Surgical Endoscopy

, Volume 22, Issue 6, pp 1487–1492

Ondansetron, granisetron, and dexamethasone compared for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy

A randomized placebo-controlled study

Authors

    • Department of Surgery, Faculty of MedicineCelal Bayar University
  • Elvan Erhan
    • Department of Anesthesiology, Faculty of MedicineEge University
  • Hasan Aydede
    • Department of Surgery, Faculty of MedicineCelal Bayar University
  • Okan Yumus
    • Department of Surgery, Faculty of MedicineCelal Bayar University
  • Alp Yentur
    • Department of Anesthesiology, Faculty of MedicineCelal Bayar University
Article

DOI: 10.1007/s00464-007-9656-3

Cite this article as:
Erhan, Y., Erhan, E., Aydede, H. et al. Surg Endosc (2008) 22: 1487. doi:10.1007/s00464-007-9656-3

Abstract

Background

Laparoscopic cholecystectomies are associated with an appreciably high rate of postoperative nausea and vomiting (PONV). This study was designed to compare the effectiveness of ondansetron, granisetron, and dexamethasone for the prevention of PONV in patients after laparoscopic cholecystectomy.

Methods

A total of 80 American Society of Anesthesiologists (ASA) physical class I–II patients scheduled for laparoscopic cholecystectomy were included in this randomized, double blind, placebo-controlled study. All patients received a similar standardized anesthesia and operative treatment. Patients were randomly divided into four groups (n = 20 each). Group 1, consisting of control patients, received 0.9% NaCl; group 2 patients received ondansetron 4 mg i.v.; group 3 patients received granisetron 3 mg i.v.; and group 4 patients received dexamethasone 8 mg i.v., all before the induction of anesthesia. Both nausea and vomiting were assessed during the first 24 h after the procedure.

Results

The total incidence of PONV was 75% with placebo, 35% with ondansetron, 30% with granisetron, and 25% with dexamethasone. The incidence of PONV was significantly less frequent in groups receiving antiemetics (p < 0.05). The differences between dexamethasone, granisetron, and ondansetron were not significant.

Conclusions

Prophylactic dexamethasone 8 mg i.v. significantly reduced the incidence of PONV in patients undergoing laparoscopic cholecystectomy. Dexamethasone 8 mg was as effective as ondansetron 4 mg and granisetron 3 mg, and it was more effective than placebo.

Keywords

PONVLaparoscopic cholecystectomyOndansetronGranisetronDexamethasone

Postoperative nausea and vomiting (PONV) are distressing and frequent adverse events of anesthesia and surgery, with a relatively high incidence (53%–72%) after laparoscopic cholecystectomy [8, 15]. These effects may prolong recovery time, delay patient discharge, and increase hospital costs [12]. Numerous antiemetics have been studied for the prevention and treatment of PONV in patients scheduled for laparoscopic cholecystectomy [2, 6, 7, 12, 15, 18]. Traditional antiemetics, including anticholinergics (e.g., scopolamine), antihistamines (e.g., dimenhydrinate), phenothiazines (e.g., promethazine), butyrophenones (e.g., droperidol), and benzamide (e.g., metoclopramide) are used for the control of PONV. The available nontraditional antiemetics for the prophylaxis against PONV are dexamethasone and propofol. Serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron), compared with traditional antiemetics, are highly efficacious for PONV. None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade of one type of receptor [8].

Among the antiemetics currently prescribed for PONV, serotonin subtype 3 antagonists (e.g., ondansetron and granisetron) are expensive [15]. Other currently used, lower-cost antiemetics (e.g., anticholinergics, antihistamines, and dopamine receptor antagonists) have side effects, such as sedation, dry mouth, restlessness, changes in arterial blood pressure, and extrapyramidal symptoms [14]. Dexamethasone, a corticosteroid, is an inexpensive and effective antiemetic drug, with minimal side effects after a single-dose administration. It was first reported as an effective antiemetic in patients receiving cancer chemotherapy [1]. Since then, dexamethasone has been widely applied in the prevention of nausea and vomiting after chemotherapy. Dexamethasone also reduces the incidence of PONV [10]. The goal of this prospective randomized, double-blind, placebo-controlled study was to compare the efficacy of dexamethasone with the two serotonin subtype 3 antagonists ondansetron and granisetron in preventing nausea and vomiting in patients after laparoscopic cholecystectomy.

