Comparison of effect of Amisulpride and Dexamethasone with Ondansetron and Dexamethasone for postoperative nausea and vomiting after post-chemotherapy breast cancer surgeries: A Randomised Active Controlled Double Blind Study

Introduction :

Postoperative nausea and vomiting (PONV) is an unpleasant and one of the most distressing symptom for any patient undergoing surgery. Breast cancer is most commonly occurring cancer in women and surgery is one of the most important treatments. PONV is common concern in patients undergoing breast cancer surgery. Consequences of PONV are wound dehiscence ,dehydration, aspiration of gastric contents, delayed recovery and prolonged hospital stay, psychological impact on patient and relatives.

PONV is defined as nausea and vomiting occurring within 24 hrs after surgery. Risk factors for PONV includes Female gender, Non smoker, History of motion sickness or Experience of previous PONV, Volatile anaesthesia, Perioperative use of opioids and nitrous oxide.

Activation of vomiting center is due to involvement of three nerves and seven neurotransmitters, which makes the prophylaxis and treatment complex. The antiemetic premedication can reduce the rate of postoperative nausea and vomiting. Neumerous pharmacological agent,regimens,and techniques have evolved from time to time, but they have limited efficacy due to various side effect.

5-hydroxytryptamine subtype 3 (5-HT3) receptor antagonists are effective antiemetic drugs with higher safety and favorable side effect profiles as they lack the sedation, dysphoria, and extra-pyramidal side effects of other commonly used antiemetics. Ondansetron is5-HT3 antagonist, used alone or in combination for the prophylaxis due to its lower cost.  Amisulpride is a selective dopamine-2(D2), dopamine-3(D3) receptor antagonist. D2 receptors are located in the chemoreceptor trigger zone(CTZ) and respond to the dopamine released from nerve endings. Activation of CTZ relays stimuli to the vomiting center which is involved in emesis.Dexamethasone with a  5-HT3 antagonist  is an attractive combination , because ondansetron is most effective against early vomiting ,whereas dexamethasone is effective against both early and late (2–24 h) nausea and vomiting, itslate efficacy being pronounced.

Several clinical trials have reported that,when compare to placebo, amisulpride significantly reduce the incidence of PONV as well as rescue antiemetic requirement. In addition the dosage of amisulpride used for PONV prophylaxis is not associated with significant risk of QT interval prolongation or extra-pyramidal side effects compared to other antiemetics.

A double blind,randomized, placebo-controlled,multicenter trial with Amisulpride shows 57.7% complete response rate in amisulpride group and 46.6% in control group. Amisulpride was safe and effective for prophylaxis of PONV when used along with other class of antiemetics in patients high risk for postoperative nausea and vomiting.

Systematic review and meta-analysis study for efficacy of amisulpride on PONV results shows that single low dose of IV amisulpride is safe and efficacious for prevention of PONV compared to placebo.

Objective :

The purpose of this Randomised controlled study is to compare the efficacy of Amisulpride with dexamethasone versus Ondansetron with dexamethasone for PONV in post-chemotherapy  breast cancer surgeries.

Study Design- Prospective, Randomised controlled, Double Blind interventional study

Methodology-

This prospective, randomized, double blinded,controlled trial will be conducted in the department of anesthesiology, Critical Care and Pain after approval from IEC and registration with CTRI. Informed written consent will be taken as per patient’s preferred language either in Hindi,Marathi or English a day prior to surgery. Pre-anaesthetic checkup and optimization will be done as per institutional protocol.Before taking patient to the operation theatre randomization will be done by computer generated random number using RedCap software. After randomization patient will be taken to operation theatre, standard monitors ( Electrocardiogram, noninvasive blood pressure, pulse oximetry and capnography) will be attached followed by securing intravenous access.

Anaesthesia will be induced using inj fentanyl 1-2 mcg/kg, injpropofol 2-2.5 mg /kg.Airway will be secured using an endotracheal tube or LMA, whichever is appropriate for the patient, as per the discretion of OT anesthesiologist. Depth of Anaesthesia will be maintained using inhalational anesthetic agent (Sevoflurane or Isoflurane at appropriate MAC) in O2-N2O mixture in 1:1 ratio. Use of muscle relaxation will be as per OT anaesthetist’s discretion.  Intraoperative analgesia will be maintained by intermittent IV boluses of inj fentanyl and parenteral doses of paracetamol and diclofenac, as per the standard institutional practice.

After induction of anaesthesia study drug will be given as per randomization group :

Group A patients will receive  IV Amisulpride 5 mg + Dexamethasone 4 mg

Group B patients will receive Ondansetron 8 mg +Dexamethasone 4 mg

In addition, patients in group A will receive IV normal saline 2ml three times a day for 24 hours in postoperative period whereas group Bwill receive IV ondansetron 4 mg three times a day for 24 hours postoperatively. Study drugs will be prepared by an anesthesiologist who will not be a part of postoperative monitoring and data collection team.The resident anesthesiologist giving drug to the patientswill also be unware of the group allocation of the patient.Pain can be one of the factor for PONV so all patients will be given paracetamol 15 mg/kg 8 hours for next 24 hours. If there is any routine use of diclofenac at the end of surgery and postoperatively, that will be noted. For rescue analgesia (if VAS for pain is >4) diclofenac 50 mg will be given. Pain score will be noted till 24 hours postoperatively. Intravenous metoclopromide10 mg will be used as rescue antiemetic.Opioids will be avoided in postoperative period,if at all necessary can be given.

The primary end point of this study will be the overall incidence of PONV between the groups. The incidences of PONV will be assessed in postanesthesia care unit every half an hour for 2 hours and then in the ward at intervals of 2 to 6, 6 to 12 and 12 to 24. hours postoperatively. Nausea will be defined as a subjectively unpleasant sensation with concomitant awareness of the urge to vomit. Vomiting will be defined as the forceful expulsion of gastric contents through the mouth. Retching, the labored spasmodic rhythmic contractions of the respiratory muscles without the expulsion of the gastric contents, will also be regarded as vomiting. If the patients discharged before 24 hours postoperatively, her pain and PONV data will be collected by telephonic followup.

 Secondary end points will be to compare the intensities of nausea (verbal rating scale, 0 = no nausea, 10 = worst nausea imaginable) and pain (verbal rating scale, 0 = no pain, 10 = worst pain imaginable). Additionally, cumulative volume of opioid administered during each observation period, rescue analgesics and antiemetic requirements, and adverse events will be assessed.

 Study withdrawl criteria :

 Metoclopromide will be given as rescue medication first episode of vomiting followed by as and when needed with maximum three doses in a day as rescue medication. This is the standard effective drug in the treatment of PONV. If the patient needs another treatment for PONV, we will exclude those patients.

  Statistical Methods:

Demo graphical data is summarized as mean±SD, median or frequency (%).Categorical variables like nausea, vomiting episodes, number of doses of rescue antiemetic and analgesic etcwill be analyzed using Chi Square test or Fisher Exact test. Continuous variables like age, height, BMI, duration of surgery and anaesthesia,  etcwill be analyzed using independent T test or Mann Whitney U test as per the distribution of data. P-value < 0.05 will be considered statistically significant. SPSS 20 will be used for analysis