A Comparative Clinical Study of Methylprednisolone with Ondansetron versus Ramosetron in Preventing Postoperative Nausea and Vomiting in Patients Undergoing Middle-Ear Surgeries.

Background: One of the most troublesome complications after middle-ear surgeries has been postoperative nausea and vomiting (PONV). A notable decrease in PONV has been observed with the use of 5-hydroxytryptamine type 3 receptor antagonists and glucocorticoids. Aim: This study aimed to evaluate the effectiveness of the combination of intravenous methylprednisolone and ondansetron with ramosetron alone in preventing PONV in patients undergoing middle-ear surgeries. Settings and Design: This was a prospective, randomized, double-blind study that comprised sixty patients in the age group of 18-60 years belonging to the American Society of Anesthesiologists (ASA) physical status classification I or II and undergoing middle-ear surgery. Materials and
Methods: With the help of computer-generated randomization table, sixty patients in the age group of 18-60 years belonging to ASA physical status classification I or II and undergoing middle-ear surgery were randomly allotted to receive a combination of methylprednisolone 40 mg (given at the beginning of surgery) and ondansetron 4 mg (given near the end of surgery) (Group MO, n = 30) or ramosetron 0.3 mg (near the end of surgery) (Group R, n = 30). In both the groups, the incidence of PONV was studied. Statistical Analysis: Chi-square test or Fisher's exact test was utilized to analogize the categorical variables. Independent t-test was utilized to analogize the continuous variables.
Results: In the first 2 h after the surgery, the difference between the two groups regarding the incidence of PONV was insignificant. Between 2 h and 24 h, the incidence of nausea was lowered significantly in the group MO compared to the group R (P = 0.01). Between 24 h and 48 h, the incidence of nausea was more in group R compared to the combination therapy group, which was statistically significant.
Conclusion: The combination therapy is better than ramosetron alone for the prevention of PONV after middle-ear surgery. Therefore, we advocate a combination of methylprednisolone and ondansetron for prophylaxis for PONV in middle-ear surgeries. Copyright:

INTRODUCTION

One of the most troublesome complications after middle-ear surgeries has been postoperative nausea and vomiting (PONV). It can lead to medical complications, unanticipated admissions, and prolonged stay in the postanesthesia care unit.[123] PONV can be very discomforting for the patient and may postpone oral intake.

Ondansetron, a 5-hydroxytryptamine type (35-HT3) receptor antagonist provides a significant reduction in early PONV.[4] It is an effective drug for both prophylaxis and treatment of PONV. Ondansetron was considered to be the first universally effective antiemetic for PONV, and it was later found to have less anti-nausea and more anti-vomiting efficacy.[5]

Both early PONV and late PONV have been efficaciously minimized by ramosetron, a relatively newer long-acting 5-HT3 antagonist when compared to ondansetron.[6]

Glucocorticoids like dexamethasone and methylprednisolone have been proved to exhibit very good antiemetic properties. The mechanisms behind their antiemetic effect have not been well understood. Conventionally, dexamethasone has been found to be very effective in the prevention of nausea and vomiting following chemotherapy and so also in the prevention of postoperative nausea and vomiting.[7] Similarly, methylprednisolone has also been shown to be successful in the prevention of chemotherapy-induced emesis.[89]

Ondansetron was useful mainly in the prevention of early PONV,[4] and dexamethasone was mainly useful in the prevention of late PONV.[101112] Their combination was found to be more successful than individual drugs in reducing the incidence of PONV following middle-ear surgeries.[13]

Methylprednisolone has also been found to be effective in prevention of late PONV.[1415] A Medline search to the best of our ability did not find a study which has evaluated/compared the virtue of methylprednisolone in reducing the incidence of PONV following middle-ear surgeries. Hence, the present study was planned to compare the efficacy of the combination of intravenous (i.v.) methylprednisolone and ondansetron with ramosetron alone in preventing PONV in patients undergoing middle-ear surgeries.

