Spinal anaesthesia is considered as the anaesthetic technique of choice for the caesarean section owing to its safety and speed. However, there are a few trivial yet disturbing side effects observed with this technique. One of the most important is intra-operative nausea and vomiting (IONV). Nausea and vomiting during regional anaesthesia for caesarean section cause significant distress to the patient and interfere with the surgical procedure.

Comprehensive reviews on post-operative nausea and vomiting in case of caesarean section under spinal anaesthesia are widely available in various studies. But there is scarcity of literature showing reviews on IONV in case of obstetric anaesthesia. Although the incidence of IONV varied among different studies; the rates up to 60–80% being reported.[1] One of the strong associations of  IONV is immediate contractions of diaphragm which could lead to both patient discomfort and protrusion of the abdominal viscera; the latter would contribute to the increased probability of visceral injuries. From anaesthesia point of view, abrupt contractions add to the hazard of aspiration of gastric content, especially in full stomach pa-tients and are recommended to be prevented or at least reduced. This can be achieved using drugs, including droperidol, metoclopramide etc. But these drugs have some side effects such as agitation, extra-pyramidal symptoms, and dystonic reactions etc.[2,3]

The aetiologies of IONV includes progesterone-induced reduction in the lower esophageal sphincter tone, increased intra-gastric pressure, hypotension, exteriorization of the uterus, visceral stimulation, and the use of neuraxial opioids etc. Although few anti-emetics can be used prophylactically to reduce the incidence of IONV during spinal anaesthesia; there are some side effects shown. The strong diaphragmatic contractions involved in vomiting or retching can cause extrusion of abdominal contents that risk perforation of a viscus and make closure difficult if not impossible. In patients with a full stomach, there is the additional risk of aspiration.[4] The other causes of IONV includes psychogenic factors, uncorrected hypotension with concomitant hypoxia of the central nervous system, visceral traction, narcotic supplementation and inadequate sensory level of spinal anaesthesia.

Recently, it has been shown that low doses of propofol can reduce IONV during spinal anaesthesia for caesarean section more efficiently than droperidol and metoclopramide. [5,6,7]  Benzodiazepines have been reported to have some benefits with regard to nausea and vomiting by reducing anxiety via lowering dopaminergic input to chemoreceptor trigger zone (CRTZ). [8.9,10] It has been postulated that a possible mechanism for the anti-emetic effect of benzodiazepines could be an action at the chemoreceptor trigger zone. It reduces synthesis and release of dopamine and simultaneously reduces postsynaptic effect of the same. [9] Low-dose intravenous infusion of midazolam was beneficial in persistent PONV. [10]

With this background the present study was designed to compare the efficacy in between the subhypnotic doses of midazolam and propofol in preventing intra-operative nausea and vomiting (IONV) during spinal anaesthesia in case of caesarean delivery. Secondary objectives were to compare the amount of ondansetron used as an intra-operative rescue anti-emetic, the hemodynamic changes and the requirement of cumulative phenylephrine dose used to control episodes of hypotension in between these two study groups.

The study was a prospective randomised comparative study which was conducted under Department of Anaesthesiology in the Obstetrics and Gynaecology operating rooms of North Bengal Medical College and Hospital for a period of one year after getting permission of Institute’s Ethics Committee and approval from The West Bengal University of Health Sciences.

Sample size calculation: From the previous studies it was evident that the percentage of patients showing decrease incidence of IONV using propofol as anti-emetic was 25%. Expecting a 20% difference of efficacy in preventing IONV would be considered as statistically significant in between propofol and midazolam as an anti-emetic and setting the power of study at 80% with 95% confidence limit, the calculated sample size was 50 in each group. Expecting a 10% drop out, the sample size is increased to 55 patients for each group. So, for the two groups 110 patients were enrolled for this study.

Inclusion Criteria: Pregnant women who were scheduled for elective caesarean section at Obstetrics and Gynaecology operating rooms with American Society of Anaesthesiologists (ASA) physical status I & II, aged 20-30 years having regular antenatal clinic attendance with singleton pregnancy.

