INTRODUCTION:

Postoperative nausea and vomiting (PONV) often occur after general anesthesia, occurring in 30% to 40% of all patients. The etiology of PONV is usually multifactorial and relates to anesthetic and analgesic agents, surgical procedures, and intrinsic factors of the patient, such as a history of motion sickness. An increased incidence of nausea and vomiting was reported after opioid administration, intraperitoneal surgery (especially laparoscopy), gynecology, and strabismus surgery. The most prominent incident seems to happen in young women. Nausea may become more common during menstruation. Propofol decreases the incidence of PONV and a history of smoking¹.

Until now, ideal anti-emetic drugs that can be given as prophylaxis or post-surgical therapy with minimal side effects have not been standardized. As reported from several studies, anti-emetic administration as prophylaxis in patients suspected of being at high risk for vomiting nausea gives better results². Ondansetron is the most used drug as an anti-emetic compared to others due to its effectiveness and safety, however, the relatively expensive cost of ondansetron is one of the significant factors limiting its use for routine prophylaxis^1,3. Ondansetron is a medication used mainly as an antiemetic to prevent nausea and vomiting after chemotherapy. Ondansetron is a serotonin 5-HT3 receptor antagonist reduces the activity of the vagus nerve, which deactivates the vomiting center, and also blocks serotonin receptors in the chemoreceptor trigger zone. It affects both peripheral and central nerves⁴.

Manipulation of foods and herbal supplements has also been investigated for the management of postoperative nausea and vomiting. Ginger, with the main content of curcumin, is an herbal supplement that has been shown to have efficacy in small amounts of studies to reduce the severity of postoperative nausea and vomiting, morning sickness, and motion sickness⁵. Its mechanism of working is possible due to the increase in gastric motility, anti-hydroxytryptamine activity, and central anti-emetic effects that have been put forward. These findings point out the potential role of diet and herbal supplements in modulating pain and nausea sensations, which are important to pursue with further research⁶.

Curcuma xanthorriza contains the active substance curcumin, which serves to inhibit the growth of helicobacter pylorii bacteria and has antioxidant and anti-inflammatory properties that work directly on the gastric mucosa⁷. Klainhovia hospita is an herbal remedy that widely been used because it can help heal and stop inflammation and pain. In addition, Klainhovia hospita also has the ability as an anti-allergy. People use Klainhovia hospita as a headache remedy and to reduce abdominal pain due to gastritis⁸. Gastritis occurs more than inflammatory bowel disease, gastroesophageal reflux disease, and peptic ulcer disease⁹.

PONV rarely causes a fatal condition, but it can be felt bothersome for patients. It will have an impact on the satisfaction of the treatment they undergo. In some cases, even patients prefer to delay repatriation from the hospital due to PONV which will increase the cost of care needed¹. The study aimed to analyze differences in the effectiveness of ondansetron administration alone compared to the administration of ondansetron and the combination of Curcuma xanthorriza and Kleinhovia hospita against the incidence of PONV at Dr. Moewardi Hospital.

MATERIALS AND METHODS:

The type of this research is an experimental study with a double-blind randomized controlled trial design. In this study, neither the study subjects nor the researchers were aware of the treatment/intervention given. The research has been done at the Central Surgical Installation of Dr. Moewardi, Surakarta Hospital. The sample was then randomized to get premedication treatment of ondansetron tablets 8mg in 15 people, and 15 others got a combination of ondansetron 8mg with Curcuma xanthorriza and Kleinhovia hospita 1g.

Research subjects:

Subjects that included in this study were those who use inhalation agents and N₂O; Taking duration of operation for 2-3 hours; Using opioids during surgery; the patient's age is between 18 and 50 years; Body Mass Index (BMI) classification is Normoweight; Physical status of ASA I or ASA II; It's not an emergency operation; The patient has no counter-indications of drug administration/ drug content studied.

Patients that excluded in this study were: Patients that have allergies to drugs/drug content studied; have gastrointestinal abnormalities (gastroparesis); Have a history of motion sickness; Patients who get chronic steroid therapy; Patients with impaired kidney and liver function; Pregnant women; Patients with heart abnormalities (Elongation of Q-T intervals). If the duration of anesthesia is not met, the patient occurs massive bleeding during surgery, during surgery hemodynamic is unstable, the patient initially agrees but ultimately decides to exit the study, and if the patient dies, they were dropped out from this study.

PONV rating:

Complaints of nausea and vomiting will be measured using PONV assessment score (Table 1).

Table 1. PONV assessment score

Score	Subject
0	Patients do not feel nausea and Vomiting
1	Patients only feel nauseous
2	Patients experiencing vomiting
3	Patients experience nausea for more than 30 minutes or vomit ≥ 2 times

Data analysis:

The results of observations and primary data are recorded on the form that has been provided, then statistical analysis of data analysis is performed using SPSS version 25 for Windows. The Shapiro-wilk test was conducted to look at the data distribution from a sample of research. To test the differences between the treatment group and the control group, an independent t-test was used for normally distributed data, as well as a Mann-Whitney test for data that was not normally distributed. All statistical analyses are conducted at a confidence interval of 95% (α = 0.05; p < 0.05).

