Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 10  |  Issue : 1  |  Page : 144-148

Aprepitant for attenuation of postoperative nausea and vomiting with a decrease in postoperative analgesic needs after laparoscopic surgery


Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Web Publication3-Aug-2018

Correspondence Address:
Mostafa M Hussein
5 Abdel-Azim Salama Street, Nasr City, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/asja.asja_110_16

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  Abstract 


Background Postoperative nausea and vomiting (PONV) is one of the most common postsurgical complications. Multiple drugs have been used to prevent its occurrence. Ondansetron and aprepitant block the emetic effect of serotonin and neurokinin, respectively. Corticosteroids are well known for their anti-inflammatory effects, but the basis behind their use as antiemetics is not well understood.
Objective The aim was to investigate the effect of combining aprepitant with ondansetron and dexamethasone compared with ondansetron and dexamethasone alone on PONV in patients undergoing laparoscopic cholecystectomy.
Patients and methods A total of 60 patients with American Society of Anesthesiologists physical status I/II undergoing laparoscopic cholecystectomy (with preoperative two or more Apfel four-point risk factors) were recruited into the study and were randomly divided into two equal groups. In both groups, dexamethasone was administered intravenously at the beginning of surgery, and ondansetron was administered intravenously at the end of surgery. In the aprepitant group, oral aprepitant was given 2 h before anesthesia with a sip of water. The primary outcome measure was complete response (no PONV and no rescue antiemetics) up to 24 h postoperatively. The secondary outcome measure was the amount of rescue postoperative analgesics given during the first 24 h postoperatively.
Results There was a statistical significant difference between the two groups in complete response at the sixth hour after surgery. In the aprepitant group, none of the patient experienced a verbal numeric rating scale score greater than 3. Moreover, none of the patients of the aprepitant group had received rescue antiemetics during the first 24 h after surgery compared with the control group. In addition, no difference existed regarding postoperative pain score, although the score was slightly lower in the aprepitant group.
Conclusion Oral aprepitant when combined with intravenous ondansetron and dexamethasone is effective in suppressing early PONV up to 24 h postoperatively.

Keywords: analgesia, aprepitant, dexamethasone, ondansetron, postoperative nausea and vomiting


How to cite this article:
Hussein MM, Mostafa RH. Aprepitant for attenuation of postoperative nausea and vomiting with a decrease in postoperative analgesic needs after laparoscopic surgery. Ain-Shams J Anaesthesiol 2017;10:144-8

How to cite this URL:
Hussein MM, Mostafa RH. Aprepitant for attenuation of postoperative nausea and vomiting with a decrease in postoperative analgesic needs after laparoscopic surgery. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2018 Oct 15];10:144-8. Available from: http://www.asja.eg.net/text.asp?2017/10/1/144/238441




  Introduction Top


Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia [1].

PONV is uncomfortable for patients, can prolong hospitalization, and can lead to more serious complications, including aspiration. Accurately predicting which patients are at risk of PONV can help physicians decide when to recommend prophylactic antiemetics [2].

The Apfel score is a simplified risk score for predicting PONV incidence. It includes four variables and assigns one point for each: female sex, history of PONV and/or motion sickness, nonsmoking status, and postoperative use of opioids. When 0, 1, 2, 3, or 4 factors are present, the risk of PONV is 10, 20, 40, 60, or 80%, respectively [3].

In addition to aforementioned risks pointed in Apfel score, increased intra-abdominal pressure during laparoscopic procedures can increase the risk of PONV [4].

Aprepitant is a neurokinin-1 receptor antagonist that blocks the emetic effects of substance P (SP) at neurokinin-1 receptors in the gastrointestinal tract. Another mechanism for their action is through inhibiting signals received from the chemoreceptor trigger zone by the nucleus tractus solitarius in the brain stem [5].

Recently, several studies have demonstrated that aprepitant is effective for preventing PONV especially when combined with other antiemetics, particularly corticosteroids and 5-hydroxytryptamine (5-HT3) receptor blockers. The typical dose is 40 mg orally preoperatively, most commonly given within 3 h of surgery [6].

The aim of this randomized, double-blind controlled study was to investigate the prophylactic effect of combining aprepitant 80 mg with ondansetron and dexamethasone on PONV in patients undergoing laparoscopic cholecystectomy compared with ondansetron and dexamethasone alone.