Patients and methods

The study enrolled 80 patients (61 women and 19 men) scheduled for laparoscopic cholecystectomy with general anesthesia. They ranged in age from 21 to 75 years (mean: 51.5 years). Each patient gave his or her written consent to participate in the study. The study was approved by the Medical University ethics committee. The exclusion criteria included American Society of Anesthesiology (ASA) physical class III–IV; age over 75 years; body mass index above 30; pregnancy; smoking; signs of gastrointestinal, endocrine, renal, hepatic or immunological disease; use of opioids or tranquillizers less than 1 week before the operation; treatment with steroids; history of alcohol or drug abuse; history of motion sickness; preoperative diagnosis of gallbladder empyema and previous endoscopic sphincterotomy for common bile duct stones; and conversion to open cholecystectomy. Study medications were prepared by a technician anesthetist in identical 5-ml syringes and administered in a double-blind fashion. Patients were randomly divided into four groups (n = 20 each). Group 1, consisting of control patients, received 0.9% NaCl; group 2 patients received ondansetron 4 mg i.v.; group 3 patients received granisetron 3 mg i.v.; and group 4 patients received dexamethasone 8 mg i.v. all 15 min before the induction of anesthesia .

The same standardized anesthesia technique was used in all patients. Patients were monitored during anesthesia by continued electrocardiogram (ECG), noninvasive blood pressure, pulse oximetry, and capnometry. General anesthesia was induced with propofol (2 mg/kg), and fentanyl (2 μg/kg). In all groups vecuronium (0.1 mg/kg) was given to facilitate tracheal intubation. Anesthesia was maintained with 1.0%–2.5% (inspired concentration) isoflurane in oxygen. Additional fentanyl and vecuronium were used if necessary. Ventilation was controlled mechanically and was adjusted to keep end-tidal CO2 between 35 and 40 mmHg. After tracheal intubation, a nasogastric tube was placed to promote baseline emptying of the stomach of air and gastric contents. The intravenous fluid used during surgery was 0.9% saline. If required, reversal of muscle relaxation was achieved with atropine and neostigmine at the end of surgery.

First-generation cephalosporine was given at the induction of anesthesia. During surgery the patients were placed in the reverse Trendelenburg position. Pneumoperitoneum was created with a closed Veress needle technique, and laparoscopic cholecystectomy was performed through two ports of 10 mm and two of 5 mm in the standard position with the legs closed, maintaining a 12 mmHg intra-abdominal pressure. The gallbladder was retracted via a supraumblical 10-mm trocar port or via the other 10-mm trocar port. If necessary, a fascial incision of 1 cm was made to ease retraction of the gallbladder. During laparoscopy, intra-abdominal pressure was maintained at 12 mmHg. CO2 was carefully evacuated at the end of surgery by manual compression of the abdomen with open trocars. Both 10-mm port sites were closed with a nonabsorbable suture at the end of the procedure. The nasogastric tube was removed at the end of the procedure.

After surgery, patients were observed for 24 h. Diclofenac sodium 75 mg i.m. was given routinely for the prevention of postoperative pain. When patients complained of pain and requested analgesia, 75 mg of diclofenac sodium i.m. was given.

The incidence of nausea and vomiting was recorded during three assessment periods, 0–6 h, 6–12 h, and 12–24 h, by nursing staff without knowledge of which antiemetic the patients had received. Both nausea and vomiting were assessed. The rescue antiemetic was metaclopramid, 10 mg i.v.

Results were calculated as mean ± standard deviation (SD). Parametric data were analyzed with one-way analysis of variance (ANOVA), and for nonparametric variables we used the chi-square test; p < 0.05 was considered significant.

