Prophylaxis of intra- and postoperative nausea and vomiting in patients during cesarean section in spinal anesthesia

Background

Caesarean section in spinal anesthesia has become increasingly popular in recent years and is now a commonly performed surgical procedure. Regional anesthesia is performed in 80% of anesthetized patients compared to 20% who receive general anesthesia [1,2]. While consciousness allows the patient to enjoy the early intimate contact with the newborn child (bonding), the procedure may be associated with various important problems [3]. Arterial hypotension and headache, insufficient or abundant anesthesia, and psychologic distress may be some of the adverse effects of regional anesthesia for caesarean section [4,5].

A common problem in caesarean section is intra- and postoperative nausea and vomiting under regional anesthesia [6–8]. NV can happen during and after the birth and may affect the well-being of mother and family [9]. The well-being of patients may be severely compromised [10]; 72% of patients are afraid of NV [11] and 71% feel significant discomfort [12]. Critical anesthesiological complications such as airway obstruction, aspiration pneumonitis, and wound dehiscence are rare and mainly related to postoperative nausea and vomiting in general surgical patients [13,14]. In addition to postoperative pain, NV is one of the most frequent anesthesiological complications. Previous reports and our observations suggest both nausea and vomiting as a frequent phenomenon, with incidences up to 80% [5,9,15,16].

Necessary therapeutic measures, the use of personnel, and room and material resources represent an enormous economic burden and are being closely monitored by health system administrators [17]. Due to the complex pathophysiology, the treatment and prophylaxis of NV is difficult. To keep the costs low, alternative treatments like acupressure and acupuncture are used [8,18–20]. The pharmacological interventions available include a wide range of drug medication, including dopamine and serotonin receptor antagonists, corticosteroids, antihistamines, sedatives, and anticholinergic drugs [9,16,21].

The major risk factor for nausea and vomiting during or after spinal anesthesia in cesarean section is arterial hypotension due to the blockade of the sympathetic nerve system [9]. NV may be influenced by hormonal changes during pregnancy, which alter the sphincter tone of the esophagus and the stomach and the activity of the small bowel and esophagus, as well as adverse effects of uterotonic drugs, intraoperative manipulation of the uterus, and/or psychological distress aggravated by insufficient or excessive anesthesia [22–24].

Previous studies have addressed the efficiency of different anti-emetics in terms of reduction of PONV risk in cesarean section patients, mostly using only 1 agent [9,21]. In a recently published study, we were able to find a multimodal prophylactic regimen for breast surgical procedures [25]. There are several studies in spinal anesthesia indicating that multimodal prophylaxis is preferable to prevent NV, especially in caesarean section [5,9,21].

The goal of the present study was to investigate multimodal pharmacological approaches with tropisetron and metoclopramide (Group II) and dimenhydrinate and dexamethasone (Group III) compared to a mono therapy with tropisetron (Group IV) versus no prophylaxis (Group I) to prevent NV intra- and postoperatively in patients undergoing cesarean section under spinal anesthesia.

Material and Methods

STATISTICAL ANALYSIS:

To assess the individual risk of the patients and the risk reduction through the anti-emetic prophylaxis, a multivariate statistical analysis was performed. The variables considered (eg, duration of the operation, events of hypotension) were used to build a statistical model with SAS/STAT (SAS Institute Inc., Cary, NC). During multiple steps, all factors with p>0.05 were removed. The remaining factors significantly affected the observed endpoint, which was the incidence of nausea and vomiting. The degree of association of the considered factors and the endpoint were determined using odds ratios. Results were considered statistically significant at p<0.05.

Results

INTRAOPERATIVE NAUSEA AND VOMITING:

Patients without any prophylaxis given experienced the most nausea intraoperatively (63.2%). Every prophylaxis given significantly lowered the incidence of nausea intraoperatively. The most effective prophylactic medication against intraoperative nausea was a combination of tropisetron and metoclopramide (25.6%) (Group II).

Intraoperative vomiting was also highest in Group I (15.8%) and was significantly lower in Group II (3.7%), Group III (8.9%), and Group IV (1.4%).

POSTOPERATIVE NAUSEA AND VOMITING:

In the early postoperative period (0–2 h) the incidence of nausea was highest in the non-treated group I (9.2%), and was lowered by prophylaxis in Group II (6.1%), Group III (5.1%), and group IV (4.2%). Differences were marginally significant.

