Therapeutic Efficacy of Two Different Doses of Dexmedetomidine on the Hemodynamic Response to Intubation, the Intubating Conditions, and the Effect on the Induction Dose of Propofol: A Randomized, Double-Blind, Placebo-Controlled Study.

CONTEXT: The hemodynamic response associated with laryngoscopy and tracheal intubation is a common concern for the anesthesiologist, especially in high-risk patients. The use of dexmedetomidine has found favor in obtunding this response, in addition to providing better intubating conditions and reducing the dose of other anesthetic drugs. Most of the current literature states a loading dose of 1 μg/kg dexmedetomidine to be superior to lower doses in this regard. However, using a lower dose may be advantageous by reducing incidence of adverse effects such as hypotension and bradycardia which are likelier with the use of higher dose, in addition to being more cost-effective. AIMS: The aim of the study was (1) to evaluate and compare the effect of loading doses of 1 μg/kg and 0.5 μg/kg dexmedetomidine on attenuation of hemodynamic response to laryngoscopy and intubation and (2) to evaluate the efficacy of dexmedetomidine in reducing the induction dose of propofol for achieving better intubating conditions.
MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study was planned on ninety American Society of Anesthesiologists I and II patients scheduled for elective surgery under general anesthesia. Patients were divided into three groups. Two groups received different loading doses of dexmedetomidine infusion before induction and the third group was a control group. The induction dose of propofol required to abolish the verbal response was noted and compared in all the three groups. All patients were assessed for the intubating conditions and hemodynamic response. STATISTICAL ANALYSIS: Nonparametric data were compared using the Chi-square test and parametric data were compared using Student's t-test using SPSS 16.0 software.
RESULTS: Both the loading doses of 1 μg/kg and 0.5 μg/kg dexmedetomidine were equally effective in reducing the induction dose of propofol, improving the intubating conditions and blunting the hemodynamic response to laryngoscopy and intubation. The incidence of adverse effects such as hypotension and bradycardia was lesser with the loading dose of 0.5 μg/kg.
CONCLUSIONS: Dexmedetomidine when used as infusion in the loading dose of 0.5 μg/kg is therapeutically as effective as when used in the dose of 1.0 μg/kg not only in reducing the induction dose of propofol but also in providing good intubating conditions and blunting the hemodynamic response to intubation. A lower dose is associated with a lesser incidence of adverse effects such as hypotension and bradycardia.

INTRODUCTION

Dexmedetomidine, the S-enantiomer of medetomidine, a relatively newer alpha-2 adrenoreceptor agonist was first used in 1999 as a sedative during premedication primarily in the Intensive Care Units.[123] However, with the passage of time, dexmedetomidine has proved to be a novel drug which is currently used for the purpose of analgesia,[4] day-care surgeries,[5] short procedures such as colonoscopies,[67] and as an adjunct to general anesthesia for the purpose of co-induction.[8] The term co-induction of anesthesia has been applied to the use of two or more drugs to induce anesthesia. Co-induction of anesthesia is practiced by anesthesiologists exploiting drug interactions, particularly synergism. It can produce an improvement in all phases of anesthesia including induction, maintenance, and recovery.[9] Till date, no perfect drug or drug combination that would blunt the hemodynamic response completely without causing unwanted side effects has been found, but dexmedetomidine promises to be a good option.[10] It was found that patients sedated with dexmedetomidine could be easily aroused for cooperation with procedures and it may protect against myocardial ischemia and reduces the requirement of opioid analgesia. Furthermore, the dose of induction agents such as propofol and thiopentone for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine.[11] The hemodynamic response to laryngoscopy and intubation is also decreased with the administration of dexmedetomidine.[12131415] Existing comparative studies of different doses of dexmedetomidine in blunting the hemodynamic response have found the use of a higher loading dose of 1 μg/kg to be more effective compared to lower doses and advocated the use of higher dose.[16] However, this advantage may be offset by adverse effects such as hypotension and bradycardia which are likelier to occur with higher dose. A lower dose of 0.5 μg/kg, besides blunting the hemodynamic response, would be safer in terms of having a reduced incidence of adverse effects and being more cost-effective.

