Etomidate is an imidazole derivative that is mainly used to induce anesthesia, especially in patients with compromised cardiovascular systems and the elderly. Compared to other regular induction medicines like Propofol which causes cardiovascular depression, Thiopentone which has a risk of bronchospasm, and Ketamine which causes cardiovascular stimulation, ^{1, 2} Etomidate has the benefit of having little impact on the respiratory and cardiovascular systems.³ Etomidate's beneficial qualities led to its usage in critically ill patients for induction, anesthetic maintenance, and extended sedation.

Subsequent research, however, revealed that etomidate inhibits the synthesis of cortisol because of reversible adrenal suppression. It has been demonstrated that etomidate reduces cortisol level by causing a dose-dependent inhibition of the enzyme 11ß-hydroxylase, which is responsible for converting 11-deoxycortisol to cortisol. ⁴ It has been demonstrated that etomidate infusions in critically ill patients are linked to decreased cortisol synthesis due to adrenocortical suppression, multiple organ failure, and a significant rise in mortality. ⁵ Etomidate has been linked to reversible adrenocortical suppression for several hours when administered as a single dose to patients who are relatively fit for the purpose of inducing anesthesia.⁵

When compared to other traditional medications for the induction of anesthesia, etomidate had better effects on patient hemodynamics, but its utility as an induction agent was limited due to cortisol suppression.

After obtaining the Institutional Ethical Committee clearance and written informed consent from all patients, the study was conducted.

Sample size:

Sample size for the study is estimated with 95% confidence interval and power of 90%.

The Sample size for each group =  

Formula ⁶

Based on the reference taken from study by Navid Nooraei et al. ⁷

20 patients were enrolled in the study after sample size calculation

A. Inclusion Criteria:

1. Patients scheduled for elective ENT surgery with American society of anesthesiologist (ASA) Physical status grade I and II
2. Patients 18-60 years
3. Patients willing to give written informed consent
4. Patients of either sex, free of any endocrine disease

B. Exclusion Criteria:

1. Known to allergy to any of study drugs
2. Pregnancy and Lactation
3. Patient with history of any sepsis - which required hospitalization
4. Patients with history of steroid intake

• Patients who meet the inclusion criteria were enrolled into the trial after receiving informed consent
• After proper pre-anaesthetic optimization, all patients were examined again the day before Patients of both groups were given Tab.Ranitidine 150mg and Tab.Alprazolam 1mg orally, the night before surgery.
• Patients were randomly assigned to group vitamin C - Group C or Control group - Group E based on the computer-generated randomization
• On the day of surgery all patients were received in the pre-operative room and An 18-gauge intravenous cannula was inserted in the pre-op room for intravenous fluid therapy, administration of peri-operative medications and blood sample was collected for pre-operative serum cortisol.
• Then, 1 hour before induction of surgery, 1 gram of intravenous vitamin C was administered to the patients in group C. Group E received the same volume of normal saline. Both groups received drugs in covered infusion
• After shifting patients to OT, Standard ASA monitoring (pulse oximeter, electrocardiogram, and noninvasive blood pressure) applied to all patients and pre-operative drill
• Baseline vitals are recorded, and Vitals are recorded every at every 2 mins from start of induction of anaesthesia till the end of surgery,
• Patients were pre-oxygenated with 5 lit/min 100% O2 for 5
• For premedication, fentanyl 2μg/kg, midazolam 02mg/kg and glycopyrrolate 0.004mg/kg is administered.
• Five minutes later the anaesthesia is induced by Etomidate 3mg/kg and Lidocaine 1.5mg/kg.
• Neuromuscular blockade is achieved by Vecuronium 0.1mg/kg to facilitate endotracheal Appropriate Endotracheal tube size is selected for intubation. Anaesthesia was maintained with 1 Minimum Alveolar Concentration (MAC) Isoflurane and 50% nitrous oxide/50% oxygen.
• After surgery, when the patient is fully awake, and after signs of neuromuscular recovery elicited the neuromuscular block was reversed (Neostigmine-0.05mg/kg + Glycopyrolate- 01mg/kg) and patient was extubated after recovery from neuromuscular blockade and recovery signs noted.
• After shifting to recovery room, patients were given supplemental Oxygen via face
• Fluid therapy was performed as per standard method and monitored for vitals as per institutional
• 4 hours after induction 2nd blood sample was drawn to assess serum
• Serum free cortisol levels were assessed in all

Table 1:

Figure 1

Figure 2

Figure 3

20 individuals were enrolled in this randomized clinical trial; and 10 of them were randomly allocated to each of the groups. Ten of them got 1g IV vitamin C, and the other ten patients got normal saline.

The baseline vitals and demographic variables were comparable in both groups. Pre-operative cortisol was comparable in both groups

Serum Cortisol was reduced within physiological range in Group E from 14.45±3.4 μg/dl in pre- operative to 4.7±1.69 in post-operative (p=0.0005).