Results

All 80 patients enrolled in the study had their surgical procedures completed. The mean values for age, weight, height, time of surgery, and time of anesthesia are given in Table 1. Groups were comparable with respect to demographic data, time of surgery, and time of anesthesia. The mean values for the incidence of nausea and vomiting in the respective groups of patients at intervals 0–6 h, 6–12 h, and 12–24 h after laparoscopic cholecystectomy are given in Table 2. In the first interval (0–6 h) after the operation, nausea and vomiting were most frequent in the control group compared with the other three groups, all of which were given antiemetics (p < 0.05). At that time (0–6 h), the need for rescue antiemetic vomiting was also most frequent in the control group compared with the other three groups given antiemetics (p < 0.05) (Table 2).
Table 1

Demographic data, time of surgery, and time of anesthesia (mean ± SD) for four groups of patients treated prophylactically for postoperative nausea and vomiting (PONV)

Group

Age (years)

Gender (M/F)

Weight (kg)

Height (cm)

Time of surgery (min)

Time of anesthesia (min)

Control

52.5 ± 13.9

6/14

63.9 ± 11.2

163.1 ± 8.3

77.3 ± 33.1

93.0 ± 38.2

Ondansetron

50.3 ± 14.6

3/17

62.1 ± 7.9

161.0 ± 4.6

69.3 ± 16.9

82.0 ± 17.4

Granisetron

50.1 ± 13.0

3/17

61.2 ± 5.7

160.8 ± 5.3

74.0 ± 25.0

93.0 ± 29.4

Dexamethasone

53.4 ± 7.6

7/13

62.9 ± 5.8

163.1 ± 6.0

72.0 ± 43.6

85.8 ± 45.5

Table 2

Number of patients (%) with nausea and vomiting, at intervals 0–6 h, 6–12 h, 12–24 h after the end of surgery

 

Control (n = 20)

Ondansetron (n = 20)

Granisetron (n = 20)

Dexamethasone (n = 20)

0–6 h

  Nausea

8 (40%)

5 (25%)

2 (10%)*

1 (5%)*

  Vomiting

6 (30%)

1 (5%)*

2 (10%)

2 (10%)

  Total

14 (70%)

6 (30%)*

4 (20%)*

3 (15%)*

  Rescue antiemetic

11 (55%)

3 (15%)*

2 (10%)*

2 (10%)*

6–12 h

  Nausea

2 (10%)

0 (0)

2 (10%)

1 (5%)

  Vomiting

2 (10%)

1 (5%)

0 (0)

2 (10%)

  Total

4 (20%)

1 (5%)

2 (10%)

3 (15%)

  Rescue antiemetic

3 (15%)

1 (5%)

0

2 (10%)

12–24 h

  Nausea

1 (5%)

0 (0)

0 (0)

0 (0)

  Vomiting

1 (5%)

0 (0)

0 (0)

0 (0)

  Total

2 (10%)

0 (0)

0 (0)

0 (0)

  Rescue antiemetic

2 (10%)

0 (0)

0 (0)

0 (0)

* p < 0.05 compared to control

The total incidence of PONV during 24 h was 75% in the control group, 35% in the ondansetron group, 30% in the granisetron group, and 25% in the dexamethasone group. The incidence of PONV in the control group was higher than the other groups given antiemetics (ondansetron, granisetron, and dexamethasone) (p < 0.05) (Table 3). During the 24-h study period there was no difference in the antiemetic effect between the ondansetron, granisetron, and dexamethasone groups. The rate of complete response (no PONV) was 25% in the placebo group, 65% in the ondansetron group, 70% in the granisetron group, and 75% in the dexamethasone group. No significant side effects were found after the use of ondansetron, granisetron or dexamethasone when compared with the use of saline.
Table 3

Overall incidence of PONV in each of four treatment groups

 

Control (n = 20)

Ondansetron (n = 20)

Granisetron (n = 20)

Dexamethasone (n = 20)

0–24 h

  Nausea

8 (40%)

5 (25%)

4 (20%)

1 (5%)*

  Vomiting

7 (35%)

2 (10%)

2 (10%)

4 (20%)

  Total

15 (75%)

7 (35%)*

6 (30%)*

5 (25%)*

* p < 0.05 compared to control

Discussion

The laparoscopic approach has decreased discomfort associated with cholecystectomy and has become a universally accepted procedure for symptomatic cholelithiasis. Laparoscopic cholecystectomy is a procedure that usually is well tolerated by the patient. However, an increased incidence of PONV in patients after laparoscopic cholecystectomy has been reported, with an incidence of 53%–72% [8, 15]. In our study, we found that the total incidence of PONV was 75% within the first 24 h after patients underwent laparoscopic cholecystectomy when no antiemetic was given prophylactically. After pretreatment with dexamethasone 8 mg, the incidence of PONV was significantly reduced to 25%. We also found that dexamethasone 8 mg was as effective as ondansetron 4 mg and granisetron 3 mg for this purpose.