RESULT:

This study has been conducted on patients undergoing laparotomy surgery with general anaesthetics at central surgical installations and inpatient rooms of Dr. Moewardi Surakarta Hospital from March to May 2021. After passing the inclusion and exclusion criteria, 31 patients were willing to be subjects in the study. Of the 31 samples taken, there was 1 patient who dropped out because the duration of surgery was too long (>180 minutes), so only 30 patients remained.

Demographic data (Table 2) obtained the height of the subjects were normally distributed (p>0.05) with an average height 157.03±2.64 cm. While the age, weight and BMI data were not normally distributed with the median age being 41.5 years, the median of weight 54.5 kg, and the median of BMI 20.5kg/m². In addition, the duration of operations in the study was normally distributed (p = 0.116) with mean 140±5.17 minutes. PONV score was found to be not normally distributed, with a median value of 2.

Table 2. Demographic data of the subjects

Variable	Mean/ Median	SD/IQ R	P value
Age	41,5	14	0,01
Height	157±2.64	7,078	0.459^*
Weight	54,5	13	0,041
BMI	20,5	3,83	0,005
Duration of OP	140±5.17	13,834	0.116^*
PONV	2	1	<0.001

^* Test shapiro-wilk with a confidence interval of 95% (p > 0.05)

Table 3. Characteristics of the subjects

Variable	N (%)
Physical Status
ASA II	30 (100)
Gender
Man	11 (36,7)
Woman	19 (63,3)
History of Smoking
Smokers	6 (20)
Non-smokers	24 (80)
Diagnosis
Adeno Ca Sigmoid	2 (6,6)
Ca Cervix	3 (10)
Ca Colon Ascenden	1 (3,3)
Ca Endometrium	2 (6,6)
Ca Recti	2 (6,6)
Choledocholithiasis	1 (3,3)
Cholelithiasis	5 (16,6)
Chocolate Cysts	1 (3,3)
Ovarian Cysts	3 (10)
Ampula Ateri Mass	1 (3,3)
Intra Abdominal Mass	4 (13,3)
Myoma Uteri	2 (6,7)
Post Illeustomi ec Volvulus	1 (3,3)
Tumor Colon Ascenden	1 (3,3)
Ovarian Tumors	1 (3,3)

In Table 3, all subjects have ASA II physical status. Subjects were predominantly female by 19(63.3%) subjects, and nonsmokers by 24(80%) subjects. Cholelithiasis and intra-abdominal mass were the most common diagnoses found in study subjects (16.6%; 13.3%).

Table 4. Bivariate analysis

Variable	Mean/median		Value p
Variable	Group A	Group B	Value p
Age (years)	38.53±4,94	43	0.389^a
Height (cm)	157.8±4.08	156.27±3.85	0,562^b
Weight (kg)	51.93±4.07	53.53±3.6	0.647^a
BMI (kg/m²)	20	21,879 ±1.03	0.068^a
Duration of	138.33±7.73	141.67 ±7.74	0.519^b
Operation (minutes)	138.33±7.73	141.67 ±7.74	0.519^b
PONV	2	1	0,017^a

Mann-Whitney test results between PONV scores and gender showed insignificant differences (p=0.625). In addition, smoking history also showed an insignificant difference (p=0.527). This implies that the sex and smoking history in each treatment group are no different, so those risk factors did not affect the results in the study. In addition, it shows that statistically, what makes a significant difference to each group is the administration of different premedications before surgery.

Table 5. Bivariate analysis between PONV and other variables

Variable	Value p^*
Gender	0,625
Smoking history	0,527

Mann-Whitney test results (Table 4) found a significant difference in PONV scores between group A and group B with a value of p=0.017. In addition, in other variables such as age, weight, height, body mass index, and duration of surgery, there was an insignificant average difference (p>0.05). Researchers also tested confounding variables that can affect PONV scores such as gender and smoking history (Table 5).

DISCUSSION:

This study is a double-blind randomized control trial. In this study, patients were randomly selected for the treatment given. In addition, patients were unaware of the premedication given and PONV assessors in this study did not know the premedication given to the study subjects. The study used patients who had undergone laparotomy surgery with general anesthesia as the subject of the study. All patients are found to have ASA II physical status. PONV risk factors in this study were recorded, including gender, age, weight, height, BMI, physical status, PONV history, and history of disease that were considered for inclusion criteria and exclusion, where 31 samples were obtained that met the requirements. Of the 31 samples taken, one patient dropped out because the duration of the surgery was too long (>180 minutes).

Demographic data and characteristics of the subjects:

In this study, demographic data was obtained in the form of median age 41.5 years, median BB 54.5kg, and median BMI 20.5kg/m². with a mean of height 157.03±2.64cm and mean of the duration of operation 140±5.17 minutes, with normally distributed data (p> 0.05 on the Shapiro-wilk test) only height and time of operation. Besides, the female was 19(63.3%) subjects, and nonsmokers were 24(80%) subjects.

