004.
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[6] Steinbacher DM. Propofol: a sedative-hypnotic anesthetic agent for use in ambulatory procedures. Anesth Prog 2001;48:66–71 [PubMed:: 11515950]. [7] Reves JG, Glass PSA, Lubarsky DA, McEvoy MD. Intravenous nonopioid anesthetics. In: & Miller RD, editor. Miller's anesthesia. Philadelphia: Elsevier Churchill Livingstone; 2005, pp. 318–79. [8] Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011;114:695–707. [9] Stockham RJ, Stanley TH, Pace NL, Gillmor S, Groen F, Hilkens P. Fentanyl pretreatment modifies anaesthetic induction with etomidate. Anaesth Intensive Care 1988;16:171–6. [10] Zacharias M, Dundee JW, Clarke RS, Hegarty JE. Effect of preanaesthetic medication on etomidate. Br J Anaesth 1979;51: 127–33. [11] Schwarzkopf KR, Hueter L, Simon M, Fritz HG. Midazolam pretreatment reduces etomidate-induced myoclonic movements. Anaesth Intensive Care 2003;31:18–20. [12] Hüter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007;105:1298–302. [13] Hwang JY, Kim JH, Oh AY, Do SH, Jeon YT, Han SH. A comparison of midazolam with remifentanil for the prevention of myoclonic movements following etomidate injection. J Int Med Res 2008;36: 17–22.
[14] Fujii Y, Itakura M. Antiemetic efficacy of low-dose midazolam in patients undergoing thyroidectomy. Otolaryngol Head Neck Surg 2011;144:206–9. [15] White PF, Song D. New criteria for fast-tracking after outpatient anesthesia: a comparison with the modified Aldrete's scoring system. Anesth Analg 1999;88:1069–72. [16] Cheney FW. The American Society of Anesthesiologists Closed Claims Project: what have we learned, how has it affected practice, and how will it affect practice in the future? Anesthesiology 1999;91:552–6. [17] Matta JA, Cornett PM, Miyares RL, Abe K, Sahibzada N, Ahern GP. General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc Natl Acad Sci U S A 2008;105:8784–9. [18] Van Aken H, Meinshausen E, Prien T, Brüssel T, Heinećke A, Lawin P. The influence of fentanyl and tracheal intubation on the hemodynamic effects of anesthesia induction with propofol/N2O in humans. Anesthesiology 1988;68:157–63. [19] Ulsamer B, Doenicke A, Laschat M. Propofol in comparison with etomidate for the induction of anesthesia. Anaesthesist 1986;35: 535–42. [20] Jakobsson J, Oddby E, Rane K. Patient evaluation of four different combinations of intravenous anaesthetics for short outpatient procedures. Anaesthesia 1993;48:1005–7. [21] Bocian D, French S. Propofol (Diprivan) — a new intravenous anesthetic with applications for outpatient ambulatory surgery. J Foot Surg 1992;31:603–6.