Our study was conceptualized to evaluate and compare the effects of two different doses of dexmedetomidine, i.e. 1 μg/kg and 0.5 μg/kg not only for attenuation of hemodynamic response to laryngoscopy and intubation but also to evaluate the efficacy to reduce the induction dose of propofol for achieving better intubating conditions.

MATERIALS AND METHODS

This study was conducted in a tertiary care hospital from the period of June 2013 to June 2014 with prior approval from the Ethical Committee of the Institution. Informed written consent was obtained from ninety patients between the ages of 18 and 65 years categorized as physical status Class I and II according to American Society of Anesthesiologists (ASA), scheduled to undergo endotracheal intubation and general anesthesia for elective surgery. Patients with age <18 years and >65 years or with the previous history of difficult or failed intubation, physical characteristics suggesting difficult intubation – Mallampatti Grade III and IV, body mass index >30, history of uncontrolled hypertension, cardiovascular disorders, and pregnant patients were excluded from the study.

A preanesthetic checkup of all included patients was conducted 1 day before the surgery which included a detailed history, a thorough physical examination, and both general and systemic with basic/relevant investigations. Patients were randomly assigned using a computer-generated block randomization schedule, to compose three groups of thirty patients each.

Group I received loading dose of 1 μg/kg body weight of dexmedetomidine in 10 ml saline over 10 min intravenously before induction

Group II received a loading dose of 0.5 μg/kg body weight of dexmedetomidine in 10 ml saline over 10 min intravenously before induction

Group III: Control group received normal saline 10 ml bolus before induction over 10 min intravenously before induction.

The patient as well as the anesthesiologist performing intubation was not aware of the group to which the patient belonged and the study drug was prepared by an anesthesiologist who was not participating in the study. Hence, our study was double-blinded. However, in case of any adverse event related to the study drug, the anesthesiologist who prepared the drug was authorized to reveal the drug.

All patients received premedication with pantoprazole 40 mg perorally, a proton-pump inhibitor for acid prophylaxis and midazolam 7.5 mg, a benzodiazepine for anxiolysis perorally on the eve of surgery. All the patients were kept fasting overnight for 8 h.

On the day of surgery, all the patients (n = 90) included in the study were started with Ringer's lactate infusion at the rate of 60 ml/h. Subsequently, injection fentanyl (a potent synthetic opioid analgesic with a short duration of action) in the dose of 1 μg/kg body weight, followed by injection ondansetron (a serotonin 5HT3 receptor antagonist for the prevention of postoperative nausea and vomiting) in the dose of 0.1 mg/kg body weight and injection ranitidine (a histamine H2 receptor antagonist) in the dose of 50 mg were administered intravenously.

Following this, study drug was infused intravenously over a period of 10 min, and all the patients were preoxygenated during this time using a face mask. As soon as the study drug infusion was over, the induction of anesthesia began with 1% propofol intravenously at the rate of 0.5 ml/s which continued till the patient's verbal response was abolished. The dose of propofol required for abolishing this response was noted after which neuromuscular blockade was achieved with injection rocuronium administered intravenously in the dose of 0.9 mg/kg body weight. Subsequently, endotracheal intubation was attempted after 90 s. While intubation was performed, all patients were assessed for five variables – face mask ventilation, jaw relaxation, positioning of vocal cords, movement of vocal cords on intubation, and reflex movement on tracheal intubation.

Baseline electrocardiography, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and oxygen saturation (SPO2) were recorded at the time of starting study drug and then after every 2 min till intubation. Subsequently, vitals were recorded at 2, 5, and 10 min after intubation. Any variation in BP and HR was recorded. Hypotension (reduction in arterial pressure of 20% or more from baseline) was noted and planned to be treated primarily by increasing the intravenous (IV) infusion rate and was followed by 10 mg bolus dose of ephedrine (a sympathomimetic amine) as per requirement. Hypertension (increase in arterial pressure 20% or more from baseline) was treated by deepening the level of anesthesia with inhalational anesthetic agent isoflurane. Bradycardia (HR <45 beats/min or 20% decrease from baseline) was treated with 0.5 mg IV bolus of atropine, a competitive muscarinic acetylcholine receptor antagonist. Tachycardia (HR >100 beats/min or 20% increase from baseline) was planned to be treated by injection esmolol 0.2 mg/kg an ultra-short acting cardioselective β1 receptor blocker. Other side effects such as erythema, allergic reactions, or arrhythmias were also evaluated and dealt with accordingly.

