The Effect of Pre-emptive Dose of Dexamethasone on Pain, Nausea, Frequency of Vomiting, and Postoperative Restlessness in Patients Undergoing Septorhinoplasty: A Randomized Control Clinical Trial Study.

INTRODUCTION
Airway, ear, nose, and throat surgeries, including sinus endoscopic rhinoplasty–septoplasty, are among the common elective surgeries that, despite their relative simplicity, have side effects that are worrying and annoying for the patient.[1] Studies have shown that patients undergoing surgery were afraid of postoperative nausea and vomiting) PONV) to the extent of pain at the surgical site.[2] Severe and frequent PONV can cause airway bleeding, aspiration of food into the airway, and hypoxia after ear, nose, and throat surgeries.[3] Airway edema after surgery in these patients, together with the use of nasal mesh and sometimes bleeding after surgery, in total causes insufficient breathing of the patient, hidden hypoxia, and therefore the patient’s agitation, which must be treated.[3]
Opiates are generally used to treat postoperative pain, and sometimes, acetaminophen is used in the form of Apotel. Since narcotics aggravate the patient’s respiratory depression, it is better to use alternative or combined methods such as the use of Apotel or nonsteroidal anti-inflammatory drugs, each of which has its own advantages and disadvantages.[1]
Since nonsteroidal anti-inflammatory drugs increase bleeding in patients, they are not a suitable option for controlling airway pain and edema after ear, nose, and throat surgery.[4]
Bantie et al.[5] have shown that the release of serotonin during surgery from the enterochromaffin cells of the gastrointestinal tract causes the stimulation of the Vague nerve by 5-HT3 receptors, which itself acts in the direction of increasing PONV. Considering that corticosteroids reduce the production of this receptor, a justifiable mechanism to reduce PONV in the case of dexamethasone is proposed.
All the points above indicate the importance of using different methods to reduce pain and nausea after surgery. In the studies conducted between two drugs, dexamethasone and propofol for reducing these complications, it has been shown that in 24 hours after the operation, the use of dexamethasone has a better performance in reducing nausea and vomiting, but the peak effect of this drug was at first 12 hours.[5]
Dexamethasone is a steroidal anti-inflammatory with a nuclear mechanism, which by inhibiting the release of inflammatory cytokines from macrophages, monocytes, and lymphocytes reduces leukocyte infiltration and chemotaxis. Reducing edema and fibrosis is one of the proven effects of dexamethasone, but the mechanism of its effect on nausea and vomiting has not yet been proven. Some believe that it bypasses the BBB and has a direct effect on the nausea center, and some believe that it has an effect on nausea by reducing edema and inflammation.[6] The findings of a study show that the intranasal use of dexamethasone with a dose of 8 mg compared to saline is associated with a decrease in PONV and postoperative pain, a decrease in the use of ondansetron and pethidine, and an increase in patient’s satisfaction.[7]
Postoperative restlessness in the patient is also a potentially dangerous complication that can cause harm to the patient himself and to the medical personnel and cause more use of resources such as medicine and additional care. Therefore, it seems that according to previous studies and potential benefits of dexamethasone, it can be used to reduce postoperative restlessness in airway surgeries, which could cause increased inflammation, congestion, and pain in the airway and the creation of hidden hypoxemia in patients.[78]
According to the studies conducted and also the experiences of the researcher doctor, besides the importance of reducing stress and pain, nausea, and vomiting of patients before and after elective surgeries, this study aims to compare the effectiveness of dexamethasone with placebo on the incidence and severity of anesthesia complications in patients undergoing surgery septorhinoplasty.

MATERIALS AND METHODS
This study is a triple-blind, randomized controlled clinical trial study that was conducted in 2023–2024 in Kashani Hospital of Isfahan with registered ethic code IRI.MUI.MED.REC.1402.048 and IRCT code IRCT20240208060937N1. The target population of the study was patients who were candidates for septorhinoplasty.
Inclusion criteria include:

Age range of 18–55 years

ASA class I and ASAII

Absence of underlying disease including cardiopulmonary diseases and diabetes

Noninclusion criteria

No long-term use of anti-nausea and vomiting drugs

No long-term use of corticosteroids

Nonsmoking

Elective surgery

No GERD reflux

Patient’s consent to participate in the study.