Exclusion criteria: Obstetric patients with ASA physical status III & IV, those with any history of diabetes, hypertension, thyroid disease, obesity, gastrointestinal disease, anaemia or any other condition requiring long-term medication and major complications of pregnancy (pregnancy-induced hypertension, preeclampsia, gestational diabetes) in the antenatal period.

Study Technique:

Eligible patients were included into the study considering both inclusion and exclusion criteria.

After selection, patients were explained about the procedure to be done and the risks as well as benefits associated with it, in their vernacular language. They were explained their right to opt out from the study at any time during the study period. A written informed consent was obtained from all patients included in this study.  All patients were fasted for eight hours before operation and pre medicated with tab ranitidine (150mg) at the night before surgery. In the operation theatre patients were randomly allotted by closed envelope technique into either of two groups, namely Group P (Propofol group) or Group M (Midazolam group). Lactated Ringer’s solution (20 mL/kg) was administered IV for all patients prior to the induction of spinal anaesthesia, which was achieved by 11mg (2.2 mL) hyperbaric bupivacaine 0.5%. To achieve the level of insensibility at T4-T5 dermatomes, the anaesthetics were injected through a 25-gauge spinal needle at L3- L4 intervertebral interspace. Patients were placed in a left tilt position to avoid aorto-caval compression. Oxygen 5 L/ min was administered via face mask. Blood pressure was monitored with an automated cuff blood pressure monitor at 2-minute intervals until neonatal delivery and then at 5-minute intervals. Hypotension, a decline of more than 20% from baseline pressure or systolic blood pressure of less than 90 mmHg, was managed with Phenylephrine (50 mcg at incremental doses).[11] Patients were randomly allocated with computer generated envelop to propofol (20 mg bolus and 1.0 mg/kg/h, n =55) and midazolam (1 mg bolus and 1mg/hr, n =55) groups. Medications used intravenously at subhypnotic doses in bolus instantly upon umbilical cord clamping and infusion was continued until the end of surgery. Nausea and vomiting were evaluated by means of Bellville scoring system (0: no symptoms, 1: nausea 2: retching 3: vomiting). [12] An anti-emetic (ondansetron 4 mg) was administered in case of two or more emesis episodes. Sedation was assessed just after delivery and during immediate post-operative period using the modified Ramsey Sedation Scoring (where 1 = awake/alert, 8 = no response to painful stimulus). [13,14]

Data were entered into a Microsoft® Excel workbook 2019 and exported to Statistical Package for Social Sciences (SPSS) (v21.0, IBM, USA) for statistical analysis. Categorical data were presented as frequencies and analysed using the Chi-square test, while quantitative data were presented as mean±standard deviation and compared using an independent t-test. Statistical significance was set at p<0.05.

The present study included 55 participants in each of the two groups, giving a total sample size of 110. All the patients in both the groups were comparable in respect of demographic parameters such as age, weight, height, BMI, gravida and ASA physical status. No significant difference was observed in between two groups regarding height of sensory block due to spinal anaesthesia as well as duration of surgery [Table/Fig-1]. Baseline hemodynamic parameters (SBP, DBP, MAP, HR), SPO2 and RR were also comparable [Table/Fig-2].

In our study, we have observed that the low incidence of nausea, retching, vomiting in both the groups [Table/Fig-3]. With respect to post operative sedation score, for group M 100% of patients showing modified ramsey sedation score 1 during immediate post operative period and for group P 98.18% of population shows sedation score 1[Table/Fig-4]. Regarding intraoperative hypotension and mean phenylephrine consumption, for group M the amount is 72.73 mcg and for group P is 120.91 mcg.