  Patients and methods Top


The study was conducted in the operating theater of the General Surgery Department, Faculty of Medicine, Ain Shams University, during the period from January 2016 to June 2016.

After approval of local ethical committee and taking informed written consent from patients, 60 adult female patients aged between 20 and 50 years, with American Society of Anesthesiologists physical status I/II, undergoing laparoscopic cholecystectomy under general anesthesia were enrolled in our study. Patients were randomly allocated by sealed envelopes using computer-generated table into two groups (30 patients each): group A (aprepitant group) and group C (control group). Exclusion criteria included patients with allergies to components of aprepitant; pregnancy or breast feeding; patients with preoperative vomiting; patients taking drugs that are known to interact with aprepitant including pimozide, terfenadine, astemizole, cisapride, and warfarin; patients taking other antiemetics before surgery; patients with hepatic dysfunction; or patients with significant psychiatric disease or mental retardation.

The Apfel simplified risk score indicated that our patient population and the anesthesia techniques used would lead to a high risk of PONV in all treatment groups.

On the day of the surgery and before induction of anesthesia, patients were assigned into one of two groups randomly: group A (aprepitant group) and group C (control group). Group A patients received aprepitant 80 mg orally with 30-ml water 2 h before anesthesia. The patients were informed that the aprepitant was a premedication for their operation and were unaware that it was a study variable. Group C patients did not receive anything orally preoperatively.

On arrival to the operating room, 1-mg midazolam was given intravenously to all patients as a premedication. Routine intraoperative monitoring for vital data (5-lead ECG, arterial blood pressure, heart rate, capnography, and pulse oximetry) was done. Induction of anesthesia was done using propofol (2 mg/kg), fentanyl (2 μg/kg), and atracurium (0.5 mg/kg) with endotracheal intubation. Maintenance of anesthesia was done using isoflurane 2% in oxygen/air gas mixture. Fentanyl 0.5 μg/kg bolus injection was given if required. Mechanical ventilation was maintained in volume control mode with tidal volume 8 ml/kg, respiratory frequency 12 breaths/min, and positive end expiratory pressure 0–5 cm H2O to maintain an ETCO2 between 35 and 40 mmHg.

In both groups, just after induction, 8-mg dexamethasone was given intravenously. Moreover, approximately 20 min before the end of surgery, ondansetron 4 mg was given intravenously. At the end of surgery, any residual neuromuscular blockade was reversed with atropine 0.01 mg/kg and neostigmine 0.05 mg/kg.

Postoperatively, an independent nurse blinded to the patient group assessed verbal numeric rating scale (VNRS; with 0 as no nausea and 10 nausea as bad as possible) for nausea at four time points (30 min after admission to the postanesthesia care unit and at second, sixth, and 24th hour postoperatively). The primary outcome of the study was complete response up to 24 h after surgery. Complete response was defined as no PONV and no rescue antiemetics. When a patient experienced nausea at a VNRS score greater than or equal to 4 with retching or vomiting, 10 mg of metoclopramide was administered intravenously. When symptoms did not improve at follow-up, 4-mg diluted ondansetron was administered intravenously. Moreover, the use of rescue antiemetics was recorded at each time point.

In addition, any adverse events such as headache, dizziness, pruritis, hypersensitivity reactions, and pyrexia were recorded.

Patients were also asked to rate their intensity of pain using an 11-point VNRS. Postoperative pain management was standardized in the form of 1 g paracetamol/6 h intravenously and 30 mg ketorolac on demand (maximum 120 mg/24 h). The VNRS score was used to represent the pain that patients experienced in the recovery room at the 30th minute, second hour, sixth hour, and the 24th hour after surgery, and the consumption of total doses of ketorolac given. If the VNRS score was greater than or equal to 4, an additional 30 mg of ketorolac was administered and recorded.

Postoperative management and data collection were conducted according to the study protocol by another anesthesiologist and a trained member of the research group, respectively, who were blinded to the patient groupings. The patients remained unaware of their group affiliation until study completion.

Statistical analysis

Using PASS18 (NCSS, LLC. Kaysville, Utah, USA) for sample size calculation, group sample sizes of 27 in group one and 27 in group two achieved 82% power to detect a difference in the proportion of patients requiring antiemetics of 40% between the two groups. The test statistic used is the two-sided Z-test with pooled variance. The significance level of the test was targeted at 0.0500. The significance level actually achieved by this design is 0.0571.