The origin of postoperative nausea and vomiting after laparoscopic cholecystectomy performed under general anesthesia is not entirely clear, but it is probably multifactorial [7, 15]. The necessity of gas insufflation, which results in the stretching of peritoneum and increased blood pressure in the peritoneal cavity, is a very important factor provoking nausea and vomiting [12]. Prolonged carbon dioxide insufflation, residual pneumoperitoneum after CO2 insufflation, peritoneum distension, diaphragm irritation, and visceral organ irritation and manipulation have been considered to influence the incidence of PONV [7, 15]. Use of nitrous oxide, the utilization of slightly hypoxic mixtures during anesthesia, and postoperative opioid administration have been suggested as other potential risk factors [7]. The effectiveness of various antiemetics has been studied for the prevention and treatment of PONV in patients scheduled for laparoscopic cholecystectomy [2, 6, 7, 12, 15, 18].

Glucocorticoids are well known for their analgesic, anti-inflammatory, immune-modulating, and antiemetic effects. The mechanism by which glucocorticoids alleviate nausea and vomiting is not fully understood, but the effects are probably centrally mediated via inhibition of prostaglandin synthesis or inhibition of the release of endogenous opioids [2, 10]. Dexamethasone may act through serotonin inhibition in the gut [6]. It may also reduce tissue inflammation around the surgical sites and thus reduce the ascending parasympathetic impulses (e.g., vagus) to the vomiting center and reduce PONV [18]. Dexamethasone was first reported to be effective in patients receiving cancer chemotherapy in 1981 [1]. Since then, several studies have shown that glucocorticoids are equal to or better than other drugs such as metoclopramide, ondansetron, or droperidol in preventing nausea and vomiting associated with chemotherapy [13]. Recently, dexamethasone has been shown to be effective in reducing nausea and vomiting after open and laparoscopic surgical procedures [2, 3, 5, 6, 7, 9, 17, 18]. Several randomized controlled trials have shown that dexamethasone alone [2, 7, 15, 17, 18] or in combination with other drugs (granisetron, ondansetron, tropisetron, dolasetron) [3, 5, 6, 9] is effective in reducing postoperative nausea and vomiting and antiemetic requirement after laparoscopic cholecystectomy.

Wang et al. [17] evaluated the antiemetic effect of dexamethasone 8 mg i.v. compared with saline in the prevention of nausea and vomiting after laparoscopic cholecystectomy. They found that the total incidence of nausea and vomiting was 23% in the dexamethasone group and 63% in the saline group and they concluded that that dexamethasone 8 mg i.v. significantly decreased the incidence of nausea and vomiting after laparoscopic cholecystectomy. In another study, Feo et al. [7] studied the antiemetic effect of dexamethasone 8 mg i.v. compared with saline in the prevention of nausea and vomiting after laparoscopic cholecystectomy. They observed that the total incidence of nausea and vomiting was 33% in the dexamethasone group and 53% in the saline group. The authors concluded that dexamethasone 8 mg i.v. reduced postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy, with no side-effects, and may be recommended for routine use. Nesek et al. [15] evaluated the efficacy of dexamethasone 8 mg i.v., metoclopramide 10 mg i.v., and their combination to prevent PONV in patients undergoing laparoscopic cholecystectomy. The total incidence of PONV was 60% with placebo, 45% with metoclopramide, 23% with dexamethasone, and 13% with the combination of dexamethasone plus metoclopramide. The authors concluded that dexamethasone and the combination of dexamethasone plus metoclopramide were more effective in preventing PONV than metoclopramide and placebo. The total incidence of PONV was 75% with placebo, 35% with ondansetron, 30% with granisetron, and 25% with dexamethasone in our study. Our results are in accordance with the above-mentioned studies in which it was shown that dexamethasone 8 mg i.v. significantly reduced the incidence of PONV in patients undergoing laparoscopic cholecystectomy.