TABLE AND DIAGRAMS

[Table/Fig-1]: Comparison of Patient characteristics, Duration of surgery and Height of block achieved. Quantitative data were presented as mean±standard deviate

                   *Gravida, Sensory Height of Block, ASA status distribution are presented as frequency

[Table/Fig-2]: Comparison of Baseline Hemodynamic  parameters between two study groups

            *All values are presented as mean±SD

[Table/Fig-3]: Comparison of Frequency of intra-operative Nausea, Retching, vomiting and ondansatron consumption between two study groups

High incidence of IONV during spinal anaesthesia for caesarean section was confirmed in different previous studies. [1] The obstetric patient, due to the physiological changes of pregnancy, is prone to have nausea and vomiting. These physiological changes are composed of high level of progesterone and its subsequent smooth muscle relaxation, increased gastrin secretion, decreased gastrointestinal motility, and lowered esophageal sphincter tones, large gravid uterus compressing the stomach, alterations in small bowel transit time etc. [1,7] Another important factor which can be responsible for IONV during spinal anaesthesia is hypotension, especially in pregnant patients. [8] Hypotension occurring during neuraxial anaesthesia is one of the most important etiological factors for IONV. [1] It may lead to cerebral hypoperfusion and brainstem ischemia that may activate the circulatory, respiratory and vomiting centers in the medulla. Sympathetic block secondary to spinal or epidural anaesthesia may result in nausea and vomiting induced by gastrointestinal hyperactivity due to relative overactivity of the vagus. [1] Surgical stimuli that may be responsible for IONV include exteriorization of the uterus, intra-abdominal manipulation or exploration and peritoneal traction during closure. These manoeuvres produce visceral pain that is mediated by unmyelinated C-fibers. [15,16] Visceral pain is a potent stimulus for IONV during regional anaesthesia. The incidence of nausea has been reported to be 29% and vomiting 9% following an i.v. bolus of oxytocin 5 units during elective caesarean section under regional anaesthesia; the incidence after use of carbetocin is also similar. [1] Nausea and vomiting mainly occur as a result of hypotension produced by oxytocin administration. Slow administration and judicious use may reduce oxytocin-induced hypotension and IONV.

Management of IONV should essentially rely on prophylaxis. If prophylactic measures fail, treatment could be provided in the form of anti-emetic agents. But the optimal use of anti-emetic agents in the management of IONV during caesarean section under spinal anaesthesia remains unclear. Anti-emetic agents used prophylactically either before [29] or after [17] cord clamping during caesarean section under regional anaesthesia have been shown to be highly effective. However, none of these studies assessed the efficacy of anti-emetics with strict control of all the causative factors mentioned above. Also, they have their own side effects upon mother and baby. Though various anti-emetic agents such as metoclopramide, dimenhydrinate, droperidol, dexamethasone, ondansetron, ganisetron etc. have been used either prophylactically or as therapeutic agents, have shown varied responses to control in caesarean delivery under spinal anaesthesia. Besides, there are no data to support the efficacy of any anti-emetic as rescue medication for IONV during caesarean section.

The incidence and severity of nausea and vomiting can be lowered with some medications such as propofol and midazolam. In our study, we have observed that the low incidence of nausea, retching, vomiting in both the groups. In midazolam Group (group M) only 2 patients experienced episodes of nausea (3.64%) and 2 patients experienced episodes of nausea and vomiting (3.64%).  Whereas in propofol group, occurrence of nausea and nausea-vomiting were found in 2 patients (3.64%) and 3 patients (5.45%) respectively. Thus, it have been observed that the incidence of nausea and vomiting is much less in the patients either receiving midazolam or propofol in subhypnotic doses immediately after clamping of umbilical cord. But there are no significant differences in between two groups when comparison done in these regards. There are also no significant difference in ondansetron consumption as a rescue anti-emetic, in between two groups. Also, there was not any significant amount of sedation during immediate post-operative period in both the groups. It has also been observed in our study that total consumption of inj phenylephrine as a vasopressor agent is significantly higher in case of propofol group than midazolam group (P<0.001).