MATERIALS AND METHODS

A prospective, randomized, double-blind study was designed to compare the efficacy of the combination of i.v. methylprednisolone and ondansetron with ramosetron alone in preventing PONV in patients undergoing middle-ear surgeries. Institutional ethical clearance (Letter no. MIMS/IEC/2019/336 dated 25/10/2019) was obtained from our Institutional ethical committee. Written informed consent was obtained for participation in the study and use of the patient data for research and educational purposes. All procedures followed the guidelines laid down in the Declaration of Helsinki 2013.

The study group consisted of sixty patients undergoing middle-ear surgery between the age of 18–60 years belonging to American Society of Anesthesiologists physical status classification I or II. The exclusion criteria for this study included a history of recent antiemetic medication or steroid use by the patients. Patients who fulfilled all inclusion criteria were informed about the study and written consent was obtained. Patients were premedicated the night before and on the morning of surgery with tablet diazepam (10 mg, PO) for anxiolysis. Patients were administered general endotracheal anesthesia with i.v. fentanyl (2–3 μg.kg−1), propofol (2 mg.kg−1), and vecuronium (0.1 mg.kg−1) and were maintained with sevoflurane 2%–2.5% with 60% nitrous oxide in oxygen. An end-tidal concentration of CO2 between 35 and 40 mmHg was maintained with controlled mechanical ventilation. During intraoperative period, heart rate, mean arterial pressure, and minimum anesthetic concentration (MAC) were noted every 5 min during surgery. i.v. diclofenac 75 mg infusion was administered during the intraoperative period. At the end of the surgery, i.v. neostigmine (50 μg.kg−1) and glycopyrrolate (10 μg.kg−1) were administered to reverse the neuromuscular block. Trachea was extubated, after the clinical computation of degree of the reversal of neuromuscular block. The postoperative pain relief was provided to all patients by i.v. morphine 0.1 mg.kg−1 administered near the end of surgery. Throughout the perioperative period, the maintenance i.v. fluid (crystalloid) was administered at the rate of 2 ml.kg.h−1. Block randomization was done by a computer-generated random number list. With the help of this computer-generated randomization list, either a combination of methylprednisolone 40 mg (given at the beginning of surgery) and ondansetron 4 mg (given near the end of surgery) (Group MO, n = 30) or ramosetron 0.3 mg (near the end of surgery) (Group R, n = 30) was administered randomly to the patients. Anesthesiologist 1 who administered the general anesthesia and study drugs was aware of the randomization, but anesthesiologist 2 who recorded and analyzed the variables was blinded to the treatment group. The primary efficacy variables analyzed were the incidence and severity of PONV in the first 48 h after the surgery. Secondary efficacy variables analyzed included the use of additional rescue antiemetic, pain intensity, and medication-associated complications.

Assessments were conducted in the first 2 h, 2–24 h, and 24–48 h postoperatively. The severity of nausea was graded as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Visual analog scale (VAS) was utilized to gauge the intensity of postoperative pain which varied from 0 (no pain) to 10 (worst pain imaginable). As rescue antiemetic, i.v. prochlorperazine 25 mg was used to treat the patients who developed nausea or vomiting in the postoperative period. Any case of intractable PONV in spite of administering rescue antiemetics was managed with dexamethasone or any other antiemetic. Pethidine was used as a breakthrough analgesic if the patient complained of pain ≥5 on VAS. The patients were inquired about the common side effects of medication, namely headache, dizziness, drowsiness, constipation, and flushing.

Using SPSS ver. 20.0 (SPSS Inc., Chicago, IL, USA), statistical analysis was done. Chi-square test or Fisher's exact test was utilized to analogize the categorical variables. Independent t-test was utilized to analogize the continuous variables. Data were presented as mean ± standard deviation or as the number of patients and percentages. P < 0.05 was considered statistically significant.

