Introduction
Propofol is the most commonly used induction agent in day care surgery. 1 On intravenous (IV) administration it causes intense burning pain which adds to patient dissatisfaction.2 Incidence of pain on IV propofol administration into a vein on dorsal aspect of hand has wide distribution ranging from 28% to 90%.3 Patient may present with pain concurrently with IV propofol administration or later.4 Direct irritant effect of propofol on vein causes pain on concurrent administration and kinin cascade release causes the pain 10-20 seconds later.5, 6, 7 The attempts to develop pain free or lesser pain causing formulations of propofol have been futile.4 There are many medicinal and non medicinal ways to allay IV propofol induced pain.4, 8, 9 Some of medicinal methods are pretreatment with lignocaine, ketamine and opioids. Of these, pretreatment with IV lignocaine has proven to be most efficacious, by reducing propofol induced pain by nearly 60%.4 Though IV lignocaine pretreatment is better than other interventions, none of the available interventions can prevent pain on IV propofol administration in 100% of patients.4
In this context many new pharmacological agents including 5HT3 receptor antagonists have been tried to prevent pain on IV propofol administration.4, 10 Ondansetron a specific 5HT3 receptor antagonist, has shown the property of local anesthesia, which can be used to allay propofol pain on IV administration.11, 12 Granisetron, a higher congener of ondansetron is a specific 5HT3antagonist with longer period of action and has shown better antiemetic effect.13 The preliminary evidence suggests that granisetron is effective in preventing pain on IV propofol administration.2, 14 However, replication studies are needed to gather more evidence regarding the effectiveness of granisetron. In this study the efficacy of IV granisetron 2mg in 3ml with IV lignocaine 1% (30mg in 3 ml) in allying pain on IV propofol administration was compared.
Materials and Methods
Our study was a double blind randomized controlled trial and the patients were recruited after obtaining ethical committee clearance and informed consent. The sample size was calculated for the effect size of 0.3 with alpha value of 0.05 and 80% power of the study corresponding to 48 patients in each group. So, 100 patients were randomized to two groups of 50 each i.e., granisetron group (group G) and lignocaine group (group L). Patients were considered for study if they were between 18-50 years, chosen for elective surgery under general anaesthesia belonging to American Society of Anesthesiologists (ASA) physical status grades I and II. Patients with history of allergy, having received any sedatives, analgesics within 48 hours before procedure, who were pregnant and lactating, having communication disability and undergoing emergency procedures were excluded from our study. Preanaesthetic evaluation was performed one day before surgery. In the operating room, 20 G cannula was secured on the dorsal surface of hand. Standard monitors were connected, pulse rate (PR), non invasive blood pressure (BP), peripheral oxygen saturation (SpO2) and respiratory rate (RR) were measured and recorded at 3 time intervals i.e., before administering propofol and after 1 and 3 minutes of propofol administration. Tourniquet was used to occlude the venous drainage. Patients of group G received 2mg (3ml) of granisetron IV and those of group L received 30mg lignocaine (3ml of 1% solution) IV, over a period 5 seconds about 5 minutes after cannulation. The tourniquet was released after 1 minute of premedication. Initially 20 mg bolus (2ml of 1% solution) propofol was administered over 4 seconds and 15 seconds later patient was asked to rate the pain due to propofol administration. Grading of pain was done using McCrirrick and Hunter scale (Table 1), a standardized measure of pain after IV administration of propofol (15). The author PS was blind to the randomization and evaluated the pain after propofol administration using the above-mentioned scale. Following the pain rating, patient was induced with overall dose of 2 mg/kg-body weight of propofol (including the initial bolus) & intubation with appropriate tube size was done. PR, blood pressure (BP), SpO2 and RR was recorded at 1 and 3 minutes after induction. Routine maintenance and monitoring of anaesthesia was done. At the end of surgery, reversal of muscle relaxation (neostigmine 0.05mg/kg & glyocopyrrolate 10 mcg/kg, IV) was done and the patients were extubated. The PR, BP, SpO2 & RR recordings before induction, at 1 & 3 min after induction were compared between Group L and G.
The data was analyzed using the R software. The data was evaluated for the normality of the distribution. The results for continuous variables were presented as mean and standard deviation and mean difference between groups was compared using independent t test. The categorical variables between the groups were compared using Chi-Square test. Repeated measure analysis of variance (RM-ANOVA) was done to compare the PR, BP, SpO2 & RR before and after propofol induction between the groups. For all the tests probability (P) value ≤ 0.05 was considered as statistically significant.