Original research article
A comparison of anesthetic regimens using etomidate and propofol in patients undergoing first-trimester abortions: double-blind, randomized clinical trial of safety and efficacy☆,☆☆ Jing Wu a,⁎, Shanglong Yao a , Zhouyang Wu a , Zhiling Wu a , Shujuan Chu a , Geqing Xia b , Feitao Deng b a Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Received 7 May 2012; revised 31 July 2012; accepted 9 August 2012
b
Abstract Background: This prospective study compared the safety, recovery time and side effects of six distinct general anesthesia regimens for firsttrimester surgical abortion. Study Design: Two hundred forty women scheduled for surgical abortion at 6 to 8 weeks of gestation were randomized into three groups (n=40) of propofol: group P (2 mg/kg propofol alone), group PF (2 mg/kg propofol+1 mcg/kg fentanyl), group PMF (2 mg/kg propofol+1 mcg/kg fentanyl+0.02 mg/kg midazolam) and three groups (n=40) of etomidate: group E (0.2 mg/kg etomidate alone), group EF (0.2 mg/kg etomidate+1 mcg/kg fentanyl) and group EMF (0.2 mg/kg etomidate+1 mcg/kg fentanyl+0.02 mg/kg midazolam). Vital signs including pulse oxygen saturation (SpO2), mean arterial pressure (MAP) and heart rate were recorded as the primary outcomes. The recovery time and side effects were recorded as secondary outcomes. Results: During induction, SpO2 and MAP decreased significantly in all the three groups of propofol and were significantly lower than those in the groups of etomidate. Mean recovery times to both eye opening and to obeying commands were significantly shorter in group PF than those in groups P and PMF, while there were no significant differences among the three groups of etomidate. Compared with the etomidate groups, the incidence of injection-induced pain was significantly higher, while the scores of myoclonus and postoperative nausea and vomiting were lower, in the three propofol groups. Moreover, myoclonus scores as well as nausea and vomiting scores were lower in group EMF than in groups E and EF. Conclusions: The results of this study suggest that (a) etomidate is much safer than propofol for first-trimester surgical abortions and (b) using a lower dose of etomidate, supplemented with fentanyl and midazolam, is more beneficial than the use of etomidate with or without fentanyl in reducing adverse effects like myoclonus and postoperative nausea and vomiting. © 2013 Elsevier Inc. All rights reserved. Keywords: Analgesia, obstetrical; Abortion, induced; Propofol; Etomidate; Fentanyl; Midazolam
1. Introduction First-trimester surgical abortion is the outpatient surgical procedure most commonly performed in women [1]. While very safe, surgical abortion is still not completely risk-free ☆ Source of funding: This work was supported by Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. ☆☆ Registration: registration number: ChiCTR-TRC-12002115; name of trial registry: Chinese Clinical Trail Registry. ⁎ Corresponding author. Tel.: +86 02785351643. E-mail address: [email protected] (J. Wu).
0010-7824/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2012.08.014
from either a surgical or anesthetic perspective. With major complications occurring in less than 1% and a mortality of around 0.7 in 100,000, anesthesia-related events are the leading cause of morbidity for these procedures [2–4]. Nearly 68,000 women die every year from unsafe abortion, and millions are injured [5]. As a result of the large population in China and the emphasis upon abortion as a means of the family planning policy of China, safe and appropriate anesthesia regimens for surgical abortion have great public health importance. The anesthesia strategies for first-trimester surgical abortion have been explored for decades. As regards general
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anesthesia for these procedures, the use of inhalational anesthetics has largely been replaced by intravenous anesthesia for the numerous drawbacks associated with general anesthesia, such as the increased procedure-related blood loss and the obvious requirement of a vaporizer attached to the anesthesia machine [1]. Partially because of its rapid recovery profile, propofol is the most frequently used intravenous anesthetic today and has achieved widespread use in outpatient surgery [6,7]. However, the most prominent undesirable effect of propofol is its marked depression in respiratory and cardiovascular parameters. For instance, an induction dose of propofol results in a 25% to 30% incidence of apnea and a 25% to 40% reduction in systolic blood pressure [7]. Unlike propofol, etomidate administration results in minimal respiratory depression and more stable hemodynamics, and these properties set it apart from other rapid-onset induction agents, rendering it much safer [7,8]. However, due to side effects like myoclonus and postoperative nausea and vomiting, etomidate has seldom been used during surgical abortion. Since these side effects might be significantly reduced by using a combination of opioids (e.g., fentanyl) and benzodiazepines (e.g., midazolam) [9–14], which have also been found to be beneficial for preoperative anxiety and postoperative pain, the usage of etomidate in surgical abortion should be reassessed. It needs to be determined whether these adjunct agents have any impact on the safety of anesthesia or delay recovery. At present, there are too few convincing studies about the use of multiple anesthetic agents for surgical abortion. We undertook this study to evaluate the safety and performance of propofol and etomidate used alone or combined with fentanyl or fentanyl and midazolam to provide general anesthesia for surgical abortion.