RESULTS

The effectiveness of the study was analyzed in all sixty patients who completed the study protocol [Figure 1]. There was no significant difference between the two groups regarding the patient's characteristics, duration of surgery or anesthesia, incidence of motion sickness or history of PONV, and nonsmoking status [Table 1]. With regard to measured mean arterial pressure, heart rate, and MAC values, there was no significant difference between the groups. The calculated Apfel simplified score was also comparable between the groups [Table 2].

Figure 1

Consort flow diagram

Table 1

Patient characteristics, surgery, and anesthetic data

	Group MO	Group R	P
n	30	30
Age (years)	31±3.5	29±2.9	0.08
Weight (kg)	56±4.8	58±2.6	0.07
Sex, male/female	18/12	20/10	0.35
Nonsmoker	23	21	0.29
History of motion sickness or history PONV	4	5	0.06
Anesthesia duration (min)	204±1.5	199±2.6	0.45
Duration of surgery (min)	188±5.4	187±2.4	0.34
Dose of morphine (mg)	5.5±0.4	5.7±0.6	0.09
Ossiculoplasty	4	5	0.11

PONV=Postoperative nausea and vomiting

Table 2

Apfel score among the study population

Apfel’s score	Group MO	Group R
1	5 (16.7)	4 (13.4)
2	12 (40)	14 (43.3)
3	13 (43.3)	12 (40)
4	0	0

In the first 2 h after the surgery, the difference between the two groups with regard to the incidence of PONV was insignificant. Between 2 h and 24 h, the incidence of nausea was significantly lower in the methylprednisolone and ondansetron group compared to the ramosetron group (P = 0.031). The incidence of vomiting and use of rescue antiemetic were not different between the groups. The patients who never developed nausea or vomiting were considered to have had complete responses [No PONV in Table 3]. Between 2 h and 24 h, higher number of patients in the methylprednisolone and ondansetron group had a complete response compared to the ramosetron group (P = 0.036).

Table 3

Incidence and severity of nausea and vomiting and requirements for rescue antiemetic treatment

	Group MO	Group R	P
First 2 (h)
Nausea: Mild/moderate/severe	1/3/2	1/4/2	0.12
Vomiting	5	6	0.23
Rescue antiemetic	5	6	0.23
No PONV	24	23	0.32
First 2-24 (h)
Nausea: Mild/moderate/severe	1/3/3	3/7/5	0.031
Vomiting	5	7	0.23
Rescue antiemetic	5	7	0.23
No PONV	23	15	0.036
First 24-48 (h)
Nausea: Mild/moderate/severe	0/3/4	6/7/6	0.014
Vomiting	4	8	0.018
Rescue antiemetic	4	8	0.018
No PONV	24	11	0.021
No PONV in 48 (h)	23	11	0.032
Side effects
Headache	3	4	0.15
Dizziness	2	3	0.21

PONV=Postoperative nausea and vomiting

Between 24 h and 48 h, the incidence of nausea was more in the ramosetron group compared to the combination therapy group, which was statistical significance (P = 0.014). Between 24 h and 48 h, the complete response was significantly higher in methylprednisolone and ondansetron group compared to the ramosetron group (P = 0.021). Overall, a higher number of patients had a complete response in the methylprednisolone and ondansetron group compared to the ramosetron group (P = 0.036) [Table 2]. Incidences of side effects were not different between the groups [Table 3]. There was no significant difference in the pain scores between the groups [Table 4].