Propofol is a short acting rapid onset intravenous anaesthetic agent used for induction and maintenance of anaesthesia. Numaza ki et al. showed in their studies that at sub hypnotic dose (1mg/kg/hr) propofol is effective for preventing nausea and vomiting in parturients undergoing ceasarean section under spinal anaesthesia. [5] But it has been demonstrated in few studies that propofol while given in low dose bolus injection (10mg), does not reduce the incidence of emesis during spinal anaesthesia for ceasarean section. This is due to the short duration of a propofol bolus administered prior to the onset of emesis, and/or that the dose of propofol used was insufficient. But at subhypnotic dose in infusion propofol shows its anti-emetic nature. [5] In a similar study, it was highlighted that the severity of nausea was also less in patients who had received propofol than in those who had received placebo. [7] Recently, the prophylactic anti-emetic efficacy of propofol at subhypnotic dose administered after cord clamping, has been shown to be comparable to that of droperidol and metoclopramide  in parturients undergoing caesarean section under regional anaesthesia. [18] This efficacy is attributed to a direct anti-emetic property and a weak 5-HT3 antagonistic effect of propofol. In our study we have also shown that, in patients who received propofol, the incidence of nausea and vomiting has been reduced without more sedation or respiratory depression, but due to vasodilator effect of propofol, hypotension and subsequent need for sympathomimetic drug was higher than the other group.

Midazolam, a short acting benzodiazepine widely used as a premedication before surgery, for induction of anaesthesia, and for conscious sedation. Benzodiazepines induce their effects on nausea and vomiting via anxiolysis following lowered dopaminergic influx to chemoreceptor trigger zone and decrease in adenosine reuptake; nevertheless, the precise anti-emetic mechanism for midazolam is poorly understood. [8,19] It has been postulated that a possible mechanism for the anti-emetic effect of benzodiazepines could be an action at the chemoreceptor trigger zone reducing synthesis, release and postsynaptic effect of dopamine. Midazolam is normally given by I.V. infusion at subhypnotic doses (a 0.5-1 mg bolus as starter, followed by a 1 mg per hour infusion). Low dose midazolam is safe to use peri-operatively, and respiratory depression usually does not occur, even in combination with opioids. In our study, overall incidence of nausea-vomiting and anti-emetic (ondansetron) consumption was lower in both propofol and midazolam groups. There was no significant respiratory depression or sedation or haemodynamic changes in both the propofol and midazolam group. But total vasopressor consumption (by means of intermittent bolus doses of inj. Phenylephrine) is lower in case of midazolam group, which indicates more haemodynamic stability shown in this group in terms of hypotension.

Hypotension occurring during neuraxial anaesthesia is one of the most important aetiological factors for IONV. Studies have shown that there is distinct association of IONV with maternal hypotension and strict control of blood pressure can dramatically reduce intra-operative emetic symptoms. [20] Phenylephrine, a direct alpha agonist, is very much efficacious as vasopressor agent in case of spinal induced hypotension. W. D. Ngan Kee et al. In their study concluded that when phenylephrine is infused to maintain maternal BP during spinal anaesthesia for Caesarean section, the optimal regimen is to titrate it with the aim of maintaining maternal BP at values near baseline. [21] In our study, decrease in systemic blood pressure was seen in all groups after spinal anaesthesia; however, the difference between groups was insignificant. Mean phenylephrine consumption dose in propofol group was significantly higher than midazolam group (P<0.001) indicating that although the number of patients receiving phenylephrine was not significantly different, the severity of hypotension was more with propofol, which necessitates higher vasopressor consumption.

Thus, in our study it has been observed that the subhypnotic doses of midazolam are not only useful in providing sedation and anxiolysis but also are as effective as subhypnotic doses of propofol for the prevention of nausea and vomiting during and after caesarean section with spinal anaesthesia. Furthermore, as less severe haemodynamic changes are seen with midazolam, it seems that midazolam can be a much better choice than propofol in reducing IONV in case of caesarean section under spinal anaesthesia. Also, to increase the patient’s satisfaction which is an important factor in conscious patients undergone a surgery like caesarean section, we can reach to this purpose with appropriate use of low doses agents with no adverse effect of drugs overdose.

Limitation(s)

The most important limitation of our present study was inability to measure the anxiety score of the patients pre-operatively which may have some indirect influence in intra-operative incidence of nausea and vomiting. Another important limitation of our study was that we could not measure the plasma concentration of the study drugs. If measured it might help to comment an optimum anti-emetic plasma concentration of propofol and midazolam. In future, further studies can be carried out with different doses of propofol and midazolam to find out the optimum dose to achieve their anti-emetic effect.