2. Materials and methods 2.1. Patients and group assignment A double-blind, randomized clinical trial was conducted at the Union Hospital in Wuhan City, Hubei, P.R. China. The study protocol was approved by institutional review board (Tongji Medical College, Huazhong University of Science and Technology, China). After written informed patient consent, 240 healthy women, who were at 6 to 8 weeks of gestation as confirmed by an ultrasound examination, without a history of vaginal deliveries and with no psychiatric disorders, uterine anomaly or any other severe medical
conditions, were scheduled for surgical abortion between August 2010 and January 2011. Patients (The American Society of Anesthesiologists physical status I–II, age 18–35 years, body weight 45–65 kg and height 150–170 cm) were assigned to one of six groups to receive general anesthesia (40 patients per group). Women had an equal probability of assignment to the groups. The randomization code was developed using a computer random number generator to select random permuted blocks. Only one anesthetist and one surgeon were involved in each of the procedures. The anesthetist, the surgeon, the nurses, the recorders as well as the patients, except for the researcher who concealed assignments using sequentially numbered, opaque, sealed envelopes and prepared the medicine, were blinded to the group assignment. 2.2. Methods of anesthesia and operation No local anesthesia or premedication was used. After venipuncture in the dorsum of the right or left hand, a standard intravenous bolus induction dose was used for every patient as follows: 1% midazolam (Jiangsu Nhwa Pharmaceutical Co., China) or normal saline was first administered as 0.02 mL/kg; 2 min later, 0.5% fentanyl (Yichang Humanwell Pharmaceutical Co., China) or normal saline was given as 0.01 mL/kg over a period of 30 s; another 2 min later, 2% propofol (Zeneca Pharmaceuticals, Wilmington, DE, USA) or 0.2% etomidate (Jiangsu Nhwa Pharmaceutical Co., China) was administered as 0.1 mL/kg over a period of 60 s (Table 1). At the end of induction, the abortions were immediately performed by vacuum aspiration. If the patient had spontaneous movement that hampered the conduct of the procedure, as per group allocation, either 2% propofol (Zeneca Pharmaceuticals, Wilmington, DE, USA) or 0.2% etomidate (Jiangsu Nhwa Pharmaceutical Co., China) was supplemented as a 1–2-mL bolus. As regards the procedure, if needed, cervical dilation was serially performed with metal dilators. Each patient received intravenously approximately 250 mL lactated Ringer's solution during the operation and 20 U of oxytocin after the procedure for routine uterotonic therapy. After completion of the abortion, patients were monitored in the recovery room for 2 h. 2.3. Evaluation of parameters Patients were monitored by electrocardiogram, noninvasive blood pressure and pulse oximetry throughout the entire operation. Vital signs including mean arterial pressure
Table 1 Anesthesia regimens of the study Drugs
Dose
Method
Time
Midazolam (2 mg/2 mL) or NS (2 mL) Fentanyl (0.1 mg/2 mL) or NS (2 mL) Propofol (200 mg/10 mL) or etomidate (20 mg/10 mL)
0.02 mL/kg 0.01 mL/kg 0.1 mL/kg
Given slowly Given over a period of 30 s Given over a period of 60 s
Initially 2 min later Another 2 min later
Abbreviation: NS, normal saline.
