The Indian Anaesthetists’ Forum

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 23  |  Issue : 1  |  Page : 12--18

Effect of nitrous oxide and dexmedetomidine on the consumption of propofol during general anesthesia in adult patients: A randomized controlled trial


Ghansham Biyani1, Pradeep Kumar Bhatia2, Sadik Mohammed2, Pooja Bihani3, Manoj Kamal2, Swati Chhabra2,  
1 Department of Anaesthesiology, All India Institute of Medical Sciences, Mangalagiri, India
2 Department of Anaesthesiology and Critical Care, AIIMS, Jodhpur, Rajasthan, India
3 Department of Anaesthesiology and Critical Care, Dr. S. N. Medical College, Jodhpur, Rajasthan, India

Correspondence Address:
Dr. Sadik Mohammed
Department of Anaesthesiology and Critical Care, AIIMS, Jodhpur, Rajasthan
India

Abstract

Background: Use of both nitrous oxide and dexmedetomidine as anesthetic adjuvants has shown to reduce the consumption of propofol required for the maintenance of anesthesia. The present study evaluated these two agents for their propofol sparing effect which has not been compared so far. Materials and Methods: Sixty adult patients undergoing elective surgery were enrolled and randomly divided into three groups. Patients in group P received propofol started at 166 μg/kg/min and then titrated to maintain the Bi-Spectral Index (BIS) value between 40 and 60, while patients in group N and in group D received nitrous oxide as carrier gas and infusion of dexmedetomidine (1 μg/kg over 10 min followed by 0.5 μg/kg/h) respectively, in addition to propofol. Primary outcome of the study was total consumption of propofol. Secondary outcomes measured were intraoperative hemodynamics, recovery profile, residual sedation, rescue analgesic requirements, and relevant side effects. Results: Total consumption of propofol was significantly higher in group P (139.02 ± 65.24 μg) compared to group N (94.72 ± 48.04 μg) and group D (98.31 ± 39.45 μg) (mean difference [95% confidence interval] group P and N 44.3 [17.9–44.7]; group P and D 40.71 [26.0–52.8]; group N and D 3.59 [−5.3–21.5]) (P = 0.015). Although the recovery parameters (time to extubation, time to achieve BIS of 90, and time to verbal commands) were significantly prolonged in group D (P < 0.001), time to discharge from postanesthesia care unit (PACU) was comparable among all groups (P = 0.65). When arrived in PACU, patients in group D were significantly more sedated (P = 0.0005) however, the 30 min in PACU the difference was nonsignificant. None of the patients in group D had nausea and vomiting and did not require additional analgesics. Conclusion: Both nitrous oxide and dexmedetomidine significantly decreased the total consumption of propofol. Hence, both these agents can be used as potential anesthetic adjuvants to decrease the side effects associated with propofol infusion. Due to the lack of any reported environmental and long-term side effects, dexmedetomidine can be a safer and better alternative to nitrous oxide.



How to cite this article:
Biyani G, Bhatia PK, Mohammed S, Bihani P, Kamal M, Chhabra S. Effect of nitrous oxide and dexmedetomidine on the consumption of propofol during general anesthesia in adult patients: A randomized controlled trial.Indian Anaesth Forum 2022;23:12-18


How to cite this URL:
Biyani G, Bhatia PK, Mohammed S, Bihani P, Kamal M, Chhabra S. Effect of nitrous oxide and dexmedetomidine on the consumption of propofol during general anesthesia in adult patients: A randomized controlled trial. Indian Anaesth Forum [serial online] 2022 [cited 2022 Jun 29 ];23:12-18
Available from: http://www.theiaforum.org/text.asp?2022/23/1/12/340476


Full Text



 Introduction



Propofol at the recommended induction dose of 2.0–2.5 mg/kg often causes cardiovascular and respiratory depression, and is rarely but certainly reported to cause intraoperative complications such as propofol infusion syndrome, lactic and metabolic acidosis, dystonia and movement disorders even with short-term infusions.[1],[2] Moreover, the pharmacokinetics of propofol is context-sensitive and its context-sensitive half-life increases with the duration of infusion. Therefore, any drug which results in decreasing the dose requirements of propofol for the induction and maintenance of anesthesia helps in lessening the incidence of hypotension, cardiovascular instability, respiratory depression, and other side effects associated with maintenance infusion.[1]