Data were analyzed using the statistical package for the social sciences v18 SPSS 18.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Normally distributed numerical data are presented as mean±SD, and differences between groups were compared using the independent Student’s t-test, data not normally distributed were compared using Mann–Whitney test and are presented as median (interquartile range), and categorical variables were analyzed using the χ2-test or fisher exact test and are presented as number (%). All P values are two sided. P value less than 0.05 is considered statistically significant.


  Results Top


There were no significant differences between the two groups regarding patient characteristics ([Table 1]).
Table 1 Demographic data comparison between the two groups

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There was a statistical significant difference between the two groups in complete response at the sixth hour after surgery. Complete response is defined as no PONV and no rescue antiemetics up to 24 h postoperatively. When a patient experienced nausea at a VNRS score greater than or equal to 4 with retching or vomiting, 10 mg of metoclopramide was administered intravenously. In the aprepitant group, none of the patient experienced a VNRS score greater than 3, as shown in [Table 2].
Table 2 Verbal numeric rating scale score comparison for postoperative nausea and vomiting between the two groups

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One can see, none of the patients of the aprepitant group had received rescue antiemetics during the first 24 h after surgery compared with the control group, in which 12 patients had received rescue antiemetics during the sixth to the first and 24th hour after surgery ([Table 3]).
Table 3 Need for rescue antiemetics in the two groups

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In our study, aprepitant effect on postoperative pain VNRS has been evaluated. We found no difference between the two groups regarding postoperative pain VNRS, although the score was slightly lower in the aprepitant group ([Table 4]).
Table 4 Verbal numeric rating scale score comparison for postoperative pain between the two groups

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Moreover, the use of rescue analgesics with ketorolac in the postanesthesia care unit and the incidence of adverse events were similar in the two groups ([Table 5]).
Table 5 Comparison between the two groups regarding the use of postoperative rescue analgesics

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  Discussion Top


The median value of Apfel’s risk score in our study population ranged from 3 to 4, indicating that the predicted incidence of PONV ranged from 61 to 79% [7]. Such patients at high risk of PONV are excellent candidates for multimodal or combination therapy with different classes of antiemetics targeting different receptors.

Current recommendations advise the use of 5-HT3 receptor antagonists (ondansetron) and steroids (dexamethasone). Those chosen antiemetics are nowadays recommended for patients that may have moderate to severe risk of PONV. Ondansetron and dexamethasone are equally effective and each can reduce the risk of PONV by 25% [2].

The combination of ondansetron, dexamethasone, and aprepitant can be expected to be effective in preventing PONV because ondansetron blocks serotonin at 5-HT3 receptors, whereas aprepitant blocks SP at neurokinin-1 receptors. On the contrary, the precise mechanism of dexamethasone as an antiemetic is still unknown.

In combination with other antiemetics, aprepitant is recommended for treatment and/or prevention of chemotherapy-induced nausea and vomiting [8]. Aprepitant has minimum adverse effects; it is nonsedating and has been shown to be longer acting than other currently used antiemetics. Thus, it may be particularly beneficial in patients undergoing day-case surgeries for which postdischarge nausea and vomiting is a concern. Aprepitant is notably expensive when compared with other antiemetics, which may limit its use in some situations. Several studies have reported the efficacy of neurokinin-1 receptor antagonists alone or combined with other antiemetics in preventing PONV [9],[10],[11].

Our results suggest that NK1 blockade may be very efficient in suppressing PONV and is beneficial if administered before these types of procedures. When concomitantly combined with ondansetron and dexamethasone, aprepitant can effectively decrease PONV via NK1 receptor blockade in laparoscopic cholecystectomy surgeries up to 24 h postoperatively. Furthermore, our results suggest that NK1 blockade can decrease VNRS for pain.

In our study, the effect of aprepitant on PONV lasted up to 24 h in combination with ondansetron and dexamethasone. In a study of aprepitant as a medication for combination therapy with ondansetron [11], antiemesis lasted up to 48 h postoperatively, which is longer than the presented duration in our study. Our study is different from previous studies in that ondansetron and dexamethasone were added in both groups. In our study, aprepitant delayed the time to first PONV in the PACU. Moreover, our results are consistent with the previous study on laparoscopic procedures in which aprepitant was found to be more effective in acute PONV (postoperative 0–6 h) [12].