There were no differences in the incidence of nausea in the late postoperative period (2–24 h) between groups (1% in Groups I–III, and 3% in Group IV).

Postoperative vomiting was rare: 3% in Group I and none of the patients in the treatment groups experienced vomiting postoperatively.

The major influence from a statistical point of view seems to have been the type of medication given. The medication in Group II is preferable to medication of Groups III and IV.

There are no statistical differences between the effect of medication of Groups III and IV.

The other risk factors additionally investigated did not show any significant differences. There was no risk factor that influenced all groups.

The median of symptom strength among the symptomatic patients was 5.5 and the mean number of episodes was 1.5.

Discussion

PROPHYLACTIC AGENTS:

Tropisetron was one of the prophylactic anti-emetic agents used in this study. It belongs to the group of 5-HT3- or serotonin antagonists acting in the chemoreceptive trigger zone [39]. These substances block the vagal stimulated emetogen effect of serotonin. Efficacy of serotonin antagonists in prevention and therapy of PONV has been extensively proven in numerous investigations [30]. Primarily developed for the treatment of chemotherapy-induced nausea and vomiting, they now play an important role in modern anesthesia. They are considered as relatively safe – single-dose adverse effects are mostly limited to headache, tachycardia, and sedation [29]. According to the investigations of Apfel and others, serotonin antagonists are primarily used as second- or third-line drugs in preventing or treating PONV [32,40]. The relative expensiveness of these drugs may limit general use, considering increasing economic constraints in most health care systems [40,41].

Dexamethasone was also used as an anti-emetic in this study. Eberhart et al. showed that dexamethasone is as effective as other established anti-emetic drugs in PONV prophylaxis and therapy [42]. This was confirmed by the multi-center trial of Apfel et al, which demonstrated that the anti-emetic effects of dexamethasone, droperidol, and ondansetron are comparable [32]. The underlying mechanism of action is not entirely clear and needs further investigation [43]. Dexamethasone has a delayed onset of action, but a long-lasting effect [44]. In addition, it is known to lower surgery-induced inflammation [45]. No severe adverse effects are known with this drug and it is reasonably priced [42]. Dexamethasone is also well established in the context of chemotherapy induced nausea and vomiting [46,47]; low doses provide a sufficient anti-emetic effect [45].

Dimenhydrinate was another anti-emetic agent used in this study and belongs to the group of antihistamines acting on histamine receptors in the chemoreceptor trigger zone [40,48]. It is, for example, very successfully used for the treatment of motion sickness [49,50]. Its efficacy has also been proven in the context of PONV prophylaxis and therapy, although with fewer studies. Its use in anesthesia so far appears to be less frequent, although it is safe and reasonably priced [40,51]. One major drawback may be sedation caused by this agent [50].

Metoclopramide antagonizes dopamine effects in the chemoreceptor trigger zone in the brainstem. Adverse effects include sedation and in some cases agitation and extrapyramidal effects. Drugs of these group may be problematic due to the profile of adverse effects, which include not only sedation, but also Parkinson symptoms (tremor, rigor, akinesis) [34] and severe arrhythmias (torsade de pointes), which is why droperidol, one of the oldest and best established anti-emetics and also used in the context of PONV, was withdrawn from the German market, but subsequently relaunched [29]. Several investigations have shown the efficacy of metoclopramide in terms of PONV prophylaxis and therapy when it is used in high doses or in combination with other antiemetic drugs like corticoids [52].

Numerous investigations have shown that both metoclopramide and tropisetron may reduce intra- and postoperative nausea and vomiting in parturients with spinal anesthesia, dexamethasone reduces intraoperative nausea and vomiting, and antihistamines reduce postoperative nausea and vomiting, although data for the latter group of substances are comparatively sparse [5,21].

Previous studies in other surgical procedures, such as the multicenter trial of Apfel et al. in 2004, have also shown that anti-emetics in combination add their individual contribution to NV reduction and, therefore, are preferable, particularly in high-risk patients [31,48,53]. Apfel et al. demonstrated that in a combination of anti-emetics, each drug has an additional proportional effect, which means that a double or triple combination is twice or three times as effective as a single drug. Comparison of ondansetron, dexamethasone, and droperidol, for example, shows a step-wise NV risk reduction of 30% by each individual drug [48], which, however, was assessed in the context of general anesthesia.