Exclusion criteria

The occurrence of a disorder during the operation such as severe hemodynamic disturbances or transferring the patient to the intensive care unit that requires medical intervention

A change in the operation technique

The impossibility of collecting data until the end of the study due to reasons such as the death or unwillingness to continue the study.

The required sample size of the study using the sample size estimation formula to compare the averages and with a confidence level of 95%, a power of the test of 80%, an estimated standard deviation of postoperative pain intensity of about 1.17, and a minimum significant difference between the intervention and control groups of about 0.8, it was estimated that there were 35 people in each group.
The sampling method is easy, and the patients are included in the study in the order of the time they visited the hospital if they meet the entry requirements.
Randomization of patients between intervention and control groups was done using random allocation software (RAS). In this software, the total number of samples and the number of groups are entered into the software. The output of the software includes a list that randomly distributes the total sample volume in two groups by number. Patients were divided into two groups according to the mentioned list and according to the time of visit until the sample size reached the required number in each group [Figure 1].
The method of blinding was such that the patients and the data collector and statistical analyst were unaware of the type of drug used. The drugs were prepared by one of the operating room personnel who were not in the course of the study in similar and coded syringes and given to the project manager for injection.
The method of doing the work was that all the patients were explained about the purpose of the project before the operation, and a written consent was obtained from them to participate in the study. After the patients entered the operating room, the usual cardiovascular monitoring, noninvasive intermittent blood pressure measurement, pulse oximetry, capnography, and preoxygenation were done and the process of induction of anesthesia began. Before induction of anesthesia, necessary explanations were given to the patient about the use of the visual analog scale (VAS) in recovery to measure the intensity of pain and nausea. Anesthetic drugs for induction of anesthesia initially included 2 mg/kg propofol and then fentanyl with a dose of 2 mcg/kg and midazolam with a dose of 0.1 mg/kg and for muscle relaxation and also atracurium with a dose of 0.5 mg/kg. Masking and 100% oxygenation of the patient were done for 2 minutes, and then the patient was intubated with a suitable tube for the age and weight of the patient and the tracheal tube was fixed in place.
Before inserting the tracheal tube, the cuff of the tube was smeared with 10% lidocaine spray and then inserted into the trachea and fixed in the right place. In order to create analgesia during the operation, morphine in the amount of 0.1 mg.kg was used, and if an additional dose was needed according to the patient’s conditions, the additional dose was reinjected to the patient and recorded in the patient’s file.
Before induction of anesthesia, dexamethasone 0.1 mg/kg (about 8 mg for each adult) was injected intravenously in the first group. In the control group, normal saline was injected with the same volume and method, and anesthesia was continued with propofol at a dose of 0.1 to 0.2 mg.kg.min and remifentanil at a dose of 0.25 to 0.5 micg.kg.h.
Considering the ultimate goal of maintaining low blood pressure for the patient and desired hypotension (systolic blood pressure 70 mmHg and mean arterial pressure between 5.5 and 6 mmHg) and the different response of patients to the above drugs and different dosages, if higher doses of anesthetics are needed, in order to maintain blood pressure and heart rate in the normal range as well as sufficient depth of anesthesia, higher doses used and then the total dose of propofol and remifentanil used at the end of the procedure were recorded in the data collection form. If an additional dose of fentanyl and midazolam was needed, the amount of the used dose was recorded while injecting them.