Bisgaard et al. [2] studied the effects of preoperative dexamethasone on surgical outcome after laparoscopic cholecystectomy. Eighty patients were randomized to intravenous dexamethasone (8 mg) or placebo preoperatively. During the first 6 postoperative hours, the incidence and severity of nausea were significantly lower in the dexamethasone group, and vomiting was significantly reduced during the entire 0–24-h period, compared with placebo. The authors concluded that preoperative dexamethasone (8 mg) improved surgical outcome after laparoscopic cholecystectomy in terms of significantly less pain, fatigue, nausea, and vomiting, and patients resumed their recreational activity significantly faster than the placebo group. Because the regimen used was safe and without apparent side effects, the authors suggested that dexamethasone should be used as routine in otherwise healthy patients undergoing elective laparoscopic cholecystectomy. We also observed no impaired wound healing, postoperative infection, or other complications associated with the use of dexamethasone in our study. These results are similar to other trials studying dexamethasone as a prophylactic antiemetic for patients undergoing laparoscopic cholecystectomy [16]. In addition, a recent meta-analysis on postoperative nausea and vomiting has shown no increase in infectious or other complications using a single dose of dexamethasone [10]. Therefore, the evidence supports the safety of a single preoperative dose of dexamethasone (8 mg) in otherwise healthy patients undergoing minor surgical procedures such as laparoscopic cholecystectomy.

It is difficult to establish which drug can be considered the gold standard in PONV prevention after laparoscopic cholecystectomy. Because many research centers have reported that the effects of different antiemetic drugs are similar, it is wise to administer the cheapest and safest drugs.

Ondansetron and granisetron are the two most commonly used prophylactic serotonin subtype 3 antagonists in our daily clinical practice for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. However, cost is a growing concern in today’s health care system. Prophylactic antiemetic with dexamethasone is relatively inexpensive. In previous studies dexamethasone was usually combined with the serotonin subtype 3 antagonists, and it was shown that adding dexamethasone to ondansetron or granisetron improved antiemetic efficacy in PONV [3, 6, 9, 12].

In our study we compared dexamethasone alone with the two popular serotonin subtype 3 antagonists and found that dexamethasone 8 mg alone was as effective as ondansetron 4 mg and granisetron 3 mg, and it was more effective than placebo. The dose of dexamethasone used, 8 mg, was based on previous reports shown to decrease PONV when used as an antiemetic regimen [2, 6, 7, 9, 15]. The doses of ondansetron 4 mg and granisetron 3 mg were also in accordance with the previous studies in which they were used as antiemetics for PONV [3, 6, 9, 12].

Dexamethasone provided a simple, safe, cheap, and effective postoperative nausea and emesis prevention method in our study. Based on these findings, dexamethasone is a more reasonable choice than ondansetron and granisetron for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. One limitation of our study was that our sample size was small, including only 80 patients. A retrospective power analysis revealed that a group size of approximately 58 patients in each group would have been required to identify a statistically significant difference of nausea between the ondansetron and dexamethasone groups, with 80% power and p = 0.05 . Similarly, retrospective power analysis revealed that a group size of approximately 88 patients in each group would have been required to identify a statistically significant difference of nausea between the granisetron and dexamethasone groups, with 80% power and p = 0.05. Therefore further larger studies comparing dexamethasone alone with any of the other more expensive drugs are needed to support our findings.

There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone for prophylaxis against PONV. Therefore, combination antiemetic therapy can be reserved for patients with the highest PONV risk [12]. These important PONV risk factors include obesity, earlier PONV episodes, motion sickness, and illnesses of the upper alimentary track, especially gastric and duodenal ulcers, esophagitis, or hiatal hernia. Also, women are more susceptible to PONV, especially menstruating women, because of a higher level of sex hormones (e.g., gonadotropin, and mainly progesterone) than in men [4, 11, 12].

In conclusion, prophylactic dexamethasone 8 mg i.v. significantly reduced the incidence of PONV in patients undergoing laparoscopic cholecystectomy. Dexamethasone was as effective as ondansetron 4 mg and granisetron 3 mg and it was more effective than placebo. Dexamethasone provided a simple, safe, cheap, and effective postoperative nausea and emesis prevention method.

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© Springer Science+Business Media, LLC 2007