Results
Patients’ age, weight and ASA physical status were compared between the two groups (Table 2). The pain after propofol administration was absent in 76.0% and 62.0% patients of group L and group G respectively. Nearly 12.0% of the group L patients and 20.0% of group G patients had mild pain, while this percentage was 12.0% and 18.0% for moderate pain. None of the patients in both the groups had severe pain. The group difference was calculated using chi-square test for 2x3 table. The pain reduction between groups L and G (χ2 = 2.310, P= 0.315) was insignificant. There was no statistically significant mean difference between the groups in PR, RR, BP and SpO2 at baseline and on RM-ANOVA there was no significant group time interaction for these variables at the end of 1 and 3 minutes of propofol administration compared to the baseline except for RR (Table 3). RR had significant group time interaction with granisetron group having decreased RR after induction with propofol compared to lignocaine (Table 3). The post hoc comparison of the RR across different time frames suggested that compared to the baseline, mean difference in RR at the end of 1 minute (p=0.006) as well as at the end of 3 minutes (0.031) was significantly different between the groups with group G having decreased RR after induction (Table 4).
Figure 1
Difference in respiratory rate (RR) over time after induction with propofol between lignocaine and granisetron groups
Table 1
Mc Crirrick and Hunter scale of evaluation of propofol intravenous administration pain
Table 2
Demographic and clinical variables of the groups
Table 3
Group and time interaction of the clinical variables
Table 4
Post hoc analysis comparing the respiratory rates across time frames between groups
Discussion
The important finding of our study was that granisetron is equally effective as lignocaine for the management of pain on IV propofol administration. On comparison of two groups in pain reduction as well as in hemodynamic stability and peripheral blood oxygenation measured with PR, BP and SpO2 respectively was insignificant.
Propofol is a fast-acting agent and its action wears off quickly making it useful for day care procedures.15 At sub hypnotic doses, it provides excellent sedation, amnesia, anxiolysis and a state of general well being in addition to its advantageous antiemetic action. As discussed earlier, its utility is constrained by pain on IV administration occurring in significant percentage of patients.6
When compared with placebo or normal saline, lignocaine has been shown to be significantly effective in reducing pain on IV propofol administration.16 Similar to the earlier findings, in our study also nearly three fourth of the patients did not have pain on IV propofol administration after prophylactic administration of lignocaine and it is in accordance with the earlier reports of success rates ranging between 56-87%.16, 17 Interestingly, nearly two third of the patients (62%) did not have pain on IV propofol administration in the granisetron group and it is in line with the findings from the earlier study where 60% of the patients had no pain on IV propofol administration at the end of 15 seconds.18 In another study comparing the granisetron with placebo, nearly 90% of the patients on granisetron were reported not to have pain. But in this study after how many seconds of propofol administration pain was measured is not mentioned. We feel it is probable that the pain assessment was done immediately after (at 5 seconds) the propofol administration accounting for higher percentage of patients reporting no pain on IV propofol administration, as found in the Singh et al study.2, 18 Overall, the findings of our study add more evidence to the role of 5HT3 receptor antagonists in general and granisetron in specific for the management of pain on IV propofol administration.
Another important aspect of our study was the absence of significant group difference between lignocaine and granisetron for the prevention of pain on IV propofol administration although numerically greater number of patients in the lignocaine group were pain free. Our findings are consistent with previous studies showing both lignocaine and granisetron being equally effective in preventing pain on IV propofol administration.11, 19 Our study also affirms that the incidence of pain on IV propofol administration is much reduced in both the groups than patients who did not receive any pretreatment.16 Our findings suggest that the anaesthesiologist may select either agent for the prevention of pain on IV propofol administration based on the individual profile of the patient. Of these two agents, 5HT3 antagonist granisetron carries the additional advantage of having antiemetic effect in the postoperative phase.
The PR, BP (both systolic blood pressure and diastolic blood pressure), SpO2 and RR were compared during pre-induction, post induction at 1minute and 3 minutes. All the parameters remained similar except for RR which decreased in the granisetron group over time. Although there was statistically significant group difference in RR, the absolute value of the mean difference was less than 2 per minute and the clinical relevance of the same may be insignificant and needs to be tested in studies with larger sample size. In addition, the confounding effect of induction dose of propofol on RR across groups has not been assessed and we could not come across any literature on pretreatment with granisetron influencing the respiratory rate. Otherwise, both lignocaine and granisetron did not cause any significant hemodynamic disturbances in our study. Even in patients who experienced pain on propofol intravenous administration, increase in heart rate was not significant enough to cause hemodynamic instability. The findings of our study should be interpreted considering the limitation of the small sample size. Although we recommend granisetron over propofol for its anti emetic action, we could not compare the postoperative nausea/vomiting between the groups.
Conclusion
We conclude that granisetron decreases the POPI as effectively as lignocaine and both the drugs did not differ in their effect on hemodynamic factors after the induction with propofol. Granisetron has an added advantage of decreasing postoperative nausea and vomiting. Further research is needed with larger sample size to confirm the findings.