Table 4

Pain scores

	Group MO	Group R	P
VAS score in the first 2 (h)	1.8±1.0	2.0±1.1	0.43
VAS score in 2-24 (h)	2.7±0.9	2.8±0.8	0.32
VAS score in 24-48 (h)	2.9±1.3	3.0±1.1	0.40

VAS=Visual Analog Scale

DISCUSSION

PONV is a frequent, minor, and troublesome problem faced after middle-ear surgeries. Without the use of antiemetic agents, the incidence goes up to as high as 80%.[1] Multiple factors will determine the incidence of PONV after middle-ear surgeries. The presence of an abundance of 5-HT3 receptors in the proximity of trigeminal nerve and vestibular labyrinth increases the risk of PONV and simultaneously makes the 5-HT3 receptor antagonists as one of the most potent drugs in the prevention and treatment of PONV following middle-ear surgeries.[2] Early PONV has been more effectively prevented by ondansetron than late PONV, as it has a shorter duration of action (4 h). In contrast, corticosteroids have been found to be more effective in the prevention of late PONV.[345] Serotonin inhibition in the gut through prostaglandin antagonism and reduction in tissue inflammation have been proposed as the possible mechanisms of effect of corticosteroids. Corticosteroids are known to enhance the antiemetic effect of conventional antiemetic drugs such as 5-HT3 antagonists by sensitizing their receptors.[9] Consequently, the prevalence of both early and late nausea and vomiting can be more effectively reduced by an alliance of ondansetron and methylprednisolone than each of the drugs administered alone. As labyrinthic stimulation persists for a longer duration following any middle surgeries, ondansetron, a short-acting 5-HT3 receptor antagonist, may not be effective in preventing PONV following middle surgeries. Hence, combining ondansetron with corticosteroids (dexamethasone and methylprednisolone) will be a legitimate combination, as latter is effective for late-onset PONV.

Ramosetron, a relatively newer 5-HT3 receptor antagonist, has been found to be more promising than ondansetron with respect to the prevention of PONV because of its longer duration of action.[6] Its higher affinity for receptor, thus slower rate of dissociation from the target receptor, is responsible for its longer duration of action.[6] The elimination half-life of ramosetron is also longer than that of ondansetron (9 h vs. 3.5 h).[6] Ramosetron has been found to be more efficacious than ondansetron in the prevention of PONV after various surgeries as per the results of many studies.[8101112] Moreover, studies have shown that the addition of dexamethasone to ramosetron did not provide any additional antiemetic benefit over ramosetron alone,[16] and also, the efficacy of combination of ramosetron and dexamethasone has been found to be similar to that of ondansetron and dexamethasone,[17] thus indicating that the addition of corticosteroids to more potent and long-acting 5-HT3 antagonists like ramosetron may not provide any additional pharmacodynamic benefit.[17]

There are studies comparing the antiemetic effect of ramosetron with a combination of ondansetron and dexamethasone,[15] but there is no study comparing the efficacy of combination of methylprednisolone and ondansetron against ramosetron alone in the prevention of PONV. Consequently, this study was designed to compare the combination of ondansetron and methylprednisolone against ramosetron for the prevention of early and late PONV (up to 48 h) after middle surgery. We observed that PONV was better prevented by the combination of two antiemetics, ondansetron and methylprednisolone than ramosetron alone after the middle surgeries. The outcome of our study is comparable to the conclusion drawn in other studies, which propound that the combination of corticosteroid and 5-HT3 antagonist provides better prophylaxis against PONV than 5-HT3 antagonist alone.[131415] Thus, our study reaffirms that methylprednisolone like dexamethasone can be a very effective antiemetic, more so in combination with 5-HT3 receptor antagonists probably because of their different mechanisms of action. The limitation of this study was that we did not have a combination ramosetron and methylprednisolone group for comparison. Further studies on the combination of ramosetron and methylprednisolone are needed. The outcome of our study may be relevant to all the surgeries which are associated with long duration of nausea and vomiting.

Hence, the combination of methylprednisolone and ondansetron is superior to ramosetron for the prevention of PONV after middle-ear surgery. Therefore, we recommend a combination of methylprednisolone and ondansetron over ramosetron for the prevention of PONV in middle-ear surgeries.

CONCLUSION

The combination therapy of methylprednisolone and ondansetron is better than ramosetron alone for the prevention of PONV after middle-ear surgery. Therefore, we advocate a combination of methylprednisolone and ondansetron over ramosetron alone for PONV prophylaxis in middle-ear surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.