In this study, we chose 2 anti-emetic combinations (tropisetron/metoclopramide and dimenhydrinate/dexamethasone) and a single-drug regimen consisting of tropisetron in comparison to no prophylaxis. With the combination dimenhydrinate/dexamethasone, we had an excellent anti-emetic experience in a previous investigation with patients undergoing elective breast surgery under general anesthesia. On the other hand, preliminary investigations have shown that tropisetron and/or metoclopramide have a good anti-emetic effect in parturient patients with spinal anesthesia. Previous experiences have also shown that these drugs were in part randomly used and, therefore, not in a controlled, firmly-established prophylaxis.

In our study, double prophylaxis with metoclopramide/tropisetron was most effective regimen and reduced nausea to 25.6% intraoperatively and to 6.1% 1–2 h and 1% 2–24 h postoperatively. Vomiting was 3.66% lower intraoperatively. In contrast, dimenhydrinate/dexamethasone prophylaxis significantly decreased the incidence of nausea intraoperatively to 44.2% and 1–2 hrs postoperatively to 5.06% and to 1% 2–24 h postoperatively, and was just as effective as the single prophylaxis with tropisetron (45.07% intraoperatively, 4.23% 0–2 h postoperatively, 3% 2–24 h, and 1.41% intraoperatively).

In the postoperative period, there was no significant difference in nausea between the treatment groups. Vomiting, in contrast to nausea, is rare intra- and postoperatively, and was lowered by approximately the same extent in the untreated group as in the treated groups.

Why are the different anti-emetic regimes so different in their effects? One aspect to be considered is the surgical procedure itself, which is associated with an exteriorization of the uterus and often manipulation of the peritoneum and bowel, thus irritating receptors (e.g., 5-HT3 and 5-HT4 type) and the vagal nerve system, thus causing nausea and vomiting [54]. In contrast to dexamethasone and dimenhydrinate, both tropisetron and metoclopramide have a direct and pronounced effect on the bowel and the upper gastrointestinal system, respectively [30,49].

Tropisetron interacts with 5-HT3 and 5-HT4 receptors in the bowel, thus influencing motility and preventing serotonin-mediated nausea and vomiting (e.g., induced by surgical manipulation of the bowel and intestines) [11,30]. Metoclopramide increases forward motility of the upper gastrointestinal system, thus preventing reflux and regurgitation, but also interacts with 5 HT3 and 5 HT4 receptors as tropisetron and may additionally reduce nausea and vomiting by this mechanism [43,55]. Both agents interact via receptors at the chemoreceptor trigger zone, thus accentuating their anti-emetic effect [11,43].

Unfortunately, in most cases anti-emetic medication is given as a treatment, so the patients and their family are exposed to the unpleasant experience of intraoperative NV or PONV. Our results suggest that prophylaxis as applied in this study can certainly reduce the onset of intraoperative NV and PONV and the associated discomfort. Both the mono- and combination therapy with well-known and safe drugs are efficient ways of doing this.

In terms of costs and adverse effect profile, the anti-emetic combination of tropisetron and metoclopramide appears to be superior and preferable. Except for sedation, no substantial adverse effect was observed in any of our patients. Current costs for metoclopramide/tropisetron prophylaxis are in a range of 0.15–0.8 Euros in our hospital, compared to for example, 0.25/1.2 Euros for dexamethasone/dimenhydrinate. Prices, however, may vary in different hospitals.

Although a triple anti-emetic prophylaxis may have further decreased NV and PONV incidence in this study, we did not test this due to increasing risk of significant adverse effects and is advised only in extremely high-risk patients.

Conclusions

Our investigation in 308 patients experiencing cesarean section under spinal anaesthesia shows that intra- and postoperative nausea and vomiting can be significantly reduced by an anti-emetic prophylaxis combination of tropisetron 2 mg and metoclopramide 20 mg.

Therefore, this safe and reasonably priced combination should be preferred for use in preventing intraoperative NV and PONV in cesarean section patients under spinal anaesthesia.