Minimum Effective dose of Dexamethasone in Combination with Midazolam as Prophylaxis against Postoperative Nausea and Vomiting after Laparoscopic Cholecystectomy.

BACKGROUND: Postoperative nausea and vomiting (PONV) affects 20% and 30% of patients. As many as 60%-80% patients at high risk may be affected. Dexamethasone (D) and midazolam (M) are well studied as antiemetic. Use of D can be associated with certain undesirable side effects so minimum dose is preferred. M is a routinely used premedicant. Hence, this study was designed with both D and M in high risk patients for PONV to find minimum effective dose of D. AIMS: To determine the minimum dose of D that combined with M would provide effective prophylaxis of PONV after laparoscopic cholecystectomy (LC) in patients at high risk for PONV. SETTING AND
DESIGN: This is a prospective, randomized double-blind trial.
MATERIALS AND METHODS: One hundred and fifty-five patients scheduled for elective LC were randomized to 5 groups of 31 each. Group C was given normal saline, and the rest were administered D 1 mg (group MD1), 2 mg (group MD2), 4 mg (group MD4), or 8 mg (group MD8) in combination with 0.04 mg/kg M at induction. The incidence of nausea, vomiting, severity of nausea, and the use of rescue antiemetic and postoperative pain was analyzed. STATISTICAL ANALYSIS: Chi-square test was used to compare incidence of study variables. Independent Student's t-test was used for continuous variables. Demographic data were compared using ANOVA. P < 0.05 was considered statistically significant.
RESULTS: The incidence of nausea was significantly lower in group MD4 (29%) and MD8 (6%) compared to placebo group (71%) (P < 0.001) and of vomiting was significantly lower in groups of MD2 (58%), MD4 (48%), and MD8 (6%) compared with placebo (90%) (P < 0.001) at 24 h. There was significant reduction in nausea, pain severity, and incidence of use of rescue antiemetic in MD4 and MD8 groups with no discernable side effects of the drugs.
CONCLUSION: We conclude that 4 mg D with M and 2 mg D with M is effective for prevention of nausea and vomiting, respectively, in patients at high risk for PONV undergoing LC.

INTRODUCTION

Postoperative nausea and vomiting (PONV) is known to occur within 24 h (h) after surgery, affecting 20%–30% of the patients.[12] Various scoring systems have been devised to identify patients at high risk.[34] According to Apfel simplified scoring system, the incidence of PONV is quantified according to number of risk factors, namely, female gender, prior history of motion sickness or PONV, nonsmoking, and the use of postoperative opioids. If none, one, two, three, or four of these risk factors were present, the incidences of PONV were 10%, 21%, 39%, 61%, and 79%, respectively.[34] The incidence of PONV has also been reported to be very high in some commonly performed procedures such as laparoscopic cholecystectomy (LC), middle ear, and ophthalmic surgeries. It has been reported to be as high as 46%–75% after LC in patients who did not receive antiemetics.[5] Factors such as a prolonged period of exposure to CO2, female sex, and postoperative pain may contribute to PONV in this subset of patients.[124]

Prophylaxis using two or more antiemetics is recommended for patients at high risk of PONV. The effect of antiemetics acting on different receptors is additive. The efficacy of drugs is also optimized when a combination of drugs with different mechanisms of action are administered.[67] Various antiemetic drugs such as metoclopramide, ondansetron, dexamethasone, midazolam, antihistamines, and butyrophenones have been tried alone or in combination, but have undesirable side effects.[8]

Midazolam (M) is a short-acting drug with rapid onset of action and has been used for reducing PONV in LC in a dose of 0.075 mg/kg, while a dose of 0.04 mg/kg effectively reduced prolonged postoperative emesis in cancer patients treated with cytotoxic drugs.[910] A meta-analysis on the effect of intravenous (i. v.) M on PONV revealed that in studies involving high-risk surgeries for PONV, M was associated with a significantly lower incidence of 24 h PONV when used as combination therapy. Both lower dose (<0.05 mg/kg) and higher dose (≥0.075 mg/kg) resulted in similar efficacy in reducing PONV within 24 h.[11] It is routinely used for premedication in surgery. Dexamethasone (D) in a dose of 8–10 mg has been used frequently in the prevention of PONV.[12] In addition to reducing PONV, D has anti-inflammatory effects that may decrease postoperative tissue edema and analgesic consumption. Furthermore, use of D can be associated with certain undesirable side effects and so minimal dose is preferred.[131415] In comparison to other effective antiemetics, these drugs are relatively cost effective.