Nitrous oxide (N2O) is a short-acting inhalational anesthetic agent, commonly used as an anesthetic adjuvant in general anesthesia (GA) for its sedative and analgesic properties. Its use has been shown to reduce the consumption of propofol required for the maintenance of GA by 15%–25%.[3],[4],[5] Similarly, dexmedetomidine by virtue of its sedative, analgesic and anxiolytic properties, possesses all the characteristics of an ideal anesthetic adjuvant[6] and has led to a significant reduction in the propofol requirements.[1],[7]

Although the ENIGMA II trial[8] supported safe use of N2O with respect to cardiovascular complications or surgical-site infection in patients undergoing major noncardiac surgery, other studies have shown that its use is associated with increased postoperative nausea and vomiting (PONV), hazardous effects on the environment and other long-term side effects such as Vitamin B12/folic acid deficiency, teratogenicity, and infertility.[9] This is in comparison to the use of dexmedetomidine, which results in transient bradycardia, hypotension and dry mouth, but is not reported to have any environmental and other long term side effects. Moreover, in a recently reported systemic review and meta-analysis by Wang et al.,[10] the use of perioperative infusion of dexmedetomidine as an anesthetic adjuvant has shown to attenuate the perioperative stress and inflammation, and protect the immune function of surgical patients by decreasing the release of epinephrine, norepinephrine, cortisol and blood glucose. All of this may contribute to decreased postoperative complications and improved clinical outcome.

To the best of our knowledge, there is no study reported in the literature comparing the effects of these two agents on the total consumption of propofol. We hypothesize that dexmedetomidine due to its sedative and analgesic properties is a potential anesthetic adjuvant which helps in reducing the requirements of propofol and thereby its associated complications, and can be a safe alternative to nitrous oxide as it is devoid of environmental and long-term side effects. The primary outcome measure was the total amount of propofol consumed during the maintenance of GA while secondary outcome measures includes intraoperative hemodynamics, recovery parameters (time to extubation, time to achieve BIS of 90, and time to verbal commands), residual sedation, requirement of analgesia, and side effects.

 Materials and Methods



This study was conducted at a tertiary care center between May 2017 and June 2018 after getting approval from the institutional ethical committee [AIIMS/JDH/2017/259] and the trial is registered with the clinical trial registry India [CTRI/2017/05/008720]. Sixty patients of either sex, belonging to the American Society of Anesthesiologists (ASA) physical status 1 or 2, aged between 18 and 60 years, and scheduled to undergo elective surgery under GA were enrolled after getting written informed consent. Patients with a history of obstructive sleep apnea, cardiovascular disease, dysrhythmia, high risk of aspiration, morbid obesity, difficult airway, preoperative hypotension (mean arterial blood pressure <50 mmHg), bradycardia (heart rate [HR] <45 beats/min), known allergy to study drugs, patient on tricyclic antidepressant/clonidine/monoamine oxidase-inhibitor therapy, duration of surgery less than one hour and emergency surgeries were excluded from the trial. Our study adheres to the principles of declaration of Helsinki and the manuscript follows the applicable CONSORT guidelines.

All patients were examined during the preoperative visit by the attending anesthesiologist. Blood investigations, electrocardiogram (ECG), and chest-X ray were performed as per the requirements. Standard nil by mouth protocols was adhered to, and all patients were premedicated with alprazolam 0.25 mg per oral the night before and on the morning of surgery.

The computer-generated randomization sequence was used to divide the patients into three equal groups. In group P (n = 20) propofol alone, group N (n = 20) propofol and N2O, and group D (n = 20) propofol and dexmedetomidine were used as maintenance anesthetic agents. To ensure allocation concealment, the opaque envelope method was used which was opened just before the induction of anesthesia.

On arrival to the theatre, standard monitoring comprising of ECG, oxygen saturation (SpO2), noninvasive blood pressure (NIBP), and Bi-Spectral Index (BIS) electrodes (BISTM monitoring system, Covidien, Mansfield, MA, USA) were attached and baseline parameters were recorded. The neuromuscular monitoring was also attached. Ten minutes following the administration of premedication (IV midazolam 0.03 mg/kg and IV fentanyl 2 μg/kg), anesthesia was induced with IV propofol targeting a BIS value of 45–50. Tracheal intubation was facilitated with IV rocuronium 0.9 mg/kg.

