Oral Clonidine Premedication Attenuates Hemodynamic Responses of Ketamine during Total Intravenous Anesthesia.

BACKGROUND: The most commonly used drug for total intravenous anesthesia (TIVA) is ketamine which results in cardiovascular stimulation. AIMS: The primary aim of this study was to assess the effect of oral clonidine premedication on attenuating the hemodynamic responses following ketamine administration. SETTINGS AND DESIGNS: This was a prospective, observational, comparative study conducted in a tertiary care institution. SUBJECTS AND METHODS: A total of 40 female patients aged 18-55 years who were posted for elective short gynecological procedures under TIVA were recruited for this study. Group A patients were given oral clonidine 150 μg 60 min before proposed surgical procedure, whereas Group B patients received a placebo tablet. Before induction, all patients received glycopyrrolate 0.2 mg, midazolam 2 mg, and fentanyl 2 μg/kg intravenously. Anesthesia was induced with ketamine 1.5 mg/kg body weight intravenously over 2-3 min. The hemodynamics after premedication and induction were assessed. STATISTICAL ANALYSIS USED: To test the statistical significance or difference between the mean change from the basal value at various time points, student's t-test was applied.
RESULTS: At 20, 30, 40, 50, and 60 min postpremedication and after induction at 1, 3, 5, 10, 15, 20, and 30 min, Group B showed significantly higher heart rate. Systolic and diastolic blood pressures showed a significant decrease in Group A after induction up to 30 min. Nearly 6.7% of the patients in Group B had emergence delirium with none in Group A, which was not statistically significant.
CONCLUSION: Oral premedication with clonidine 150 μg, administered 60 min before the conduct of TIVA, attenuated hemodynamic responses of intravenous ketamine.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

The simplicity of total intravenous anesthesia (TIVA) along with its wide margin of safety has made it a very popular and widely practiced technique. One of the most commonly used drug for this purpose is ketamine. However, the undesired cardiovascular effects and occurrence of emergence delirium (ED) are of concern when ketamine is used for TIVA. We hypothesized that premedication with clonidine, a classical sympatholytic drug, might help to overcome these adverse hemodynamic effects.

Aim of the study

The primary objective of the present study was to assess the effect of oral clonidine premedication on attenuating the hemodynamic responses following ketamine administration in patients receiving TIVA. The secondary objective included assessment of the development of side effects, such as emergence delirium (ED), postoperative nausea and vomiting (PONV).

SUBJECTS AND METHODS

This study was an observational, comparative study conducted from September 2014 to September 2016. Based on the results on the changes in mean arterial blood pressure, as observed in an earlier quoted study by Tanaka and Nishikawa[1] with 95% confidence and 80% power, the minimum sample size was calculated to be 45 cases in each group. The study was conducted after obtaining Hospital Ethical Committee approval and informed consent of the patients.

Female patients aged 18–55 years, having the American Society of Anesthesiologists physical status classes 1 and 2, posted for elective short gynecological procedures under TIVA were included in the study. Patients with neurological abnormalities such as increased intracranial pressures, diabetes mellitus, renal and hepatic impairment, congestive, valvular or ischemic heart diseases, history of allergy to the study drugs, and those receiving psychotropic drugs were excluded from the study.

All patients were allotted to either of the two Groups A or B based on time of admission. Those patients who were admitted on the day before surgery were recruited into Group A, whereas Group B comprised patients who were admitted only on the day of surgery. After a thorough preanesthetic check-up, all patients were kept fasting for 6 h for solid food and 4 h for liquids. On the night before surgery, all patients received metoclopramide 10 mg, ranitidine 150 mg, and alprazolam 0.5 mg orally. On the day of surgery, in the preinduction area, a large bore intravenous cannula was inserted under local anesthesia and infusion of lactated Ringer's solution was started at a rate of 5 ml/kg/h. Group A patients were given oral clonidine 150 μg 60 min before the proposed surgical procedure with a sip of water, whereas Group B patients received a placebo drug which looked identical as the clonidine tablet. Baseline heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and oxygen saturation were documented before and after premedication at 10, 20, 30, 40, 50, and 60 min.