Anesthesia was maintained with oxygen, nitrous oxide, and halothane. Top-up doses of rocuronium were also given for maintenance. At the end of surgery, the neuromuscular blocking agent was antagonized with a combination of neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Patients were transferred to postanesthesia care unit after the completion of surgery.

All the observations made in the study were recorded and compared for each parameter at different intervals as per protocol. All the data were analyzed and subjected to statistical analysis for significance. Nonparametric data were compared using the Chi-square test and parametric data were compared using Student's t-test using SPSS 16.0 software(Dexmedetomidine (Trade name Dextomid), Neon laboratories limited, Mumbai, Maharashtra, India). P < 0.05 was considered statistically significant.

RESULTS

The three groups were comparable with respect to age, sex, and ASA status. The various parameters such as HR, SBP, DBP, MAP, and SPO2 were noted during the infusion of study drug after laryngoscopy and intubation. The conditions during intubation such as ease of mask ventilation, jaw relaxation, position of vocal cords and reflex movement on intubation, and dose of propofol required to abolish the verbal response during intubation were recorded.

During the infusion of loading dose of 1 μg/kg dexmedetomidine given in an infusion over 10 min, the HR showed a 19.19% decline as compared to the control. The comparison was statistically highly significant (P < 0.01) with the control group. When a loading dose of 0.5 μg/kg of dexmedetomidine was given in an infusion, a 7.17% fall of HR was seen. This comparison was also found to be significant (P < 0.01) as compared to the control [Figure 1]. Dexmedetomidine did not have any significant effect on SBP and MBP [Figures 2 and 3], whereas the DBP [Figure 4] showed a fall of 19.61% fall when 1 μg/kg dexmedetomidine was given (P < 0.01) and 7.73% when 0.5 μg/kg was given (P < 0.01).

Figure 1

Effect on heart rate

Figure 2

Effect on systolic blood pressure

Figure 3

Effect on mean arterial pressure

Figure 4

Effect on diastolic blood pressure

Following laryngoscopy and intubation, there was a fall of 10.19% (P < 0.01) and 6.74% (P < 0.01) in the HR with 1 μg/kg and 0.5 μg/kg dexmedetomidine, respectively. The SBP, DBP, and MBP also showed a significant decline with both the doses of dexmedetomidine (P < 0.01) when compared to the control group. It was seen that the SPO2 was unaffected during the infusion of the study drug as well as following laryngoscopy and intubation.

The comparison of variables of mask ventilation showed that mask ventilation was easy in 28 (93.33%) patients of Group I as compared to only 26 (86.67%) patients of Group II and III [Table 1]. The comparison was statistically significant (P < 0.01). During the study, jaw was found to be relaxed in all patients receiving 1 μg/kg dose and 29 (96.67%) patients receiving 0.5 μg/kg dose as compared to 27 (90.00%) patients in the control group (P < 0.1) [Table 2]. Position of vocal cords was significantly affected by dexmedetomidine infusion, being paramedian in 29 (96.67%), 27 (90.00%), and 25 (83.33%) patients in each group, respectively (P < 0.1). Furthermore, reflex movement of vocal cords was seen in only 1 (3.33%) patient of Group I as compared to none of the patients of Group II and 4 (13.33%) patients of Group III (P < 0.1) [Table 3]. Four (13.33%), 5 (16.67%), and 9 (30.00%) patients, respectively, of Group I, II, and III showed reflex limb movement during laryngoscopy and intubation or immediately following it [Table 4].