For maintenance of anesthesia, 1% propofol infusion was started initially at 166.66 μg/kg/min (Roberts regimen[11] 10 mg/kg/h) and subsequently the infusion rate was titrated to maintain the BIS value in the range of 40–60. In group P, the infusion of propofol alone was continued. In group D, in addition to propofol, infusion of dexmedetomidine at a dose of 1 μg/kg over 10 min followed by 0.5 μg/kg/h was started. In group N, along with propofol infusion, N2O in oxygen (60:40) was used as a carrier gas for ventilating the lungs, while in group P and group D patients' lungs were ventilated with O2:Air mixture with a FiO2 of 40%. Whenever BIS value exceeded more than 60, propofol infusion was increased by 10% of the infusion rate, and if the BIS value fell below 40, the infusion rate was decreased by 10% and observed for the next 5 min and same interventions were repeated until the target BIS value was achieved.

Volume controlled ventilation was used targeting minute ventilation to achieve normocarbia (EtCO2 35–40 mmHg). The neuromuscular blocking agent was titrated to keep a train of four counts ≤ and analgesia was supplemented with IV fentanyl 1 μg/kg/h and IV paracetamol 1 g (30 min prior to end of surgery) in all the three groups.

HR, SpO2 and NIBP were recorded at the baseline, and at 5, 10, and 15 min after induction, and then at every 15 min interval. Hypotension (mean arterial pressure [MAP] <60 mmHg) and bradycardia (HR <50/min) were managed with IV ephedrine 3 mg and IV atropine 10 μg/kg respectively. Approximately 10 min before the presumed end of the surgery, the infusions were stopped (T0) and patients were ventilated with 100% O2 in all three groups. Neuromuscular blockade was reversed and the trachea was extubated when TOF ratio approached 0.9.

The total consumption of propofol was defined as the amount of drug required from the beginning of mechanical ventilation until the end of drug infusion. Time to extubation (TEXT) (time between T0 and extubation), time to achieve BIS of 90 (TBIS90) (time between T0 and recording of BIS value 90), time to verbal commands (TVERBAL) (time between T0 and patient respond by telling his/her name), and time to discharge from postanesthesia care unit (PACU) (TDISCHAR) (time between T0 and achievement of Aldrete's score[12] ≥9) were noted. The sedation score was evaluated using Ramsay's sedation scale[13] in the postoperative period at every 30 min interval. In the recovery room, once the patient was fully awake, standard Brice questionnaire[14] were asked to record intraoperative awareness. Complications such as PONV, pruritus, respiratory depression and dry mouth were also evaluated at regular intervals. When the visual analog scale score was ≥4, IV tramadol 100 mg was administered as rescue analgesic.

Statistical analysis

The primary outcome of our study was the total amount of propofol consumed during the maintenance of GA. A pilot study was performed before patient recruitment to estimate the sample size. The pilot study included 15 subjects, 5 in each arm. The smallest effect size that would lead to a clinically significant difference was found to be equal to 0.42. The effect size was derived by entering the mean difference and standard deviation SD to calculate the sample size using a software (G * Power software version 3.1.9.2, Institute of Experimental Psychology, Heinrich Heine University, Dusseldorf, Germany).[15] An estimated mean propofol consumption of 137.2 μg in group P, 95.5 μg in group N and 98.8 μg in group D, with a pooled (SD) of 45.42 were used in the sample size calculation. A sample size of 20 participants provided a two-tailed α-value of 0.05 and 80% power (ß = 0.2).

All the data were compiled and analyzed statistically using Statistical Package for Social Sciences version 20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp., NY, USA). Descriptive statistics were presented in terms of numbers and percentages for categorical variables and in terms of the mean, SD and/or median for the continuous variables. Categorical data were analyzed using the Chi-square test. Continuous variables between the groups were analyzed using one way ANOVA with Bonferroni multiple comparisons test. Repeated measure ANOVA was used to compare continuous variables within the group.