After 30 min all patients were shifted to the operation theater and received glycopyrrolate 0.2 mg, midazolam 2 mg, and fentanyl 2 μg/kg body weight intravenously before induction. Anesthesia was induced with ketamine 1.5 mg/kg body weight intravenously administered over 2–3 min. Supplemental anesthesia, if required, was provided with 10–20 mg ketamine in incremental bolus. Intraoperatively, oxygen supplementation was administered through face mask at the rate of 4 L/min. Tachycardia (heart rate >100/min) and/or hypertension (systolic blood pressure [SBP] >140 mmHg) were managed with propofol 20–30 mg bolus. Ondansetron 4 mg was given to all patients soon after induction. All the hemodynamic variables were noted at immediate preinduction, at induction and further at 1, 3, 5, 10, 15, 20, and 30 min.

An observation was made related to adverse effects such as PONV and ED, if any, and was attended appropriately. Patients were interviewed at the time of discharge to assess any intraoperative recall of events or hallucinations.

To test the statistical significance or difference between the mean change from the basal value at various time points, Student's t-test was applied and a “P” < 0.05 was considered statistically significant. Analysis was performed using SPSS software version 2.0 (Bengaluru, India).

RESULTS

The demographics of patients in both the groups were comparable. The baseline heart rate and that recorded after 10 min of administration of clonidine did not show any significant difference between the groups (P = 0.148). However, at 20, 30, 40, 50, and 60 min postpremedication and also after induction at 1, 3, 5, 10, 15, 20, and 30 min, Group B showed significantly higher heart rate [P < 0.05, Table 1].

Table 1

Comparison of heart rates

The baseline SBP as well as the SBP till 1 min after induction was comparable in both the groups. However, the SBP recorded at 1, 3, 5, 10, 15, 20, and 30 min after induction showed a significant decrease in Group A [P < 0.05, Table 2]. The baseline DBP as well as that recorded up to 1 min following induction was comparable (P > 0.05). However, DBP recorded at 3, 5, 10, 15, 20, and 30 min after induction showed a significant reduction in Group A. From 30 min after premedication, MAP was significantly lower in group A throughout the study period [P < 0.05, Table 3 and Figure 1].

Table 2

Comparison of systolic blood pressure

Table 3

Comparison of diastolic blood pressure

Figure 1

Changes in mean arterial pressure

On comparing the incidence of postoperative ED, it was found that 6.7% of the patients in Group B had ED, whereas no such incidence was observed in Group A. However, this finding was not statistically significant (P = 0.242). The incidence of PONV did not show any significant difference between groups as an equal number of patients in both the groups (4.5%) developed it [Table 4].

Table 4

Comparison of postoperative nausea, vomiting, and emergence delirium

DISCUSSION

TIVA is a method of general anesthesia which involves the use of intravenous drugs for induction and maintenance of anesthesia without the use of inhalational agents.[2] The major advantage of using TIVA is that it does not require sophisticated anesthesia delivery systems for the conduct of anesthesia. The recovery, in general, is smooth and predictable. It produces adequate amnesia, and since inhalational agents are not used, the chance of developing malignant hyperthermia is rare.[3]

Although various drugs had been tried as TIVA agents, no single drug had been able to provide all the favorable features of an ideal intravenous agent. However, ever since its introduction into clinical practice decades back, ketamine quickly become the most popular drug for the administration of TIVA, mainly because of its analgesic and amnesic effects. However, its use in certain high-risk patients is limited due to the adverse effects on cardiovascular,[4] and central nervous system changes.[5] These effects can be of concern in normal patients also, as exaggerated hypertension and tachycardia could result in excessive surgical bleeding. The intraoperative control of hemodynamics will necessitate administration of more opioids, benzodiazepines, and sedatives, which can ultimately result in prolonged recovery from anesthesia and subsequent delays in discharge from the hospital.