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(MAP), heart rate (HR) and pulse oxygen saturation (SpO2) were recorded at baseline (T1), after the induction of anesthesia (T2), before adding anesthetics with etomidate or propofol (T3), after the procedure (T4) and before discharge (T5). The induction dose and any supplementary bolus doses of propofol or etomidate that were subsequently administered were recorded, and the addition of these values produced the total dose of propofol or etomidate administered. In addition, the ‘time until first top-up’ (time from the induction dose until administering the first supplementary dose of either propofol or etomidate) was recorded. Operative time, beginning with insertion of the speculum and ending with removal of the speculum, was recorded. Recovery was assessed by recording (a) time to eye opening (the time in minutes measured from end of anesthesia to eye opening, either spontaneously or to verbal commands), (b) time to obeying commands (the time in minutes measured from end of anesthesia to the recovery of the patients' ability to answer questions such as ‘What is your name?’ or ‘When is your birthday?’) and (c) postanesthesia care unit (PACU) recovery time (corresponding to the time in minutes from end of anesthesia to attain adequate recovery as denoted by a modified Aldrete score ≥9 [15]). Side effects, including injection-induced pain [pain at the injection site, assessed after injection of propofol, on a binary scale (yes/no)], myoclonus (a brief and involuntary twitching of a muscle or a group of muscles, recorded on a scale between 0 and 3[12]), and postoperative nausea and vomiting (using a 4-point scale, with 0=none, 1=mild, 2= moderate and 3=severe), were recorded by a trained nurse. The vital signs were recorded as the primary outcome. The doses of either propofol or etomidate and the times at which any supplementary boluses were given, recovery times and side effects were recorded as the secondary outcomes. 2.4. Statistical analysis Baseline characteristics were compared using Kruskal– Wallis H test for categorical variables and one-way analysis of variance (ANOVA) tests for continuous variables. Statistical analysis was performed using SPSS 15.0 software. A power analysis for the primary endpoint demonstrated that 34 patients were required in each group to demonstrate a significant difference of 30% in cardiovascular or respiratory parameters [6,7] based on a two-tailed p value of .05 with a 95% chance to find a true effect. ANOVA for repeated measurements was used in detecting changes in vital signs and other outcomes within each group. pb.05 was considered to represent statistical significance. All p values reported were two-tailed. 3. Results Two hundred ninety-three patients were assessed for study eligibility, 38 patients did not meet inclusion criteria, 12 patients declined to participate, and 3 patients were
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excluded for other reasons, so 240 patients were finally enrolled (Fig. 1). None of the women had excessive bleeding, so there was no need to change the pads for any patient, and all of them were discharged in good health after 2 h. There were no significant differences in groups as regards the mean age, height and weight (Table 2). 3.1. Primary outcomes: vital signs Fig. 2A shows that mean SpO2 values in the groups P, PF and PMF significantly decreased from 98.9%±1.3%, 98.9%±0.9% and 98.8%±1.2% at T1 (preanesthesia) to 94.7%±4.2%, 91.9%±9.2% and 93.7%±7.0% at T2 (during induction) (all pb.01), while they did not change significantly in groups E, EF and EMF (from 99.0%±0.6%, 98.6%±1.4% and 98.9%±1.2% at T1 to 97.4%±3.7%, 97.1%±2.8% and 97.3%±3.4% at T2, all pN.05); there were no significant differences amongst all groups at the three other time points (pN.05). At T2, mean SpO2 values in the three propofol groups were much lower than those in the three etomidate groups (pb.05). Fig. 2B shows that mean MAP significantly decreased from 89±10 mmHg, 88±9 mmHg, 85±11 mmHg, 88±7 mmHg, 89±7 mmHg and 87±11 mmHg in groups P, PF, PMF, E, EF and EMF at T1 to 75±8 mmHg, 73±9 mmHg, 73±8 mmHg, 82±8 mmHg, 79±8 mmHg and 75±8 mmHg at T2, respectively(pb.01), and then increased at T3 (during the addition of anesthetics) in groups E (97±14 mmHg, p=.007) and EF (95±10 mmHg, p=.049). However, the mean MAP values showed significant decreases at T4 (after operation) in group P (77±13 mmHg, pb.01) and group E (79±12 mmHg, pb.01). These reductions were still lower at T5 (recovery) in groups P, PF, PMF and E (72±18 mmHg, 76±13 mmHg, 73±13 mmHg and 80±11 mmHg, pb.01 or .05). At T2, mean MAP values were higher in groups E and EF than in the three propofol groups (pb.01 or .05), while there were no significant differences in all groups at the other four time points (pN.05). Fig. 2C shows that mean HR significantly decreased from 84±14 bpm, 85±18 bpm, 91±20 bpm, 92±10 bpm and 85±13 bpm in groups P, PF, PMF, EF and EMF at T1 to 75±10 bpm, 73±12 bpm, 75±11 bpm, 76±16 bpm and 72±12 bpm at T2 (pb.01) except in group E, in which mean HR did not show any significant change (from 84±10 bpm at T1 to 77±11 bpm at T2, pN.05) but increased at T3 (94±16 bpm, p=.024) (Fig. 2). And there were no significant differences in all other groups at the five time points (pN.05). 3.2. Secondary outcomes: anesthetics use and recovery As regards operative time, no statistically significant differences in mean time (7.8±1.6 min, 8.2±2.5 min, 8.2±3.6 min, 7.9±2.1 min, 7.5±3.1 min and 7.8±2.9 min in groups P, PF, PMF, E, EF and EMF, p=.843) were noted between groups (Table 3). The mean time to eye opening in group PF was significantly shorter than that in group PMF (4.5±1.7 min vs. 6.0±2.5 min, p=.026). In addition, the mean time to
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Enrollment
Assessed for eligibility (n=293)
Excluded (n=53) Not meeting inclusion criteria (n=38) Declined to participate (n=12) Other reasons (n=3)
Randomized (n=240)
Allocation Etomidate groups (group E, EF and EMF, n=40 in each group): Allocated to intervention (n=120)
Propofol groups (group P, PF and PMF, n=40 in each group): Allocated to intervention (n=120)
Follow-Up Follow-up (n=120)
Follow-up (n=120)
Analysis Analyzed (n=120)
Analyzed (n=120)
Fig 1. CONSORT flow diagram.
