Abstract
Objective
To determine the safety, efficacy, and feasibility of propofol-based anesthesia in gynecological laparoscopies in reducing incidences of postoperative nausea and vomiting compared to a standard anesthesia using thiopentone/isoflurane.
Design
Randomized single-blind (for anesthesia techniques used) and double-blind (for postoperative assessment) controlled trial.
Setting
Operation theater, postanesthesia recovery room, teaching hospital.
Patients
Sixty ASA (American Society of Anesthesiologists) I and II female patients (aged 20–60 years) scheduled for gynecological laparoscopy were included in the study.
Interventions
Patients in Group A received standard anesthesia with thiopentone for induction and maintenance with isoflurane–fentanyl, and those in Group B received propofol for induction and maintenance along with fentanyl. All patients received nitrous oxide, vecuronium, and neostigmine/glycopyrrolate. No patient received elective preemptive antiemetic, but patients did receive it after more than one episode of vomiting.
Measurements
Assessment for incidence of postoperative nausea and vomiting as well as other recovery parameters were carried out over a period of 24 hours.
Main Results
Six patients (20%) in Group A and seven patients (23.3%) in Group B experienced nausea. Two patients (6.66%) in Group B had vomiting versus 12 (40%) in Group A (p < 0.05). Overall, the incidence of emesis was 60% and 30% in Groups A and B, respectively (p < 0.05). All patients in Group B had significantly faster recovery compared with those in Group A. No patient had any overt cardiorespiratory complications.
Conclusion
Propofol-based anesthesia was associated with significantly less postoperative vomiting and faster recovery compared to standard anesthesia in patie
Keywords
emesis score; gynecological laparoscopy; ordinal logistic regression; postoperative nausea and vomiting; postoperative recovery; propofol-based anesthesia;
1. Introduction
Pain and postoperative nausea and vomiting (PONV) are two important causes of postoperative morbidity.1–3 Essentially, these factors are interrelated.4 Untreated postoperative pain is an important cause of PONV,4 and use of opioids for its management also results in PONV.5–9
In spite of the extensive understanding of the pathophysiology of PONV and the availability of a variety of antiemetics, certain surgical procedures such as gynecological laparoscopy, are still associated with unacceptably high incidence of PONV.10–13 PONV is frequently the cause of great distress to the patient. Excessive PONV may lead to dehydration, electrolyte imbalance, and dreaded complications such as pulmonary aspiration syndrome. There is also economic implication of PONV in day case surgeries such as gynecological laparoscopy, as it may result in prolonged hospital stay.14
The multifactorial nature of PONV makes it unlikely that a single therapy will be fully effective in all conditions. 5-Hydroxytryptamine-3 (5-HT3) receptor antagonists, the most commonly used antiemetics, are very effective in chemotherapy-induced nausea and vomiting, but not as effective in opioid-induced emesis or motion sickness. It is understandable that 5-HT3antagonists will not be that effective as these two factors are most relevant in PONV.15Anesthetic drugs and techniques can also influence the occurrence of PONV.16Laparoscopic techniques are highly standardized; therefore, anesthetic technique remains the main variable to influence the incidence of PONV.3
Despite the lack of substantial evidence about the advantage of any anesthetic technique in reducing the incidence of PONV, propofol-based anesthesia has been found to be more effective for such outcomes.6,11,16,17 Because of the high incidence of PONV in gynecological laparoscopy there is an unmet need for an ideal technique to minimize PONV. Thus, the current study aimed to compare the advantage of propofol-based anesthesia over thiopentone–isoflurane anesthesia in reducing incidence of PONV and time for postoperative recovery.
2. Materials and methods
After obtaining the approval of the institutional ethics committee and informed consent, 60 nonpregnant ASA (American Society of Anesthesiologists) I and II female patients between the ages 20 and 60 years were included in the study. The study was prospective, randomized, single blind (for anesthesia techniques used) and double blind (for postoperative assessment). However, the same anesthesiologist assessed all the postoperative variables to avoid interobserver variation. Sixty patients were randomized equally into two groups to receive either thiopentone–isoflurane (Group A) or propofol (Group B). Pregnant or nursing mothers, women in their perimenstrual period, those having a history of PONV, smokers, those with hypersensitivity to any of the study drugs, and those who have taken antiemetics within 24 hours of anesthesia were excluded from the study.