The patient’s vital signs including systolic, diastolic, and mean arterial blood pressure; arterial oxygen saturation; and heart rate were measured and recorded before induction of anesthesia and then every 15 minutes during surgery and recovery. The amount of fluids received and the amount of bleeding of the patient were also measured and recorded. The patient’s bleeding rate was calculated based on the number of gauzes used to control the bleeding and the amount of suction (3 ml in the 10 × 10 gauze).
In the end, a dose of 0.05 mg/kg of atropine and 0.02 mg/kg of neostigmine was used to bring the patient back to consciousness. After the patient regained full consciousness and after suctioning the airway secretions, the patient’s tracheal tube was removed.
The patient’s pain and postoperative nausea were measured and recorded based on the VAS score at the end of recovery and then every 6 hours to 24 hours. When the patient became fully awake and found the ability to answer, they were asked about the severity of nausea with the taught method, and in case of a score of 3 or higher or vomiting twice, ondansetron 0.1 mg/kg was administered to control nausea. It was administered intravenously and recorded. If nausea was not controlled after 1 hour, 10 mg of metoclopramide was used intravenously and its dose and frequency of injection were recorded. The frequency of patient’s vomit was also recorded by the PACU personnel and later by researchers at ward. For the patient’s pain, if it was above 3 according to VAS, pethidine 0.5 mg/kg was injected and recorded. The restlessness of the patient was evaluated based on the score.
Also, midazolam with a dose of 0.01 mg/kg (1 mg each time) was prescribed and recorded for patients with a restlessness score of 2 or more. In case of uncontrollable restlessness, after about 15 minutes, in the case of a higher score, 2.3 mg of haloperidol was injected intramuscularly and recorded.
Anesthesia start time, surgery start and end time, endotracheal tube removal time, and recovery time based on Aldert score (Aldert score is a scale to evaluate the patient’s readiness in recovery after anesthesia, which determines discharge and includes motor activity, respiration, circulation, consciousness, O2 satutaion, urine output, feeding, pain, dressing, and ambulation)[8] were recorded in the file. If any type of painkiller and anti-nausea and vomiting drug is taken in the ward, the type and dosage used were recorded.
The time of the start of feeding and the tolerance of liquids according to the NRS score, in which they rate their nausea from 0 to 10 (scores 1–3 indicate MILD, 4–6 MODERATE, and 7–10 SEVERE) were recorded in the data sheet. Before the operation, the necessary explanations were also given to the patient about this score.[9]
The level of patient satisfaction with the above (including reduction of pain, nausea, vomiting, and restlessness) was measured using the VAS scale and recorded in the data record sheet.
The collected information was finally entered into SPSS version 26 software. Qualitative descriptive data were presented as numbers and percentages, and quantitative data were presented as mean ± standard deviation in the form of graphs and tables. Data analysis using Chi-square tests (to compare qualitative and nominal data between two groups), Mann–Whitney test (to compare rank data between two groups), t-test (to compare quantitative data between two groups), and the repeated measures ANOVA (to analyze the trend of changes of variables during the study time within both groups and between the two groups and also to control confounding variables) were used. All tests are analyzed at a significance level of P < 0.05.