obeying commands achieved in group PF (4.6±1.7 min) was significantly shorter than that in groups P (5.7±1.6 min, p= .042) and PMF (6.2±2.4 min, p=.016). The mean PACU recovery time in group PF was significantly shorter than that in group P (11.8±2.7 min vs. 13.9±3.2 min, p=.047). The mean ‘time until first top-up’ (time from the induction dose until administering the first supplementary dose) was significantly shorter in group P than in group PF (4.2± 2.1 min vs. 5.7±3.1 min, p=.037, Table 4) but did not show any significant difference between groups P and PMF (4.2± 2.1 min vs. 5.5±4.0 min, p=.088), while those variables in group E (2.7±1.5 min) were significantly shorter than those variables in groups EF (6.2±3.3 min, pb.001, Table 5) and EMF (7.1±4.0 min, pb.001). The number of supplementary boluses of hypnotic given in group P (2.1±0.9 times) was significantly more than that in group PF (1.6±0.9 times, p= .033) and PMF (1.3±1.3 times, p=.002), while those variables in group E (2.0±1.0 times) were significantly
more than those in groups EF (1.2±1.3 times, p=.017) and EMF (1.3±1.2 times, p=.033). The total dose of propofol in group PMF (149.5±30.0 mg) was significantly less than those variables in groups P (186.4±31.5 mg, pb.001) and PF (175.6±28.0 mg, pb.001). Similarly, the total dose of etomidate in group EMF (15.8±4.2 mg) was significantly less than those variables in groups E (19.9±4.0 mg, pb.001) and EF (18.9±4.8 mg, p=.002). But the total dose did not show any significant difference between groups P and PF (p=.246) and between groups E and EF (p=.318). 3.3. Secondary outcomes: side effects As regards injection-induced pain, there was a significant difference between the propofol groups and the etomidate groups. Twenty-nine, 24 and 32 out of 40 patients in groups P, PF and PMF, respectively (72.5%, 60% and 80%), complained of injection-induced pain vs. 6, 0 and 6 out of 40 in
Table 2 Demographics of the study groups (each group n=40)
Age (years) Height (m) Weight (kg)
Group P
Group PF
Group PMF
Group E
Group EF
Group EMF
p value
27.1±4.0 1.61±0.05 52.2±7.9
28.4±6.2 1.62±0.04 53.7±4.8
28.2±5.0 1.62±0.06 53.8±4.3
27.1±5.0 1.61±0.04 51.5±8.7
29.5±6.3 1.61±0.04 52.6±7.9
27.7±5.8 1.61±0.04 53.2±6.2
.392 .379 .601
Data are mean±SD. There were no significant differences between groups with regards to mean age, height and weight.