All patients were premedicated with oral midazolam (0.5 mg/kg) 2 hours prior to anesthesia. Baseline monitoring of noninvasive blood pressure (NIBP), electrocardiogram (ECG), and peripheral oxygen saturation (Spo2) were commenced in the preanesthesia room. After adequate preoxygenation, Group A patients were induced with intravenous thiopentone (3–5 mg/kg), fentanyl (2 μg/kg), and vecuronium (0.08 mg/kg). Anesthesia was maintained with 60% nitrous oxide (N2O) in oxygen (O2), isoflurane, and intermittent vecuronium. The concentration of isoflurane was adjusted to maintain an adequate depth of anesthesia. Isoflurane was discontinued after termination pneumoperitoneum. Patients in Group B were induced with intravenous propofol (2–2.5 mg/kg), fentanyl (2 μg/kg), and vecuronium. Anesthesia was maintained with 60% N2O in O2, propofol infusion and intermittent vecuronium. A step-down propofol infusion regimen was used.18 Infusion was started at a rate of 166 μg/kg/min and then reduced to 133 μg/kg/min after 10 minutes. Infusion was reduced further to and maintained at 100 μg/kg/min after another 20 minutes. We used this technique as compared to the effector site concentration-based technique as we did not have a state-of-the-art target control infusion pump or highly sophisticated pump. Infusion rate was adjusted in between to maintain adequate surgical anesthesia and hemodynamic stability. All patients were intubated with endotracheal tube after induction of anesthesia, and ventilation was controlled. Elective hyperventilation was used in both the groups to keep end tidal carbon dioxide (Etco2) within the range of 4.5–5.3 kPa. Propofol infusion and isoflurane were discontinued after termination of pneumoperitoneum. Any elective antiemetic medication was withheld as this study was designed to estimate the effect of two anesthesia techniques on incidences of PONV.
Surgical procedures were identical in both groups. Pneumoperitoneum was created using carbon dioxide (CO2) as insufflating gas. Intra-abdominal pressure was kept within 14 mmHg. An orogastric tube was inserted to deflate the stomach. All the port insertion sites were infiltrated with bupivacaine prior to insertion. Patients were positioned in 15° Trendelenburg with lithotomy. NIBP, ECG, Spo2, end tidal capnography (Etco2), airway, and intra-abdominal pressure were monitored in every case. In addition, inspired and expired isoflurane concentrations were monitored in Group A. At the end of the surgery, residual neuromuscular block was reversed with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg). After achieving adequate recovery, the patients were transferred to the postanesthesia care unit (PACU).
In the PACU, basic postoperative monitoring (NIBP, ECG, and Spo2) was continued. Assessment of PONV and recovery parameters was carried out using a predesigned scoring system (Table 1).17 Scoring was done initially at 30-minute intervals for the first 2 hours, then every 6 hours for the following 24 hours. Thus, emesis score (ES) was recorded at each of the specified time points (0.5 hours, 1 hour, 1.5 hours, 2 hours, 6 hours, 12 hours, 18 hours, and 24 hours postoperatively) on an ordinal scale (Table 1).
Postoperative analgesia was provided with oral or intravenous paracetamol (1 g every 6 hours) and oral or intramuscular diclofenac (1 mg/kg every 8 hours) in both groups. As opioids are associated with PONV, they were withheld in the postoperative period. However, rescue analgesia was provided with boluses of intravenous fentanyl (0.25–0.5 μg/kg) when deemed necessary. Rescue antiemetic in the form of intravenous ondansetron (4 mg) was given to any patients who had more than one episode of vomiting. After adequate recovery from anesthesia (as judged by recovery score), all patients were encouraged to take oral fluids. The time for first oral intake varied from patient to patients. Again, it was determined by recovery and ward nurse as per our fixed protocol. Also, when a patient felt sick with oral intake, further oral fluid was stopped, and the score was noted as well as rescue antiemetic prescribed as per our protocol. Once the patient feels alright again and expressed the desire to have oral fluid, it was allowed. Solid food was only allowed whenever they tolerated oral fluid and was free of any PONV. All patients had uneventful recovery from anesthesia and were discharged after 24 hours of follow-up.
2.1. Data analysis
The demographic and intraoperative parameters of all patients were analyzed using Student t test. Comparison of intraoperative parameters in each group between baseline and end of anesthesia values was done using paired t test. Fisher’s exact test was used to compare PONV and recovery parameters in between the groups. A p value < 0.05 was considered statistically significant.