In Group C Serum Cortisol was 11.26±6.1 in pre-operative to 9.64±5.7 in postoperative (p=0.46). Intraoperative Hemodynamics were similar in both groups.

There were no differences in postoperative hospital stay in both groups.

According to our research, a single injection of etomidate lowers blood cortisol in the control group within a physiological range; however, this effect is mitigated when vitamin C is given as a prophylactic treatment.

In our investigation, the vitamin C group's mean cortisol levels did not considerably drop after surgery. The inhibition of 11β-hydroxylase appears to be associated with the free imidazole radical of cytochrome P-450 that binds etomidate^.8 As a result, ascorbic acid re-synthesis is inhibited, which is necessary for human steroid synthesis. Reduced synthesis of mineralocorticoids is also a result of blocking the cytochrome P-450 dependent enzyme 11β- hydroxylase, especially in individuals who are critically unwell. ⁹ Therefore, vitamin C supplementation could restore cortisol levels to normal after the use of Etomidate.¹⁰

The findings of our study are consistent with previous studies conducted when evaluating the effect of Vitamin C on Etomidate Induction dose.^7,11,12 Neither of these studies reported a significant adverse event related to short term adrenocortical suppression by single dose of etomidate injection

Studies show that Etomidate may pose a potential risk for patients undergoing high-risk surgeries, as well as for frail individuals experiencing trauma¹³, cardiac surgery¹⁴, or septic shock and It should be avoided in patients who need prolonged infusions.

LIMITATION

Role of Vitamin C in long term etomidate induced suppression of cortisol is not established by the study

Using Inj Vitamin C 1g IV infusion as premedication 1hour before surgery helps in preventing Serum Cortisol suppression during induction of Anaesthesia using Inj Etomidate.

Financial support and sponsorship Nil.

Conflicts of Interest: The authors declare that there are no conflicts of interest

1. Jaap Vuyk, Elske Sitsen, and Marije Reekers. Intravenous Anaesthetics. Michael A. Miller’s Anesthesia; 9th edition, Philadelphia; Elsevier Saunders; 2020 p.666- 670
2. James P. Rathmell, Carl E. Intravenous sedatives and hypnotics. Robert K. Stoelting. STOELTING’S Pharmacology and Physiology in Anesthetic Practice; Wolters Kluwer Health, New Delhi; Wolters (India) Pvt. Ltd.; Third Indian reprint; 2015. p168
3. Gooding JM, Weng JT, Smith RA, Berninger GT, Kirby RR. Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac Anesth Analg. 1979 January-Februray;58(1):1-40
4. Lamberts SW, Bons EG, Bruining HA, de Jong FH. Differential effects of the imidazole derivatives Etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical J Pharmacol Exp Ther. 1987; 240: 259-64
5. Absalom A, Pledger D, Kong Adrenocortical function in critically ill patients 24 h after a single dose of etomidate. Anaesthesia. 1999 September 1;54(9):7-861.
6. Machin D, Campbell MJ, Tan SB, Tan SH. Comparing two independent groups for ordered categorical Sample size tables for clinical studies. 3rd edition. Wiley: John Wiley & Sons; 2011. p.47-57
7. Nooraei N, Fathi M, Edalat L, Behnaz F, Mohajerani SA, Dabbagh Effect of Vitamin C on Serum Cortisol after Etomidate Induction of Anesthesia. J Cell Mol Anesth. 2016;1(1):28-33.
8. Boidin MP, Erdmann WE, Faithfull The role of ascorbic acid in etomidate toxicity. Eur J Anaesthesiol. 1986;3(5):417-22.
9. Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, Lévy B, et al. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical Intensive Care Med. 2005;31(3):388-92.
10. Boidin MP, Erdmann WE, Faithfull The role of ascorbic acid in etomidate toxicity. Eur J Anaesthesiol. 1986 September;3(5): 22-417.
11. Das D, Sen C, Goswami A. Effect of Vitamin C on adrenal suppression by etomidate induction in patients undergoing cardiac surgery: A randomized controlled Annals of cardiac anaesthesia. 2016 July;19(3):410.
12. Panahi, R., Paknezhad, S.P., vahedi, A. et al. Effect of vitamin C on adrenal suppression following etomidate for rapid sequence induction in trauma patients: a randomized clinical trial. BMC Anesthesiol 23, 104 (2023). https://doi.org/10.1186/s12871-023- 02065-5
13. de la Grandville B, Arroyo D, Walder Etomidate for critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol. 2012;29(11):511-4.
14. Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, Lévy B, Bollaert Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med. 2005 Mar;31(3):388-92. doi: 10.1007/s00134-004-2550-8. Epub 2005 Feb 10. PMID: 15703896.