RESULTS
In this study, 70 septorinoplasty candidate patients were assigned to two groups of 35 people receiving dexamethasone or normal saline. During the study, two patients from the dexamethasone group and three patients from the normal saline group were excluded because the anesthesia was induced with isoflurane due to adequate propofol storage.
In the initial review, according to Table 1, the two studied groups had no significant differences in terms of the distribution of demographic variables, including age and gender distribution, weight, body mass index, ASA, and underlying diseases.
According to Table 2, the group receiving dexamethasone and the control group were not significantly different in terms of duration of operation and anesthesia time, volume of fluids received, amount of bleeding, and consumed drugs including fentanyl, remifentanil, propofol, and midazolam. Also, during the period of patients’ stay in PACU, patients who received midazolam during operation were considerably few in the intervened group in comparison to the control group (P ˂ 0.001).
Table 3 shows the mean and standard deviation of the hemodynamic parameters of the patients before, during, and after the operation, separated into two groups. According to the T-test, none of the parameters including systolic blood pressure (P = 0.299), diastolic blood pressure (P = 0.11), heart rate (P = 0.52), SPO2 (0.91), heart rate (P = 0.46), and mean blood pressure (P = 0.52) before, during, and after the operation did not have significant differences between the intervention and control groups. In intragroup studies with analysis of variance with repeated data, there was a significant difference in the change process of all parameters except SPO2 (P = 0.43) from before to the end of the operation. Also, in the intergroup analysis with the mentioned test, there was no significant difference between the hemodynamic parameter changes between the intervention and control groups. Figures 2-5 show the changes in hemodynamic parameters in two groups.
In recovery, nine people from the dexamethasone group and 22 people from the normal saline group had restlessness (28.1% vs 66.7%) and the incidence of restlessness in recovery was significantly higher in the control group (P = 0.002). The average restlessness score measured by VAS score in the dexamethasone and normal saline groups was 0.94 ± 0.29 and 2.42 ± 0.39, respectively, and the difference between the two groups was significant (P = 0.004). Also, three people (9.4%) from the dexamethasone group and nine people (27.3%) from the normal saline group received midazolam in recovery, and the difference between the two groups was significant (P = 0.043).
According to Table 4, there was a significant difference between the two groups in the average pain intensity at the time of recovery (0.031). Also, 6 hours (P = 0.016), 12 hours (P=<0.001), 18 hours (P = 0.013), and 24 (P = 0.009) hours after the operation, the control group had higher pain intensity. In the intragroup analysis, the trend of changes in pain intensity from the beginning of recovery to 24 hours after the operation was decreasing in both groups. In the intergroup analysis, there was a significant difference in the changes in pain intensity between the two groups (P = 0.005), and the group receiving dexamethasone experienced a greater decrease in intensity (P ˂ 0.001).
Examining the severity of nausea from PACU until 24 hours after surgery showed that the dexamethasone group had less nausea at the PACU (P ˂ 0.001). Also, 6, 12, 18, and 24 hours after the operation, the nausea intensity was less in this group (P˂ 0.001). In the intragroup analysis, there was a decreasing trend in the changes in the severity of nausea in both groups, but in the intergroup comparison, there was no significant difference in the changes in the severity of nausea between the two groups (P = 0.11). It should be noted that during the mentioned period, six people (18.8%) from the dexamethasone group and 14 people (42.4%) from the control group had nausea and they received ondansetron as an antiemetic drug and the intervened group consumed significantly less antiemetic drug (P = 0.037). Regarding the matter of frequency of vomit, three subjects (9.4%) from the dexamethasone group have vomited and seven subjects from the control group vomited after surgery and differences between these two groups were not statistically significant (P = 0.3).
There was a significant difference in the frequency of receiving painkillers in both the intervention and control groups, and dexamethasone recipients received less painkillers (P = 0.019).
The survey of patients’ satisfaction showed that the frequency of people who were completely satisfied with the anesthesia method and postoperative complications including PONV and restlessness was higher in the dexamethasone group, but overall, there was no significant difference in patient satisfaction between the two groups (P = 0.295).
Regarding fluid tolerance in the ward, one person (3.1%) from the dexamethasone group and ten people (30.3%) from the normal saline group had fluid intolerance, and the difference between the two groups was significant (P = 0.003).
There was no significant difference between the two groups in the frequency of receiving painkillers (P = 0.14) and antinausea (P = 0.50) in the ward. The average time to start feeding in the intervention and control groups was 1.7 ± 0.095 and 1.94±0.085 hours after the operation, respectively, and the start time of feeding was shorter in the dexamethasone group (P = 0.042).
The average fluid consumption in the ward was also significantly higher in the dexamethasone group. The rate of fluid consumption on the first postoperative day was significantly higher in the dexamethasone group (P = 0.033).