With respect to the high incidence of PONV after LC, especially with high-risk patients, the need to find minimum dose of D to decrease side effects, no previous dose escalation study been done with M and D, and in addition both the drugs being cost effective, we designed this drug combination to evaluate the minimum effective dose of D that may be used along with M to provide effective relief from PONV to this group. We also assessed secondary outcomes such as incidence of use of rescue antiemetic and rescue analgesic, dose of analgesic, and the relationship to the severity of pain.

MATERIALS AND METHODS

After obtaining approval from the institutional ethical committee and written informed consent from patients, 155 patients with physical status American Society of Anesthesiologist Classes I and II, aged 18–60 years, all females, nonsmokers, who were given perioperative opioids, and were undergoing general anesthesia for elective LC were included in this prospective, randomized, double-blinded placebo controlled study over 1½ years. Assuming that average incidence of PONV following LC in high risk patients is 70%, to have 80% power (α =0.05), to detect a reduction to 35%, one would need to study 31 patients per group. Patients with a history of motion sickness, smoking, chronic respiratory disease, and bronchial asthma, patients with cardiac, pulmonary, renal, or neuromuscular disorders, and patients with contraindication of laparoscopic surgery like those with history of previous abdominal surgery were excluded from the study. Patient characteristics recorded preoperatively were age, weight, height, body mass index, and duration of surgery.

Patients meeting the inclusion criteria during the preanesthetic checkup were randomly allocated to one of five equal groups (n = 31 each) using a computer-generated random number table [Figure 1]. Study medications were prepared in two syringes with 3 mL (midazolam/normal saline) and 2 ml (dexamethasone/normal saline) of solution for each patient, by a nurse who was not part of the study and handed over to the respective OT anesthesiologist. The study groups were as follows: C-Normal saline, MD1 - Midazolam 0.04 mg/kg + Dexamethasone 1 mg, MD2 - Midazolam 0.04 mg/kg + Dexamethasone 2 mg, MD4 - Midazolam 0.04 mg/kg + Dexamethasone 4 mg, and MD8 - Midazolam 0.04 mg/kg + Dexamethasone 8 mg. The patient and investigators were blinded to the study medication.

Figure 1

Consort Flow Diagram

All patients were premedicated with tablet lorazepam 0.04 mg/kg and ranitidine 150 mg at night and 2 h before surgery with sips of water. On arrival to operation room, i. v. assess was achieved with 18-gauge venous cannula. Monitoring consisted of 5-lead electrocardiography, pulse oximeter, noninvasive blood pressure, temperature, and end-tidal CO2 monitoring. Study medications were administered i. v. at induction of anesthesia by the anesthetist who was blinded to group allocation. Following preoxygenation with 100% oxygen, patients were induced with fentanyl 2 μg/kg and thiopentone sodium (3–5 mg/kg). Intubation was facilitated by vecuronium bromide 0.1 mg/kg and thereafter mechanical ventilation was initiated. Anaesthesia was maintained using 70% nitrous oxide in oxygen and isoflurane 0.5-1% and intermittent boluses of fentanyl and vecuronium as and when required. Injection diclofenac sodium was administered intramuscularly 30 min prior to extubation. At the end of the surgery, reversal of anesthesia was done with injection neostigmine 0.05 mg/kg + glycopyrrolate 0.01 mg/kg and patients were transferred to the postanesthesia care unit (PACU).