Table 1

Mask ventilation

Table 2

Jaw relaxation

Table 3

Vocal cord position

Table 4

Reflex movement

The induction dose of propofol required to abolish the verbal response was reduced to almost half its dose in Group I and Group II with a dose of 1.19 mg/kg and 1.16 mg/kg body weight, respectively, in comparison to 2.12 mg/kg in Group III [Figure 5]. Side effects such as hypotension were seen in 1 (3.33%) patient in Group I compared to none of the patients in the other two groups. Another side effect encountered was bradycardia seen in 2 (6.67%) patients in Group I and 1 (3.33%) patient in Group II and none in Group III, respectively [Table 5].

Figure 5

Effect on average dose of propofol

Table 5

Side effects

DISCUSSION

Tracheal intubation is associated with catecholamine release and pressor response, leading to elevation in HR and arterial pressure. A number of prior studies[151617181920] have reported the use of dexmedetomidine to suppress this response as well as to reduce the dose of anesthetic agent. In our study, the hemodynamic response was significantly reduced but not completely abolished with the use of dexmedetomidine. This effect of dexmedetomidine could be attributed to its action on postsynaptic α2 receptors in the locus coeruleus and activation of endogenous sleep-promoting pathway. This effect can be particularly useful in patients suffering from cerebrovascular disorders, cardiovascular disorders, and hypertension.

Sağıroğlu et al.[16] in their comparative studies of two different doses of dexmedetomidine reported that a dose of 1.0 μg/kg was more effective than a dose of 0.5 μg/kg in blunting the hemodynamic response to laryngoscopy and intubation. In our study, the hemodynamic response was sufficiently blunted with both the doses of dexmedetomidine. HR and blood pressure remained stable and showed an increase not >20%.

In a meta-analysis of assessment of dexmedetomidine as an anesthetic agent by Piao and Wu,[21] the occurrence of adverse effects such as hypotension and bradycardia with dexmedetomidine was found to be significantly higher as compared to controls. Khan et al.,[22] in their comparative study of 1.0 μg/kg and 0.5 μg/kg doses of dexmedetomidine, reported a higher incidence of hypotension and bradycardia with the use of higher dose of the drug. In our study, the use of lower dose was associated with a lesser incidence of both these side effects. Considering the adequacy of both the low and high doses in blunting the hemodynamic response, the relative safety of lower dose with regard to these adverse effects appears to offer a definite clinical advantage, especially in patients with low blood volume and heart block.

Dexmedetomidine also sufficiently decreases the induction dose of propofol. The verbal response was abolished equally with both the doses of dexmedetomidine to almost half of the routine intubating dose. The reduction in anesthetic requirement was in concordance with earlier studies conducted by Bührer et al.,[11] Keniya et al.,[15] and Laha et al.[19]

Sağıroğlu et al.,[16] in their comparative study of two different doses of dexmedetomidine, found no difference in the quality of intubation with either dose. In our study, the anesthesiologist experienced better intubating conditions with improvement in mask ventilation and jaw relaxation. Position of vocal cords was also favorable for intubation and the movement of vocal cords and limbs' minimum when dexmedetomidine was given as an adjuvant with propofol. Both doses of 1 μg/kg and 0.5 μg/kg were equally effective in achieving these effects.

A possible limitation of our study was that opioids used in all the patients in our study themselves blunted the hemodynamic response to laryngoscopy and intubation. Other limitations were the study being confined to a single center, inability to quantify plasma catecholamine levels due to nonavailability of the facility at our institution, as well as lack of quantification of the depth of anesthesia (bispectral index).

CONCLUSIONS

Dexmedetomidine when used as infusion in the loading dose of 0.5 μg/kg is therapeutically as effective as when used in the dose of 1.0 μg/kg, not only in reducing the induction dose of propofol but also in providing good intubating conditions and blunting the hemodynamic response to intubation for better anesthetic results. A lower dose besides being cost-effective is also free of side effects such as hypotension and bradycardia which are associated with the higher dose of 1 μg/kg infusion of dexmedetomidine.

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Conflicts of interest

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