One of the practical approaches to minimize the problems of ketamine-induced sympathetic response is the concurrent use of an α2 adrenergic agonist like clonidine. It attenuates the sympathetic responses,[6] produces a significant reduction in anxiety, and provides a better quality of induction of anesthesia when used as a premedicant. It had been shown that the addition of oral clonidine 60 min before intravenous ketamine induction provided better control of hemodynamic responses.[1789]

Oral clonidine 150 μg was administered in the present study in Group A patients with an intention to attenuate the hemodynamic responses. We decided the dose as 150 μg as Singh and Arora[8] and Sung et al.[9] had proven its safety in their studies. Oral clonidine 300 μg had also been used successfully to reduce intraoperative bleeding by optimizing hemodynamic parameters during functional endoscopic sinus surgery.[10] However, we choose to use 150 μg only as there was a concern that use of higher doses might delay patient discharge since our study group comprised day-care patients who were to be discharged on the same day itself.

In this study, baseline hemodynamic variables were comparable. After ketamine administration, better heart rate control was observed in Group A as compared to Group B. This could be explained on the basis of adequate sympathetic block following clonidine premedication. However, in the study conducted by Tanaka and Nishikawa,[1] the heart rate response after ketamine administration was not affected by clonidine premedication. There was a mild increase from baseline values, which was not statistically significant. Such different results may be attributed to the difference in study designs. First, in their study, the patients were ventilated manually, and the end-tidal carbon dioxide concentration was maintained at nearly constant values, whereas in our study the patients were breathing spontaneously. It cannot be concluded if these patients had a normal level of carbon dioxide or they were retaining it. Second, after induction of anesthesia with ketamine, nitrous oxide was added to oxygen as an inhaled mixture in their group. However, in our study, patients received supplemental oxygen only, and no inhalational agents were added. As it is known that nitrous oxide has a good analgesic property, it could have prevented a higher increase in heart rate from the baseline values.

The blood pressures in patients of Group A were lower than that of Group B patients. The sympathetic block following clonidine premedication in patients of Group A could be the reason for this effect also. This observation is in agreement with previous studies by Handa et al.[7] and Tanaka and Nishikawa[1]

The association of salivation attributable to ketamine was blunted by the use of intravenous glycopyrrolate 0.2 mg, administered at induction, in our study. However, the study done by Handa et al.[7] showed that there was reduced incidence of salivation following the use of oral clonidine as premedication before ketamine induction. Such observation was made in their study when they had used clonidine at a dose of 5 μg/kg, but in our study, we have used 150 μg clonidine for all patients irrespective of their body weight. Titration of dose based on the body weight was not possible in our study as we were using clonidine tablets for premedication.

In this study, Group B patients experienced a higher incidence of ED (6.7% vs. 0) in comparison with patients in Group A, which was not statistically significant. Similar observation was made by Handa et al.[7] in their study. In the study by Malviya et al.,[11] they had found similar results but with statistical significance. This significant difference in results can be attributed to the study group characteristics. Their study was conducted in patients aged 2–10 years, whereas the mean age of the patients in our study was above 40 years. It is known that the incidence of emergence agitation is less in pediatric age group because of psychological immaturity and temperament,[512] which might have made the difference in the incidence of emergence agitation in their study. Moreover, they had used intravenous clonidine which might have also potentiated the effect.

One of the major limitations of the study was that the heart rate, systolic blood pressure, DBP, and mean arterial pressure were measured till 30 min post-induction. As the elimination half-life of clonidine is nearly 240 min, the study period should have been extended up to that period to fully evaluate the hemodynamic responses that followed clonidine administration.

We had used a fixed dose of oral clonidine for all the patients irrespective of their weight as we were using oral tablets. Intravenous administration could have allowed titration of dose based on body weight and might have provided more accurate results.

Another drawback of our study was that the patient population comprised female patients only and all of them underwent a similar form of surgery. The observations made during our study were mainly clinical. Other factors such as carbon dioxide retention, which could cause similar changes in hemodynamics, were not ruled out using accurate tests like blood gas analysis.

CONCLUSION

Oral premedication with clonidine 150 μg, administered 60 min before the conduct of TIVA, effectively attenuated the hemodynamic responses of intravenous ketamine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.