The demographic data and characteristics of the subjects in this study were not much different from studies that also examined PONV in Asia. In the double-blind study of Jeyabelan et al.¹⁰ at India, which compares ondansetron with aprepitant against PONV in patients who had a mastectomy to thyroidectomy, obtained mean of age 42.5 - 45.4 years, mean of BMI 25.6kg/m², with an operating duration of about 90-142 minutes. In addition, in the Bilgen et al.¹¹ on patients who underwent laparoscopic surgery in Turkey, the mean of age 35-40 years, the mean of weight 66.8kg, the mean of the height of 166.68cm, the number of men as much as 19.4%. The number of women as much as 80.6% and the duration of surgery 67-74minutes.

The association of premedication combination of ondansetron and combination of Curcuma xanthorriza and Kleinhovia hospita to PONV:

In this study, a significant average difference in PONV scores was found only in premedication between the ondansetron (control) group and the combination of ondansetron with Curcuma xanthorriza and Kleinhovia hospita (p=0.017). There are variables that are not normally distributed (p<0.05), such as age, weight, and body mass index were used for the next test i.e., Mann Whitney test. Mann-Whitney test results from age, weight, and BMI found an insignificant average difference (consecutive p values: 0.389; 0.562; 0.068) so that the confounding variable did not affect PONV scores in this study. When researchers grouped PONV scores by gender and smoking history, the results showed that the average of PONV score based on the sex group (male and female) found no significant difference in PONV scores (p=0.625). Likewise, based on smoking history, the group of smokers and nonsmokers obtained no significant difference in PONV scores (p=0.527). Risk factors such as smoking history and gender also did not affect PONV scores in the study.

Due to the limited number of studies discussing the provision of Curcuma xanthorriza and Kleinhovia hospita to the incidence of PONV, there are still no studies that can be used as a comparison. However, some studies have described the benefits of methanol extract in K. hospita in reducing the effects of nausea vomiting. Khan et al.¹² comparing anti-emetic drugs with methanol extract in Rumex vasicarius using animal models, it was found that R. vasicarius doses of 150 mg/kg BW had stronger anti-emetic properties than chlorpromazine, domperidone, and metoclopramide.

A study by Shin et al.¹³on the anti-emetic effects on Alpinia officinarum in animal models found curcumin derivate from A. offcinarum can be anti-emetic in the body. Because these compounds and phenol compounds are the main constituents that show inhibitory activity and dose-dependent inhibition against vomiting nausea receptors. In addition, curcumin can be anti-inflammatory^14,15. A review study by Jacob et al.¹⁶ reports several types of research that have shown that Peroxisome Proliferator-Activated Receptor gamma (PPAR-γ) has been associated with anti-inflammatory effects. Inhibition of cell signaling pathways, Akt, NF-κB, AP-1, or JNK, has been implicated as the mechanism responsible for apoptosis induction by curcumin. Curcumin can potentiate the antitumor gemcitabine effects on pancreatic cancer by suppressing proliferation, angiogenesis and lowering regulation of nf-κB and NF-κB regulated gene products¹⁷. Therefore, curcumin-induced anti-inflammation can be caused by increased regulation of PPAR-γ through the NF-κB pathway^16,18. Furthermore, the curcumin has a role as an Anti-inflammatory agent by the inhibition of eicosanoids generating enzymes including lipoxygenases, cyclooxygenases, and phospholipase A2. The synthesis and evaluation of novel curcumin derivatives (1,7-bis(4-(3-substituted) benzoyloxy-3- mthoxyphenyl) hepta-1,6-diene-3,5-dione) acts as an anti-inflammatory agent⁹. Because inflammation plays a role in the mechanism of PONV. Anti-inflammatory pathways also play a role in lowering PONV²⁰.

Flavonoid compounds in C. xanthorhiza also reduce nausea vomiting. Flavonoids can act as anti-emetics through the 5-HT₃ receptor antagonist pathway, dopaminergic inhibition, as well as Nk₁ receptor antagonists¹². In addition, flavonoids have functions such as stabilizing cell membranes and inhibiting lipid peroxidation, increasing the content of mucosal prostaglandins and mucous in the gastric mucosa by stimulating cyclooxygenase-1 (COX-1), decreasing acid and pepsinogen secretion in the stomach^21,22,23.

Based on the above discussion, premedication of ondansetron combination with Curcuma xanthorriza and Kleinhovia hospita can effectively reduce PONV through various complex pathways due to a large number of contents. Owned by these two herbs. However, the determination of therapeutic doses and toxic doses of the administration of both herbs still needs to be investigated further.

CONCLUSION:

Nausea vomiting is a thing that often occurs in patients after undergoing surgery. In addition to the administration of antimetic drugs, feeding and herbal supplementation can be used to prevent nausea-vomiting. Premedication of the combination of ondansetron and Curcuma xanthorriza and Kleinhovia hospita in this study proved more effective than ondansetron in reducing postoperative nausea.

CONFLICT OF INTERESTS:

The authors declare that there were no conflict of interests in this study.

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Received on 09.04.2022 Modified on 14.07.2022

Research J. Pharm. and Tech 2023; 16(3):997-1001.

DOI: 10.52711/0974-360X.2023.00166