DISCUSSION
Postoperative nausea and vomiting are the common side effects, and so far, no single theory has been proposed for its prevention. This study was conducted to determine the effect of pre-emptive single dose of dexamethasone on pain, nausea, vomiting, and postoperative restlessness in patients undergoing septorhinoplasty.
The findings of the study did not show a significant difference between the two groups of dexamethasone and normal saline in terms of the distribution of demographic and baseline variables.
Examination of hemodynamic parameters did not show any significant difference during the operation and recovery between the two groups, and there was no case of serious hemodynamic disorder requiring immediate medical intervention in the patients, so it is harmless to use a dose of 0.1 mg/kg of dexamethasone in these patients. The results of a study conducted by Doksord and his team conceded the fact that there are trivial hemodynamic hazards in use of dexamethasone as a pre-emptive drug.[10]
According to the present study, patients receiving dexamethasone had less postoperative nausea and less antiemetic drug use, and even the frequency of vomit did not decrease significantly in this group (P = 0.3); it could be explained by preventive administration of antiemetic drug in patients with nausea. These statistics are reconcilable with established outcomes of two robust meta-analyses done by Li and ZU, in which they investigated 614 and 2180 patients, respectively, and espoused the idea that administration of dexamethasone is a pragmatic approach to prevent PONV and excessive antiemetic use after thyroid surgeries.[1112]. Also, more recent studies have shown that the use of dexamethasone not only reduces the side effects of septorhinoplasty surgery but also improves the tissue side effects of the operation such as ecchymosis and edema, although no investigation did on this matter in our study.[13] A study showed that intranasal dexamethasone administration is a safe and effective method and can be associated with reduced incidence of nausea and vomiting and pain after hysterectomy.[14]
Barzanji et al.[15] suggested no significant difference in the incidence of nausea and vomiting between ondansetron–dexamethasone and metoclopramide–dexamethasone groups following laparoscopic gynecological surgery.
In the study of Gandomi et al.,[16] the use of 8 mg intravenous dexamethasone was effective in reducing the incidence of nausea and vomiting after tympanomastoidectomy surgery. On the other hand, in a meta-analysis study, there was not a tangible advantage in use of extra dose of dexamethasone in controlling PONV and it was suggested that although dexamethasone administration reduces PONV in various surgeries and there was a striking difference between control and intervened groups, this gap was miniscule along 4 mg and 8 mg groups. Although this parameter was not included in our study, the point worth mentioning is practicality of dexamethasone even at small doses in diminishing PONV as a complication that is relevant to our research.[17] Even though all studies above accumulated enough data for us to build the foundations of our studies and they all inspected a wide range of surgeries, the majority of these studies were conducted on PONV in thyroidectomy, pediatric surgeries, and other otorhinolaryngology surgeries. This fact proves the importance of our research as an approach to find the effects of dexamethasone in preventing PONV that is serious complication in septorhinoplasty as a common elective surgery worldwide.
In our study, the results showed a valuable decrease in pain and need for analgesic during recovery (0.031) and also 6 hours (P = 0.016), 12 hours (P=<0.001),18 hours (P = 0.013), and 24 (P = 0.009) hours after the operation. Our results are backed up with a meta-analysis by Cheng that included 734 undergoing thyroid surgeries showed an astonishing drop of pain and analgesic use.[18] In the study of Yayik et al., they measured effectiveness of bupivacaine and bupivacaine + dexamethasone in pain control in nasal surgery with the primary objective of comparing a local nerve blocker and a local nerve blocker + anti-inflammatory. This randomized clinical trial indicated that postoperative pain was lower in the dexamethasone group that validates our finding in a way that even if dexamethasone is used as a complementary drug, we would expect to see a considerable fall in pain and pain control-related complications.[19]
In Frelich et al.’s studies, which followed a similar issue in pediatric endoscopic adenoidectomy surgeries, there was a big difference between the control group and the group that received dexamethasone.[20]
As illustrated, most studies conducted with the aim of determining the effect of dexamethasone in decreasing pain after otorhinolaryngology surgeries did not examine the effectiveness of dexamethasone alone nor did they have the objective to investigate pre-emptive effects of dexamethasone in septorhinoplasty that emphasize on the importance of conducting our study even more.
Regarding the issue of postoperative restlessness in our study, it revealed a notable decline in patients’ restlessness and midazolam consumption in PACU. In a comprehensive RCT conducted by Sun et al., a decrease was reported in pediatric laparoscopic hernia repair candidate agitation and restlessness after operation who received preventive dexamethasone that is totally compatible to our studies.[21]
According to the findings of the present study, the use of dexamethasone had a significant effect on increasing fluid tolerance and also consuming more fluids up to 24 hours after surgery in the ward, while the amount of ondansetron and painkillers received in the dexamethasone group and the control group in the ward did not differ, which could be explained by administration of analgesic, sedative, and antiemetic drugs at PACU. Therefore, it seems that the significant difference between the two groups in the severity of PONV was due to the type of pre-emptive medicine used before the operation. At the same time, considering the limitations of this study, especially the small size of the sample for evaluating all the factors, the generalization of the results to all the patients’ needs further investigation and study. On the other hand, considering the adverse effects of dexamethasone in adults, especially the increase of blood sugar levels, in order to explore the systemic effects of this drug, it is suggested to conduct more studies on the effect of dexamethasone with various doses and in larger populations with an emphasis on following blood glucose after administration of dexamethasone that could provide data for concealed detrimental effects of this drug.
Eventually, the mentionable fact is that studies conducted by pervious teams to examine effects of pre-emptive and preventive doses of dexamethasone to lower the complications of otorhinolaryngology surgeries did not aim to determine the role of single dose of dexamethasone in prevention.

CONCLUSION
The findings of the present study showed that the use of intravenous dexamethasone at a dose of 0.1 mg/kg before induction of anesthesia is associated with a reduction in the intensity of pain and nausea and the need for painkillers and antinausea drugs, without causing serious hemodynamic disorders. Therefore, it seems that the use of this drug with the mentioned dose in septorhinoplasty patients is associated with a reduction in postoperative complications.

Conflicts of interest
There are no conflicts of interest.