2.2. Determining relevance of predictor variables on outcomes for comparison
Classification and Regression Tree analysis was performed to determine the relevance of predictor variables in determining the outcome (i.e., ES; Figure S1). The data on ES could be distinctly partitioned based on whether the patients received postoperative antiemetic. As shown in Figure S1, the right branch at split 1 represents the counts of ES at which the patients of either group received an antiemetic, and the left includes the counts of ES without antiemetic. Conditional on the ES without antiemetic (first left branch), the anesthetic (i.e., propofol-based anesthesia vs. thiopentone/isoflurane) during surgery becomes an important factor in predicting the severity of ES during the postoperative period. Moreover, the early postoperative period between 0.5 and 2 hours was more significant for predicting the highest probabilities of nausea and vomiting than later on (as shown on left-branch split 3). This figure also shows a table that summarizes the ability of the model to predict ES severity. It shows the R2 for the training data (255 observations) and validation data (n = 225) to be 0.40 and 0.24, respectively. This R2 value indicates that the model fits the training data (the data used to create the model). The fact that this number is low hints that the model can be enriched, perhaps by adding more predictor variables in similar studies in the future.
After determining the relevance of this model, ordinal logistic regression model was used to test whether treatment with Group B versus Group A had an effect on postoperative ES over time. The levels of ES (0–3) were specified in descending order during ordinal logistic regression analysis, with the higher scores ranked higher in the order. Effect of “time” of recording ES and “group” were determined in the final multivariate model. Because the use of antiemetics was significantly different between Group A and Group B, this effect was excluded from the final model. This model used in the analysis reduced the log likelihood that yielded a likelihood ratio chi-square value of 37.05 for the whole model with 8 degrees of freedom, and showed the difference in ESs between groups to be highly significant (p < 0.0001). The “lack of fit” test determined the ordinal response model compared to the nominal model. The nonsignificance (p = 0.1154) of “lack of fit” justified the rationality of the ordinal model.
The partitioning model was also evaluated by receiver operating characteristic (ROC) analysis (Figure S2). In this analysis, the power of the model's predicted values to discriminate between Group A and Group B patients was quantified by the area under the ROC curve (AUC). The c-statistic (or concordance index) values for vomiting, retching, nausea, and no symptoms (ES = 3, 2, 1, and 0) in the immediate and early recovery period were 0.8525, 0.9427, 0.8817, and 0.8525, respectively. Thus, this curve indicates that incidences of PONV are more sensitive, and are therefore more influenced in Group B versus Group A in the immediate postoperative period (≤2 hours).
2.3. Ethical statement
The study involved human patients. Patients' consent was obtained for the study as well as publication of the data.
3. Results
Demographic and intraoperative vital parameters (heart rate, BP, Spo2, and Etco2) were comparable between both groups except for the requirement of antiemetics, which was significantly less in Group B (p < 0.001; Tables 2 and 3). There were no episodes of significant bradycardia, hypotension, hypoxia, or arrhythmia (Table 3). Only one patient in Group A momentarily developed hypercarbia (Etco2 = 6.11 kPa).
It is thus evident from this study that propofol-based anesthesia had a favorable outcome in relation to PONV (Table 4, Figure 1). Seven (23.33%), four (13.33%), and 12 (40%) patients had nausea, retching, and vomiting in Group A, respectively. A total of 23 patients (76.66%) in Group A had PONV. The corresponding figures in Group B were eight (26.66%), one (3.33%), two (6.66%), and 11 (36.66%), respectively (Table 3; p < 0.01; Figure 1).
While comparing patients having emesis or no emesis between the groups, a statistically significant difference was found in Group B (Table 4). As shown in Table 5, in the Type 3 analysis of effects, the “group” effect is statistically significant (p < 0.0001). Although for the overall effect of the time of recording the ES did not reach statistical significance, the ESs at 0.5 hours, 1 hour, and 1.5 hours were significantly higher than the ES at 24 hours (i.e., at the time of discharge; Table 5). The negative coefficients of “Group B versus Group A” (est. = –1.5169, p < 0.0001) meant a significant negative relationship of Group B with ES, and likewise the statistically significant positive coefficients (est. = 1.57, 1.47, and 1.52 at 0.5 hours, 1 hour, and 1.5 hours after anesthesia) corresponded to a significantly high ES at these time points compared to ES at discharge (Table 5).
Patients in Group B also recovered significantly faster compared with patients in Group A. Recovery time for all variables was much shorter in patients of Group B (Figure 2). Times for eye opening and response to verbal command were significantly faster in patients in Group B compared with patients in Group A (p < 0.001). Orientation to place, person, and date of birth was also attained earlier in Group B. All patients in Group B achieved maximum score in ventilation and movement much earlier (p < 0.001; Figure 2).