 Results



A total of 73 patients were initially screened for the study, and out of them 13 patients (3 refused to participate and 10 not meeting inclusion criteria) were excluded [Figure 1]. Demographic profile (age, gender, ASA status and body mass index), baseline HR, baseline MAP, duration of surgery/anesthesia, and type of surgery were comparable among all the groups [Table 1]. In group D, after starting the infusion of dexmedetomidine infusion, there was a significant decrease in HR from the baseline which remained significantly low throughout the intraoperative period (P < 0.001), while the HR in group P and in group N did not vary significantly from the baseline [Figure 2]. Intraoperative MAP at different time intervals was comparable among the groups [Figure 2].{Figure 1}{Figure 2}

Total consumption of propofol was significantly higher in group P (139.02 ± 65.24 μg), compared to group N (94.72 ± 48.04 μg) and group D (98.31 ± 39.45 μg) (mean difference [95% confidence interval] group P and N 44.3 [17.9–44.7]; group P and D 40.71 [26.0–52.8]; group N and D 3.59 [−5.3–21.5]) (P = 0.015) [Table 2]. The use of N2O and dexmedetomidine as adjuvants decreased the total intraoperative consumption of propofol by 31.6% and 29.4%, respectively. The TEXT, TBIS90, and TVERBAL were significantly prolonged in group D (18.05 ± 5.05 min, 21.9 ± 6.8 min, and 26.2 ± 4.6 min, respectively) compared to group P (12.15 ± 3.24 min, 16.95 ± 5.31 min, and 19.45 ± 4.82 min, respectively) and group N (11.75 ± 4.8 min, 15.1 ± 6.6 min, and 17.23 ± 3.23 min, respectively) (P < 0.001) [Table 2].{Table 1}{Table 2}

The recovery profile of patients after arrival to PACU is shown in [Table 2]. Patients in group D had significantly higher sedation score compared to group P and group N (P = 0.0005), while at 30 min all patients had comparable sedation score (P = 0.08). In terms of analgesia, 4 (20%) patients in group P and 2 (10%) patients in group N required rescue analgesic in the form of IV tramadol, while none of the patients in group D required any analgesics during their stay in the PACU. With respect to PONV, 3 (15%) patients in group N had episodes of vomiting, while none of the patients in group P and group D had PONV. None of the patients had awareness about intraoperative events in all the groups. Furthermore, there was no significant difference among the groups regarding TDISCHAR (P = 0.65) from PACU.

 Discussion



Our study demonstrated that both N2O and dexmedetomidine significantly decreased the total consumption of propofol. Although dexmedetomidine infusion significantly prolonged anesthesia recovery the time to discharge from PACU was comparable among groups. Dexmedetomidine provides stable intraoperative hemodynamics, better postoperative analgesia, and protection against PONV.

The administration of GA without the use of any adjuvants requires higher doses of inhalational or intravenous maintenance anesthetic agents and thereby increases the incidence of adverse effects. The number of drugs having synergistic effects such as opioids, magnesium sulfate, alpha-2 agonists (clonidine and dexmedetomidine), and lidocaine have been used as adjuvants, as they possess either analgesic and/or anesthetic sparing actions.

N2O has lower blood: gas partial coefficient, and thereby has a faster onset and offset of actions. Its mechanism of action is through N-methyl-D-aspartate receptor antagonism providing it the analgesic properties, which is different from the majority of conventionally used, anesthetic agents which are predominantly gamma-aminobutyric acid (GABA) agonists, lacking analgesic properties. Recently published qualitative reviews[16],[17] and the results of the ENIGMA II trial[8] have supported its safety and concluded that it may remain an option in the practice of contemporary anesthesia. However, due to the diverse range of concerns associated with its administration, its routine use is declining in western countries.[18] Dexmedetomidine on the other hand is an highly selective α-2 adrenergic receptor agonist having analgesic, anxiolytic, sedative and sympatholytic properties.[4] There is evidence to suggest that perioperative infusion of dexmedetomidine attenuates hypothalamic-pituitary-adrenal axis and sympathoadrenal response. The concentrations of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein were also decreased. All of this is indicative of its anti-inflammatory potentials.[8] Other studies have also found that the use of dexmedetomidine preserves the neurocognitive functions, attenuate emergence agitation and protect against ischemia-reperfusion injury.[19],[20]