In conclusion, subhypnotic doses of midazolam is as effective as subhypnotic doses of propofol for the prevention of nausea and vomiting during and after caesarean section under spinal anaesthesia without causing any significant amount of sedation among the parturients post-operatively. Furthermore, as less severe haemodynamic changes are seen with midazolam, it seems that midazolam can be considered as a much better choice than propofol in reducing IONV in case of caesarean section under spinal anaesthesia.

1. Balki M, Carvalho JC. Intraoperative nausea and vomiting during cesarean section under regional anesthesia. Int J Obstet Anesth. 2005;14(3):230-241.
2. Mishriky BM, Habib AS. Metoclopramide for nausea and vomiting prophylaxis during and after Caesarean delivery: a systematic review and meta-analysis. Br J Anaesth. 2012; 108(3):374-83.
3. Santos A, Datta S. Prophylactic use of droperidol for control of nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg. 1984;63(1):85-87.
4. Santos A, Datta S. Prophylactic use of droperidol for control of nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg. 1984; 63(1):85-87.
5. Numazaki M, Fujii Y. Subhypnotic dose of propofol for the pre¬vention of nausea and vomiting during spinal anaesthesia for caesarean section. Anaesth Intensive Care. 2000; 28(3):262–5.
6. Hosseinzadeh H, Eidy M, Golzari SE, Vasebi M. Hemodynamic stability during induction of anaesthesia in elderlyPatients: propofol+ ketamine versus propofol+ etomidate. J Cardiovasc Thorac Res.  2013; 5(2):51.
7. Seyedhejazi M, Eydi M, Ghojazadeh M, et al. Propofol for laryngeal mask airway insertion in children: Effect of two different doses. Saudi J Anaesth. 2013; 7(3):266-269.
8. Rodolà F. Midazolam as an anti-emetic. Eur Rev Med Pharmacol Sci. 2006; 10(3):121-126.
9. Di Florio T. The use of midazolam for persistent postoperative nausea and vomiting. Anaesth Intensive Care. 1992; 20(3):383-386.
10. Di Florio T, Goucke CR. The effect of midazolam on persistent postoperative nausea and vomiting. Anaesth Intensive Care. 1999; 27(1):38-40.
11. Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section. Br J Anaesth. 2004; 92(4):469-474.
12. Bellville JW, Bross ID, Howland WS. A method for the clinical evaluation of antiemetic agents. Anesthesiology.1959; 20(6):753-60.
13. Sheahan CG, Mathews DM. Monitoring and delivery of sedation. Br J Anaesth. 2014;113 Suppl 2:ii37-47.
14. Gill M, Green SM, Krauss B. A study of the Bispectral Index Monitor during procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2003; 41(2):234-241.
15. Alahuhta S, Kangas‐Saarela T, Hollmen AI, Edström HH. Visceral pain during caesarean section under spinal and epidural anaesthesia with bupivacaine. Acta Anaesthesiol Scand. 1990;34(2):95-8.
16. Ishiyama T, Yamaguchi T, Kashimoto S, Kumazawa T. Effects of epidural fentanyl and intravenous flurbiprofen for visceral pain during cesarean section under spinal anaesthesia. J Anesth. 2001;15(2):69-73.
17. Ashley EM, Quick DG, El‐Behesey B, Bromley LM. A comparison of the vasodilatation produced by two topical anaesthetics. Anaesthesia. 1999;54(5):466-9.
18. Numazaki M, Fujii Y. Reduction of emetic symptoms during cesarean delivery with antiemetics: propofol at subhypnotic dose versus traditional antiemetics. J Clin Anesth. 2003;15(6):423-427.
19. Reid M, Herrera-Marschitz M, Hökfelt T, Terenius L, Ungerstedt U. Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P. Eur J Pharmacol. 1988; 147(3):411-420.
20. Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev. 2006;(4):CD002251. Published 2006 Oct 18. doi:10.1002/14651858.CD002251.pub2
21. Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section. Br J Anaesth 2004;92(4):469-74.