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4. Discussion
This study demonstrated that, in gynecological laparoscopic surgeries, the propofol-based anesthesia technique is associated with significantly lesser incidence of PONV as well as better and faster recovery profile without any of the dreaded adverse effects. Multivariate analyses in this study determined that: (1) propofol-based anesthesia was associated with significant reduction in ES; and (2) the odds of having a high ES are significantly higher in the immediate and early postoperative periods (≤1.5 hours).
In general, laparoscopic surgeries are associated with remarkably high incidence of PONV (20–51%),17,19 and among them gynecological laparoscopy is reported to have even higher rate of PONV (50–80%).10–13 The reason for this higher emesis is still not clear; however, several hypotheses have been put forth:
•Mechanical factor: pressure on stomach and intestine caused by pneumoinsufflation
•Neurological factors: stimulation of autonomic nervous system and peritoneum resulting in parasympathetic stimulation
•Chemical factor: probable influence of hypercarbia on vomiting center17,19
This extremely high rate of PONV in laparoscopy warrants antiemetic prophylaxis. But as our study was aimed at evaluating superiority between two anesthetic techniques on PONV, routine use of antiemetic was withheld. As thiopentone is a prototype intravenous inducing agent, it was used in Group A. In comparison to other anesthetic agents, propofol is constantly found to have antiemetic property and quicker recovery.6,11,16,17 Thus, it was used as the sole anesthetic in Group B to compare the difference between the two groups. Although there are several reports that reversal agents such as neostigmine can influence PONV,20,21 it was not possible to avoid this drug in our hospital setup, especially when vecuronium was used for muscle relaxation. However, whatever the effect may be, it was found to be similar in both groups. Similarly, although opioids are incriminated for PONV,5–9avoidance of opioid analgesia in the intraoperative period might result in excessive pain, which leads to patient discomfort and higher rate of PONV.4,5 However, postoperative pain in this surgical technique is not as severe and opioid analgesia can be omitted postoperatively. Instead, nonsteroidal anti-inflammatory drug and paracetamol were used for postoperative analgesia instead of opioids to minimize the concern of emesis further.3,8,15Laparoscopic surgery was chosen for our study as it is considered as a model for the study of PONV, similar to squint surgery. Furthermore, gynecological laparoscopy is better suited in this regard because of the higher PONV rate.10–13 Female patients between ages 20 and 60 years were selected for our study as this age range and sex group are seen to be associated with the highest incidence of PONV.9,19,22 Nonpregnant patients were selected to eliminate the influence of pregnancy on PONV and gastric emptying.23
Surgeries consisted mainly of laparoscopic procedures for infertility and pelvic inflammatory diseases. Although proper care was taken to avoid user bias, total elimination was not possible because of the distinct milk-like color of propofol. Thus, anesthetic technique was single blinded. However, postoperative assessment was double blinded as neither the observer nor the patient knew anything about the anesthesia techniques used. A single person undertook postoperative observations to avoid interpersonal bias.
Aspiration of the stomach was done routinely in all cases after intubation as there is a theoretical possibility of gastric regurgitation because of pneumoperitoneum and to avoid trocar-induced surgical trauma to the stomach.24
Intraoperative heart rate in all patients decreased compared to their preinduction value. This represents the negative chronotropic effect of propofol as well as adequate anesthetic plane. However, no patient developed any significant bradycardia or hypotension. Also, there was no significant difference in perioperative vital parameters between the two groups. This explains the safety of propofol-based anesthesia like standard anesthesia.17
It is evident from postoperative recovery parameters that propofol-based anesthesia had favorable outcome in regard to PONV.6,11,17 Results in the current study match those of other similar studies.6,16,17,25,26 Klockgether-Radhke et al,17 in a similar study involving laparoscopic cholecystectomy or herniotomy, observed 20% incidence of postoperative vomiting in the thiopentone–halothane group and 0% in the propofol group. In that study, the overall incidence of emesis was 43% and 23% in the control and propofol groups, respectively.12 The higher overall incidence of emesis in both groups combined in the current study in emetic incidence can be explained by female patients and gynecological laparoscopy, both of which are reported to have higher incidence rates of PONV.9,12,13,22
The exact mechanism for the lower incidence of emesis with propofol-based anesthesia is not yet known. Still, propofol is not known to have any receptor-specific antiemetic effect including effects on chemoreceptor trigger zone, 5-HT3, and dopamine 2 receptor.17,27Rather, it increases the dopamine concentration in the nucleus accumbens.28 It has been propounded that this antiemetic activity may be attributable to the decrease in serotonin level in area prostema, probably mediated through its action via the gamma aminobutyric acid receptor.29 Propofol has been used in subhypnotic dose as an antiemetic and is known to be superior to ondansetron.19 Whether the antemetic effect of propofol is because of its true antiemetic property or depressant effect on the central nervous system, remains to be resolved. However, this study—similar to previous other studies—proved that propofol-based anesthesia is associated with significantly reduced emetic sequel.