The usual dose of propofol required for the maintenance of GA ranges from 100 to 200 μg when used alongside the opioid analgesics, muscle relaxants and/or N2O. Our study showed that the use of either N2O or dexmedetomidine significantly decreases the intraoperative consumption of propofol (by approximately 30%) under BIS guidance, without increasing the incidence of intraoperative awareness. Dube et al.[3] observed a significant reduction in the requirement of the maintenance doses of propofol when used along with N2O (71.26 ± 11.78 versus 90.82 ± 19.13 μg). Similarly, Hemelrijck and colleagues[4] noted a significant decrease in propofol requirements when N2O was used as an adjuvant under electroencephalography (EEG) guidance compared to the use of propofol alone (123 ± 5.27 vs. 150 ± 2.77 μg). Different dose requirements of propofol in these studies could be explained by the variable duration of propofol infusion as well as the inclusion of different types of surgeries.

Dexmedetomidine has also shown to have propofol sparing effects (15%–50% reduction in the dose requirements of propofol) when used as an adjuvant in the maintenance of anesthesia.[1],[7] A recent study evaluated the effect of dexmedetomidine on the propofol and remifentanil requirements during the BIS-guided closed-loop anesthesia and showed that infusion of dexmedetomidine reduces the requirement of propofol by 29% for a similar BIS value.[21] Moreover, the authors have also assumed that the actual difference in the propofol requirements could have been more than observed, because more propofol than actually necessary may have been delivered in the dexmedetomidine group as it provokes spindle-type EEG activity mimicking arousal and an α-pattern on the EEG.[21],[22] However, this assumption can be argued as both the agents induces increased spindle power on EEG during moderate sedation, while during deep sedation, dexmedetomidine increases fronto-central spindle power but propofol increases spindle power in the frontal area.[23]

Similar to other studies' findings, we also observed delayed recovery in the dexmedetomidine group as assessed by TEXT, TBIS90, and TVERBAL.[7],[24] This could be attributed to the sedation effect of dexmedetomidine. As dexmedetomidine infusion was associated with prolongation of recovery parameters by 5–7 min, we are of the opinion that stopping the infusion well before the skin closure could have negated this difference. Patients in the dexmedetomidine group were more sedated with a higher sedation score in the recovery, but this became comparable at 30 min and did not prolong the PACU stay.

None of the patients in the dexmedetomidine group required additional analgesics during their stay in the PACU, demonstrating its analgesic potentials. PONV was observed only in the N2O group, while none of the patients belonging to group P and group D had PONV. None of the patients in any of the groups had awareness about the intraoperative events. Fifth National Audit Project (NAP5) estimated the incidence of awareness under GA to be 1:19,000 anesthetics, but the influence of N2O on awareness was not supported by NAP5.[25] Moreover, the use of N2O was recommended by NAP5 for caesarean sections under GA considering the lower incidence of awareness with its use. Similarly, Ahmed et al.[26] evaluated the effects of dexmedetomidine on awareness in cardiac surgery and found it to be effective in reducing the incidence of perioperative awareness and recall.

Our study had few limitations. First, as it was an open-label trial, observer bias inherent to the study design cannot be excluded. In addition, we did not use closed-loop drug delivery system for the administration of propofol. Second, we did not perform cost calculation during different anesthesia regimen and addition of dexmedetomidine might have increased the direct cost. However, if we consider both direct and indirect cost of adding an adjuvant to the anesthesia regimen, the difference in the overall cost might not be significant. Third, the use of target-controlled infusion device would have better than a manual infusion regimen. Fourth, the compound effect of N2O and dexmedetomidine on BIS might have affected the results in favor of dexmedetomidine. A validated monitor of the depth of anesthesia having the same degree of effect on N2O and dexmedetomidine could have yielded similar or different results. Hence, further RCTs with larger sample size are required to validate the finding of our study.

 Conclusion



We conclude that both nitrous oxide and dexmedetomidine significantly decreased the total consumption of propofol. Hence, both these agents can be used as potential anesthetic adjuvants to decrease the side effects associated with propofol infusion. Due to the lack of any reported environmental and long-term side effects, dexmedetomidine can be a safer and better alternative to nitrous oxide.

Acknowledgment

We would like to acknowledge the support of Dr. Rakesh Kumar, Associate Professor, Department of Anaesthesiology and Critical Care and Dr. Jaykaran Charan, Associate Professor, Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur (India), for their help in the preparation and proofreading of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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