SP is one of neurotransmitters found in both the central and peripheral nervous systems, and it is known that after binding to the NK1 receptors, SP regulates many biological functions in the central nervous system such as emotional behavior, stress, depression, and anxiety [13]. These effects were also investigated in animals, and it was found that NK1 antagonism has decreased postoperative pain significantly.In our study, VNRS pain scores were not significant between NK1 and control groups but were lower suggesting an increased pain tolerance. This finding is consistent with previous study [12], but contrary to our results, there were significant low pain scores with obvious decrease in analgesic consumption postoperatively.

In our study, combining aprepitant and ondansetron did not increase the incidence of adverse events such as headache, dizziness, sedation, delayed passage of flatus, and pruritus. This finding is consistent with previous studies [9],[10].

In conclusion, this study showed that the addition of aprepitant 80 mg orally to ondansetron and dexamethasone was superior to ondansetron and dexamethasone alone in preventing early PONV with respect to a high incidence of complete response (no PONV and no rescue antiemetics up to 6 h postoperatively) and decreasing the use of antiemetics from the sixth hour up to 24 h. postoperatively in patients undergoing laparoscopic cholecystectomy. Moreover, the addition of aprepitant to ondansetron and dexamethasone did not produce clinically serious adverse effects.

Furthermore, our data suggest that aprepitant may have partial analgesic effects by increasing pain tolerance as VNRS scores for pain were lower in NK1-treated groups, although not statistically significant [14].


  Conclusion Top


Orally administered aprepitant combined with ondansetron and dexamethasone is effective in suppressing early PONV up to 24 h postoperatively. This is mainly owing to additive effects of being binded to different receptors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I et al. for the IMPACT Investigators. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004; 350:2441–2451.  Back to cited text no. 2
    
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Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross validations between two centers. Anesthesiology 1999; 91:693–700.  Back to cited text no. 3
    
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Bradshaw WA, Gregory BC, Finley CR, Ross A, Wilds T, Still M et al. Frequency of postoperative nausea and vomiting in patients undergoing laparoscopic foregut surgery. Surg Endosc 2002; 16:777–780.  Back to cited text no. 4
    
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Diemunsch P, Joshi GP, Brichant JF. Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting. Br J Anaesth 2009; 103:7–13.  Back to cited text no. 5
    
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Roberts SM, Bezinover DS, Janicki PK. Reappraisal of the role of dolasetron in prevention and treatment of nausea and vomiting associated with surgery or chemotherapy. Cancer Manag Res 2012; 4:67–73.  Back to cited text no. 7
    
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Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Clark-Snow RA et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21(Suppl 5):v232–v243.  Back to cited text no. 8
    
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Diemunsch P, Gan TJ, Philip BK, Girao MJ, Eberhart L, Irwin MG et al. Single-dose aprepitant vs. ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind phase III trial in patients undergoing open abdominal surgery. Br J Anaesth 2007; 99:202–211.  Back to cited text no. 9
    
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Gan TJ, Apfel CC, Kovac A, Philip BK, Singla N, Minkowitz H et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007; 104:1082–1089.  Back to cited text no. 10
    
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Vallejo MC, Phelps AL, Ibinson JW, Barnes LR, Milord PJ, Romeo RC et al. Aprepitant plus ondansetron compared with ondansetron alone in reducing postoperative nausea and vomiting in ambulatory patients undergoing plastic surgery. Plast Reconstr Surg 2012; 129:519–526.  Back to cited text no. 11
    
12.
Kakuta N, Tsutsumi YM, Horikawa YT, Kawano H, Kinoshita M, Tanaka K et al. Neurokinin-1 receptor antagonism, aprepitant, effectively diminishes postoperative nausea and vomiting while increasing analgesic tolerance in laparoscopic gynecological procedures. J Med Invest 2011; 58:246–251.  Back to cited text no. 12
    
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Altorjay A, Melson T, Chinachoit T, Kett A, Aqua K, Levin J et al. Casopitant and ondansetron for postoperative nausea and vomiting prevention in women at high risk for emesis: a phase 3 study. Arch Surg 2011; 146:201–206.  Back to cited text no. 13
    
14.
Singla NK, Singla SK, Chung F, Kutsogiannis DJ, Blackburn L, Lane SR et al. Phase II study to evaluate the safety and efficacy of the oral neurokinin-1 receptor antagonist casopitant (GW679769) administered with ondansetron for the prevention of postoperative and postdischarge nausea and vomiting in high-risk patients. Anesthesiology 2010; 113:74–82.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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