J. Wu et al. / Contraception 87 (2013) 55–62
Group P
A
Group PF
Group PMF
Group E
59
Group EF
Group EMF
100 98
abc abc ab **
SPO2(%)
96 94
**
92
**
**
90 88 86 84 82 80 T1
T2 Group P
B
T3
Group PF
T4
Group PMF
Group E
T5
Group EF
Group EMF
120
MAP(mmHg)
110 100 ** *
90 **
**aabbcc **abbcc
80 70
* * ** **
**
** ** **
60 T1
C
T2 Group P
T3
Group PF
T4
Group PMF
Group E
Group EF
T5 Group EMF
120 110
HR(bpm)
100 *
*
90 80 ** ** ** ** **
70 60 T1
T2
T3
T4
T5
Fig 2. Mean SPO2 (A), MAP (B) and HR (C) levels of six study groups (each group n=40). Data are mean±SD. Two-way ANOVA determined significant differences. a or aa: pb.05 or .01 differences between group P and each of the other groups. b or bb: pb.05 or .01 differences between group PF and each of the other groups. c or cc: pb.05 or .01 differences between group PMF and each of the other groups. ⁎ or ⁎⁎: pb.05 or .01 differences between the values at T1 and each of the four other time points. Abbreviations: T1, preanesthesia; T2, induction; T3, adding anesthetics; T4, after operation; T5, recovery.
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J. Wu et al. / Contraception 87 (2013) 55–62
Table 3 Operative and recovery times of study groups (each group n=40) Group P Operative time (min) Recovery time (min) Time to eye opening Time to obeying commands PACU recovery time
Group PF
Group PMF
Group E
Group EF
Group EMF
F
p value
7.8±1.6
8.2±2.5
8.2±3.6
7.9±2.1
7.5±3.1
7.8±2.9
.408
.843
4.7±1.2 5.7±1.6 b 13.9±3.2 b
4.5±1.7 4.6±1.7 a 11.8±2.7a
6.0±2.5 b 6.2±2.4 b 12.7±4.3
5.2±5.1 5.1±3.1 12.0±5.7
5.4±2.1 5.8±2.3 13.6±5.0
4.6±2.1 4.7±2.2 12.8±5.0
1.709 3.372 1.264
.133 .006 .281
Data are mean±SD. One-way ANOVA determined significant differences. a: pb.05 differences between groups P and PF. b: pb.05 differences between groups PF and P, and between groups PF and PMF. Time to eye opening (the time in minutes measured from end of anesthesia to eye opening, either spontaneously or to verbal commands). Time to obeying commands (the time in minutes measured from end of anesthesia to the recovery of the patients' ability to answer questions such as ‘What is your name?’ or ‘When is your birthday?’). PACU recovery time (the time in minutes from end of anesthesia to attain adequate recovery as denoted by a modified Aldrete score ≥9).
the E, EF and EMF groups, respectively (12.5%, 0% and 12.5%). There were no significant differences in pain levels amongst the three groups of propofol or etomidate. As concerns myoclonus and postoperative nausea and vomiting, these two side effects in the propofol groups were lower than in the etomidate groups. Three, 1 and 1 out of 40 patients in groups P, PF and PMF, respectively (7.5%, 2.5% and 2.5%), recorded myoclonus vs. 18, 24 and 13 out of 40 in the E, EF and EMF groups, respectively (45%, 60% and 32.5%). Zero, 1 and 0 out of 40 patients in groups P, PF and PMF, respectively (0%, 2.5% and 0%), recorded myoclonus vs. 23, 20 and 9 out of 40 in the E, EF and EMF groups, respectively (57.5%, 50% and 22.5%). There were no significant differences in incidence of myoclonus and postoperative nausea and vomiting amongst the three groups of propofol. But the incidences of myoclonus and postoperative nausea and vomiting in group EMF (32.5% and 22.5%) were lower than those in groups E (45.0% and 57.5%) and EF (60% and 50%) (Table 6).