Data collection and analysis was done by another investigator. All the episodes of nausea and vomiting while in the hospital, during the 0–6 h, 6–12 h, and 12–24 h intervals after surgery, were recorded and the severity of nausea and pain was recorded using a 10-point visual analog scale (VAS, 0 = no nausea and 10 = maximum nausea).[16] Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit. Vomiting was the forceful expulsion of gastric contents from the mouth. If patients experienced nausea of more than 5 on VAS scale or for more than 30 min or an emetic episode occurred, rescue antiemetic treatment, consisted of metoclopramide 10 mg i. v., was given. The intensity of postoperative pain was measured between initial 6 h using a 10 cm VAS (0 = no pain and 10 = most severe pain), as the patients stayed in the PACU for about 6 h and i. v. opioid administration in the ward is not practiced in our institute. For postoperative pain management, fentanyl 0.5 ug/kg i. v., repeated in 5 min as required, was used in all patients for the first 6 h if pain on a 0–10 VAS scale was more than 3. The total doses required over 6 h were calculated. Side effects from use of any of the study drugs (itching, urinary retention, constipation, and dizziness) were recorded.

Statistical analysis

Data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 17 (IBM SPSS Inc, Version 17.0, Armonk, NY :IBM Corp). Chi-square test was used to compare the incidence of PONV between control group and different experimental groups. ANOVA was used to compare baseline parametric variables. Independent Student's t-test was used to compare between continuous variables, i.e., group differences in duration of analgesia. P < 0.05 was considered statistically significant. The values were represented in number of patients, %, and mean ± standard deviation.

RESULTS

Demographic data were comparable among all the groups (P > 0.05) [Table 1]. Over 24 h, the incidence of nausea reduced significantly from 71% in control to 29% and 6% in Group MD4 and Group MD8, respectively (P < 0.001) [Table 2]. As with incidence, the severity of nausea was even significantly reduced in the MD4 and MD8 group (P < 0.001) [Table 3].

Table 1

Patient demographic characteristics and clinical data (n=31)

Table 2

Comparison of incidence of nausea, vomiting and use of rescue antiemetic at different time intervals till 24 hours (h) after surgery (n=31)

Table 3

Comparison of postoperative nausea severity between the groups at different time interval till 24 hours (h) after surgery (n=31)

The incidence of vomiting reduced significantly in Group MD2, Group MD4, and Group MD 8%–58%, 48%, and 6%, respectively, when compared to Group C (90%) (P < 0.001). Rescue antiemetic requirement in the 24 h postoperative period decreased by 50% in Group MD4 while in Group MD8 further reduction was found [Table 2].

Postoperative pain was assessed for initial 6 h. Groups MD4 and MD8 had significant reduction in severity of pain (P < 0.001) and in the same group incidence of use of rescue analgesia also reduced from 87% in control to 42% and 39%, respectively. However, dose of rescue analgesia used in 6 h was significantly reduced in Group MD8 only (P = 0.03) [Table 4]. In the current study, no discernable side effects were noted from any of the study drugs.

Table 4

Comparison of postoperative pain assessment between the groups at 0-6 hours (h) (n=31)

DISCUSSION

This prospective randomized study showed that combination therapy with 0.04 mg/kg M with 4 mg of D prevents nausea and 0.04 mg/kg M with 2 mg of D prevents vomiting effectively in high-risk patients undergoing LC. Our study included nonsmoker females, with use of postoperative opioids, undergoing laparoscopic surgery under general anesthesia of more than 1 h along with the use of volatile anesthetics. According to Apfel simplified risk score, these risk factors make our group of patients, a high-risk group for PONV.[345]

PONV is one of the most distressing side effects after anesthesia. The etiology of PONV has been identified to be multifactorial with the involvement of many receptors.[27] There is no “gold standard” antiemetic regimen for complete eradication of PONV, but a rational three-step approach to minimize PONV can be taken into consideration: identification of patients at risk, keeping the baseline risk low, and multimodal anti-emesis for patients who are identified as high risk patients.[1] The recommended pharmacologic antiemetic for patients at high risk for PONV is prophylactic therapy with combination (>2) interventions/multimodal therapy.[6]

There is consensus on the fact that M decreases nausea/vomiting compared to placebo. It has been postulated that a possible mechanism for the antiemetic effect of benzodiazepines could be an action at the chemoreceptor trigger zone reducing synthesis, release and postsynaptic effect of dopamine. Dopaminergic neuronal activity and 5-hydroxytryptamine release may also be reduced by binding of M to the GABA benzodiazepine complex; Thus, anxiolysis as a secondary effect may also contribute to antiemesis.[17]