Patients in Group B also experienced significantly faster recovery compared to those in Group A similar to previous studies.16,17,26,30,31 In addition, the recovery times for all postoperative variables were much shorter in Group B patients, thus demonstrating a better recovery profile with propofol-based anesthesia compared to a standard anesthesia.
In our study, all patients were discharged in the 2nd postoperative day in order to facilitate the recording of the parameters over 24 hours. Worldwide, gynecological laparoscopies are usually managed as day cases and discharged on the same day. However, discharge may be delayed because of higher incidences of postoperative emesis and associated complications leading to delayed recovery. Thus, propofol-based anesthesia has an advantage over standard anesthesia because of its significantly lower incidence of PONV and faster recovery profile. One disadvantage is that propofol-based anesthesia is more expensive than standard techniques.31 However, considering the value-added effect of better patient experience and faster recovery through prevention of the stressful effects and complication of PONV as well as reduced hospital stay, propofol is more cost-effective and therefore a better choice in day case surgeries such as gynecological laparoscopies.31
4.1. Limitations
There are several limitations in our study that we could not avoid.
1.We could not completely avoid perioperative opioids in our patients. This may have increased the overall incidences as opioid is a well-known cause of PONV. But then again in such procedures complete avoidance of opioids was not possible because of the nature of the surgery. Also, it is very well known that untreated perioperative pain can lead to PONV. We thus decided to use short-acting fentanyl for both intra- and postoperative rescue analgesia. We also added paracetamol and diclofenac to reduce overall fentanyl consumption and thus the incidence of PONV. However, whatever the incidence may be, it was equal in both groups and thus was nullified in the statistical analysis.
2.Similarly, we should have avoided the use of nitrous oxide in our cases, knowing that it increases the incidence of PONV. However, this was not possible in our setup; we do not have the necessary facilities to use air in all cases. The issue of PONV and nitrous oxide is not as severe as was thought previously, and the problem can be solved with the mere use of antiemetics. Moreover, it adds to analgesia and thereby reduces intraoperative opioid consumption, and thus also reduces some amount of impact on overall PONV. At any rate, whatever the effect may be, it was equal in both groups and thus again got nullified in the statistical analysis.
3.The use of neostigmine for the reversal of residual neuromuscular block could not be avoided in our setup even knowing that it was previously thought to increase incidences of PONV. However, in our setup, mivacurium is not available and our PACU as well as ward staffing were not particularly well equipped to tackle any postreversal residual paralysis, which could have been a major threat to our patient than accepting a slightly higher incidence of PONV, which is easily manageable. Moreover, recently the role of neostigmine in the overall rate of PONV has become a subject of debate.
4.A major risk of total intravenous anaesthesia (TIVA) is a higher risk of intraoperative awareness. Thus, it is highly recommended that bispectral index equipment be used to monitor the depth of anesthesia. Unfortunately, this was not available in our setup. We used the well-tested infusion protocol that is known to maintain a proper level of anesthesia. In addition, we used nitrous oxide and monitored the vital parameters as well as the patient's movement. Thus, to our consideration, awareness was not an issue and no patient reported about intraoperative awareness of any sort afterward.
5. Conclusion
Propofol-based anesthesia is associated with significantly lower incidences of PONV and faster recovery compared to standard anesthesia using thiopentone and isoflurane. Therefore, in day case surgeries such as gynecological laparoscopy, where reduced PONV and faster recovery profile are of prime importance, propofol is a better choice.
Conflicts of interest
The authors report no conflicts of interest.
Acknowledgments
No funding other than personal was used in conducting the audit as well as writing the manuscript. We declare that we have no financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) our work.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
Figure S1. Classification and Regression Tree (CART) for determining the fitness and contribution of predictor variables.
Figure S2. Receiver operating curve (ROC) as determined by ordinal logistic regression analysis. As determined in the multivariate analysis (Tables 5), the immediate postoperative period (<1.5 hours) and the treatment (B vs. A) were significant predictors of severity of emesis score (ES). As shown in this figure, the probability of vomiting (ES = 3) and retching (ES = 2) as predicted by CART analysis is highly sensitive, and thus incidence of vomiting and retching is significantly influenced by treatment variables (i.e., propofol vs. thiopentone/isoflurane) in the early postoperative period.