4. Discussion The results of this study suggest that etomidate is much safer than propofol for surgical abortion and that the adjuncts (fentanyl and midazolam) reduce its dose and side effects with minimal effects on safety and recovery. Intravenous anesthetics are associated with some adverse effects, including decreases in arterial blood pressure, apnea, injection-induced pain, nausea and vomiting, and myoclonus [6,7]. As a profound cardiovascular depressant, propofol often decreases systemic blood pressure during induction
and produces a high incidence of apnea, lasting longer than 30 s, which exposes the patient to the risks of a decrease in SPO2 [6,7]. As brain damage related to respiratory events is the leading cause of morbidity in anesthesia-related events, the safety of anesthesia is of primary importance [16]. In contrast, the hemodynamic stability and minimal respiratory depression following the use of etomidate are unique characteristics among the rapid-onset induction agents, so etomidate provides a wider margin of safety than barbiturates or propofol [8]. Our study found similar results; during induction, mean SPO2 values were higher in the three etomidate groups than in the three propofol groups, with significant decreases in the propofol groups but not in the etomidate groups. As for mean MAP values, they were higher in groups E and EF than those in the three propofol groups. However, there was no significant difference in recovery times between etomidate and propofol. Injectioninduced pain at the injection site is cited as a frequent side effect of propofol and etomidate [6–8]. Our study found a higher incidence of injection-induced pain in the propofol groups (60% to 80%) than in the etomidate groups (0% to 12.5%) which may be partly because of the high concentration (2%) of propofol in our study and the differences in lipid emulsion. At high concentrations, both propofol and etomidate activate transient receptor potential type A1 cation channels, a mechanism that may underlie injection-induced pain [17]. In regards to other side effects, in agreement with many studies, etomidate has been found to be associated with a high incidence of nausea and vomiting (30% to 40%), which is higher than that following propofol administration [18]. The incidence of myoclonus following etomidate is also highly variable (0% to 70%) [8,19]. Our study found
Table 4 Requirement of propofol: a group-wise comparison (each group n=40)
Time until first top-up (min) Number of supplementary boluses (times) Total dose (mg)
Group P
Group PF
Group PMF
F
p value
4.2±2.1 b 2.1±0.9 b 186.4±31.5
5.7±3.1 a 1.6±0.9 a 175.6±28.0
5.5±4.0 1.3±1.3 aa 149.5±30.0 aabb
2.569 5.446 16.122
.081 .005 b.001
Data are mean±SD. One-way ANOVA determined significant differences. a or aa: pb.05 or .01 differences between groups P and PF, and between groups P and PMF. b or bb: pb.05 or .01 differences between groups PF and P, and between groups PF and PMF. Time until first top-up (time from the induction dose until administering the first supplementary dose of either propofol or etomidate).
J. Wu et al. / Contraception 87 (2013) 55–62 Table 5 Requirement of etomidate: a group-wise comparison (each group n=40) Group E
Group EF ee
Time until first 2.7±1.5 top-up (min) Number of 2.0±1.0 e supplementary boluses (times) Total dose (mg) 19.9±4.0
6.2±3.3
dd
1.2±1.3 d
18.9±4.8
Group EMF F 7.1±4.0
dd
1.3±1.2 d
15.8±4.2 ddee
p value
21.372 b.001 4.634
.012
9.830 b.001
Data are mean±SD. One-way ANOVA determined significant differences. d or dd: pb.05 or .01 differences between groups E and EF, and between groups E and EMF. e or ee: pb.05 or .01 differences between groups EF and E, and between groups EF and EMF. Time until first top-up (time from the induction dose until administering the first supplementary dose of either propofol or etomidate).