Fujii and Itakura found that i. v. M alone as an antiemetic, in a dose of 0.05 mg/kg in laparoscopic gynecologic surgery, was found to be effective.[18] Furthermore, Di Florio and Goucke reported that low-dose i. v. infusion of M significantly reduces persistent PONV.[19] Honarmand et al. concluded that M 0.75 mg/kg and ondansetron 4 mg combined were better than either drug alone in PONV prevention in patients undergoing middle ear surgery.[20] Grant et al. in a recent meta-analysis analyzed that in high risk surgeries, combination therapy with either low (<0.05 mg/kg) and higher dose (≥0.075 mg/kg) midazolam lowers PONV for 24 h.[11] We used a lower dose of M (0.04 mg/kg) in this study for combination therapy.

Several studies have been conducted with D as an effective antiemetic in a dose ranging between 2.5 and 10 mg in scenarios with different risks of PONV in different surgical population.[212223] The mechanism of antiemesis is not fully understood but may involve central inhibition of prostaglandin synthesis. Another theory involves a decrease in 5HT turnover in the central nervous system.[24] As per the safety of perioperative D is concerned, the data are inconclusive. In most studies, a single dose of perioperative D does not appear to increase the risk of wound infection. However, a study by Percival et al. reported that intraoperative D 4–8 mg may confer an increased risk of postoperative infection.[13] In addition, studies showed significant increases in blood glucose that occur 6–10 h postoperatively in normal cases and type 2 diabetic surgical patients who receive D 8 mg or 10 mg.[1415] In view of this evidence, it is imperative to use minimum effective dose of the drug.

In patients undergoing LC, Elhakim et al. found 8 mg to be the minimum effective dose of D in combination with 4 mg ondansetron for PONV.[12] In a recent study, 5 mg D added to 0.3 mg of ramosetron proved better in spine surgery for PONV.[25] Yeo et al. showed that the combination of 10 mg D and 0.075 mg/kg M was better than D alone in reducing the incidence of vomiting in female patients undergoing middle ear surgery under general anaesthesia.[26] Riad et al. concluded that prophylactic M 0.05 mg/kg with or without D 0.5 mg/kg reduces the incidence of PONV in children undergoing strabismus repair.[27] In another strabismus surgery in children, Riad and Marouf used dose combinations of various agents, granisetron, ondansetron, and 50 ug/kg M with fixed dose 0.5 mg/kg D and concluded that all combinations are equally effective in decreasing the incidence of PONV.[28] El-Deeb et al. found that prophylactic use of ondansetron 4/8 mg D or 2 mg M/8 mg D, compared with placebo, was effective for reducing PONV in patients undergoing thyroid surgery. Midazolam/dexamethasone combination was preferred due to cost.[29] All these studies have used higher doses of D as well as M in comparison to our study.

In our study, fixed dose M 0.04 mg/kg was used with variable doses of D. Minimum dose for prevention of nausea was 4 mg of D and for vomiting it was 2 mg. There was significant reduction in nausea and pain severity as well as in incidence of use of rescue antiemetic and analgesics in 4 mg and 8 mg group of D compared with placebo. Our results are similar to those of Yeo et al., Riad et al., and El-Deeb et al., in that combination of study drugs is more effective for PONV prevention but our results state that lower doses of these drugs can be effective for PONV in high risk patients.

There are some limitations of our study. M as a sole antiemetic was not used in any group. Hyperglycemia as a side effect was not monitored. Another limitation was administration of fentanyl as a postoperative rescue analgesic for initial 6 h only and thus estimation of pain severity and rescue analgesic was made for initial 6 h. Larger trials are required to evaluate effect of low dose D on hyperglycemia postoperatively.

CONCLUSION

The minimum effective dose for prevention of postoperative nausea is 4 mg of D in combination with M and 2 mg for vomiting in high risk patients undergoing LC with added advantage of analgesia in the early postoperative period. Further reduction in incidence and severity of PONV can be achieved with a dose of 8 mg. Larger trials monitoring further side effects would further propose its use as a routine combination therapy for PONV in high risk surgical population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.