that the incidences of nausea and vomiting and myoclonus in the three etomidate groups (32.5% to 60%, 22.5% to 57.5%) are much higher than those in the three propofol groups (2.5% to 7.5%, 0% to 2.25%). Addition of opioids to the general anesthesia regimen has been found to be beneficial for postoperative pain and myoclonus [1,8–10,20]. However, the use of an opiate alongside propofol increases the incidence of apnea, especially prolonged apnea, and appears to augment the decrease in arterial blood pressure [6,7,18,21], as well as further increasing the incidence of nausea and vomiting related to etomidate [12,13]. However, our study did not find any significant differences in these adverse effects between the fentanyl-treated groups and the nonopioids groups. This may be due partly to the dose of fentanyl used in our study (on average, a dose of around 0.05 mg), which is much less than that in other studies (0.1 mg) [9,10]. Our results showed that vital signs, total dose and side effects did not show significant differences between groups P and PF and between groups E and EF, but the time until obeying commands and the PACU recovery time in group PF are significantly shorter than those in group P. The addition of midazolam has been advocated for reducing the incidence of myoclonus and postoperative nausea and vomiting related to intravenous anesthetics [11–14]. Table 6 Incidence in the severity of myoclonus and nausea and vomiting in the study groups (each group n=40) Side effects Myoclonus
Nausea and vomiting
0 1 2 3 0 1 2 3
Group E
Group EF
Group EMF
H
p value
22 (55.0) 12 (30.0) 0 (0.0) 6 (15.0) 17 (42.5) 2 (5.0) 3 (7.5) 18 (45.0)
16 (40.0) 10 (25.0) 8 (20.0) 6 (15.0) 20 (50.0) 6 (15.0) 4 (10.0) 10 (25.0)
27 (67.5) 8 (20.0) 2 (5.0) 3 (7.5) 31 (77.5) 3 (7.5) 2 (5.0) 4 (10.0)
6.928
.001
5.138
.007
Data are presented as n (%) with p value from Kruskal–Wallis H test. For all variables, missing data were ≤0.05%. Grade of severity or score of myoclonus and nausea and vomiting as assessed on a 4-point scale, with 0= none, 1=mild, 2=moderate and 3=severe.
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Low-dose intravenous midazolam (0.015 mg/kg) reduces etomidate-induced myoclonus and does not prolong recovery in unpremedicated patients undergoing short procedures [12]. Furthermore, midazolam 0.05 mg/kg is effective in the prevention of postoperative vomiting after anesthesia in patients undergoing thyroidectomy [14]. Our study found similar results; both myoclonus and nausea and vomiting were less frequent in group EMF (0.2 mg/kg etomidate+1 mcg/kg fentanyl+0.02 mg/kg midazolam) than in groups E and EF. In contrast, there were no differences in the propofol groups because of the antiemetic effect of propofol. We also found that propofol or etomidate, combined with fentanyl and midazolam, showed similar vital signs and recovery times with much fewer total doses, but the times until eye opening and until following commands in group PMF were significantly longer than those in group PF. These results suggest that midazolam is more appropriate to combine with etomidate than with propofol because the combination with etomidate shows fewer side effects coupled with shorter recovery times. A possible limitation of the current study is the lack of additional data about patients’ satisfaction and postabortion pain. Although this study gives credence to the hypothesis that low-dose fentanyl and midazolam reduce the dose and side effects of etomidate with minimal effects on safety and recovery, a larger trial powered to detect differences is needed to confirm these findings before we recommend a change in clinical practice as regards the use of multiple anesthetic agents for surgical abortion. In conclusion, the administration of etomidate is much safer than that of propofol for first-trimester surgical abortions, and etomidate combined with low doses of fentanyl and midazolam is more beneficial than etomidate alone for reducing myoclonus, nausea and vomiting. Acknowledgments We thank all the patients, doctors and nurses who participated in this study. And we also thank Gunsham Purusram for suggestions and revision. References [1] Renner RM, Jensen JT, Nichols MD, Edelman AB. Pain control in first-trimester surgical abortion: a systematic review of randomized controlled trials. Contraception 2010;81:372–88. [2] Bartlett LA, Berg CJ, Shulman HB, et al. Risk factors for legal induced abortion-related mortality in the United States. Obstet Gynecol 2004;103:729–37. [3] Hakim-Elahi E, Tovell HM, Burnhill MS. Complications of firsttrimester abortion: a report of 170,000 cases. Obstet Gynecol 1990;76: 129–35. [4] Lawson HW, Frye A, Atrash HK, Smith JC, Shulman HB, Ramick M. Abortion mortality, United States, 1972 through 1987. Am J Obstet Gynecol 1994;171:1365–72. [5] World Health Organization. Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2000. 4th ed. Geneva, Switzerland: World Health Organization; 2004.
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