European Journal of Cardiovascular Medicine

Propofol is a short acting, hypnotic amnestic agent most commonly used as intravenous induction agent due to its rapid onset of action and rapid recovery of cognitive and psychomotor skills with minimal excitation and lower incidences of postoperative complications.1 It is routinely used in ambulatory anesthesia, day care surgeries and sedation in intensive care unit. However, a few properties make this drug less than ideal to use as a sole induction agent as it causes marked fall in systemic blood pressure of all the intravenous induction drugs.2

This is mainly due to significant reduction in systemic vascular resistance and cardiac output. The fall in systemic blood pressure is dose dependent. Hence, to alleviate this problem, administration of opioid prior to Propofol is conceptualized as a part of balanced anesthesia as opioids reduce the Propofol dose required for induction of anesthesia and help improve hemodynamic stability.3 Several combinations of pharmacological agents have been introduced to decrease the hemodynamic instability in Propofol induction.

Fentanyl is a potent synthetic opioid which acts as mu receptor agonist. It is the most popular opioid used in the intraoperative period throughout the world for analgesia. It acts synergistically with Propofol and attenuates hemodynamic response to laryngoscopy and endotracheal intubation.4 the dose- effect relationship of both Fentanyl and Propofol have been described separately as well as together.5 However, the ideal time interval between administrations of Fentanyl and Propofol is yet to be established. In various studies, Fentanyl is given immediately before Propofol6 or after the interval of 3 to 5 minutes7 between the drugs.

To find out the temporal relationship of administration of these two drugs, we believe that if Propofol is injected after the peak effect of Fentanyl is achieved it will lead to significant reduction in required Propofol dose and hence further decreases the associated side effects of Propofol. There is sparse evidence in the available medical literature in comparing the efficacy of varying intervals between Fentanyl and Propofol administration on the dose of Propofol required to achieve loss of consciousness during induction of anesthesia and evaluate hemodynamic stability among a subset of cancer patients posted for elective oncosurgeries and hence this study is proposed.

The study was conducted to find out the temporal relationship of administration of these two drugs to establish if there exists a significant reduction in required Propofol dose and if it further decreases the associated side effects of Propofol.

A randomized prospective clinical study was conducted at Kidwai Memorial Institute of Oncology, Bangalore from February 2021 to December 2021. We decided to enroll 40 patients in each group, with a total sample size of 120 patients.

INCLUSION CRITERIA

• Patients aged >18 and <60 years.

• American Society of Anesthesiologists (ASA) status 1 and 2.

• Patients undergoing elective oncosurgeries.

EXCLUSION CRITERIA

• Patient refusal.

• History of allergy to study drug.

• Obesity (BMI >30kg/m2

• Anticipated difficult airway.

• History of cerebrovascular accident, ischemic heart disease, systemic hypertension,

Chronic obstructive lung disease.

• Impaired renal function test and impaired liver function test.

• History of alcohol or drug use.

• Hemodynamic instability.

• Emergency surgery.

Procedure

After obtaining approval from the ethics committee, data was collected from patients who were admitted to Kidwai Memorial Institute of Oncology for elective oncosurgeries performed under general anesthesia from February 2021 to December 2021. Patients fulfilling the inclusion criteria were briefed about the procedure and written informed consent was taken. Patient’s demographic details were noted. The following investigations were conducted preoperatively as a part of preanaesthetic evaluation:

Complete Blood count, Serum electrolytes, Random blood sugar, liver function test, Blood Urea Nitrogen and Serum Creatinine, ECG, X-Ray chest, if indicated 2D ECHO was also done. Informed/written consent was obtained from patients before starting the study. Patients were kept nil per oral for 8 hours prior to the surgery and were premedicated with Tab Pantoprazole 40 mg on the night prior to the surgery.

Patients were randomized using computer generated random number tables and were assigned to one of the three groups:

Group A: Patients received Propofol immediately after the administration of injection Fentanyl 1mcg/kg.

Group B: Patients received Propofol 3 minutes after the administration of injection Fentanyl 1mcg/kg.

Group C: Patients received Propofol 5 minutes after the administration of injection Fentanyl 1mcg/kg.

In the operation theatre, patients were connected to standard monitors including Electrocardiography, pulse oximetry and non-invasive blood pressure and baseline parameters were recorded followed by recordings at 1 minute intervals. An intravenous line was secured and patients were started on Ringer lactate solution as maintenance fluid @100ml/hr. Patients were pre oxygenated with 100% oxygen for 3 minutes.

All hemodynamic data such as Heart rate (HR), Systolic Blood pressure (SBP), Diastolic Blood pressure (DBP), Mean Arterial Pressure (MAP) were recorded on arrival in OT followed by recordings at 1 minute intervals. Maintenance of anaesthesia was by 40% O2, 60% N2O and Isoflurane (0.8 to 1 MAC), 0.02 mg/kg Vecuronium was used to maintain intraoperative neuromuscular blockade. At the completion of the surgery, Inj. Ondansetron 0.15mg/kg I.V was administered. The residual neuromuscular blockade was antagonized with Neostigmine 0.05mg/kg and Glycopyrrolate 0.01mg/kg intravenously. Patient was extubated after adequate spontaneous ventilation was established.

Statistical Analysis

The Mean and Standard deviations of Heart Rate (HR), Systolic Blood pressure (SBP), Diastolic Blood pressure (DBP) and Mean Arterial Pressure (MAP) in each of the groups were analyzed by Analysis of Variance (ANOVA). The intragroup analysis was done by paired Student’s t-test. P<0.05 was considered as significant. Statistical analyses were performed using SPSS version 22.0 for Windows. Results on continuous measurements are presented as Mean±SD and results on categorical measurements are presented as Number (%). The Mean and Standard deviations of Heart Rate (HR), Systolic Blood pressure (SBP), Diastolic Blood pressure (DBP) and Mean Arterial Pressure (MAP) in each of the groups were analyzed by Analysis of Variance (ANOVA). The intragroup analysis was done by paired Student’s t-test. Chi-square /Fisher Exact test was used to find the significance of study parameters on categorical scale between the two groups. P value <0.05 was considered significant.

Table 1: Patient characteristics

45% of the subjects in our study belonged to the age range of 51-60 years. Mean age was found to be 52.7 years in Group A, 51.8 years in Group B and 52.9 years in Group C.

Table 2: Difference between the groups in terms of age and body weight

The study comprised of patients in the age group 18-60 years. In the study, all 3 groups were comparable in terms of mean age. There was no statistical significance with p value of 0.54. In Group A, mean weight was 63.8 kg. In Group B, mean weight was 59.9kg, and in Group C mean weight was 61.2kg. All three groups were comparable in terms of body weight. There was no significant statistical difference (p=0.7).

Table 3: ASA physical status of the study subjects

Majority of the subjects belonged to ASA physical status II in all the 3 groups and there was no statistical significance.

Table 4: Heart rate, MAP variability at baseline

Heart rate was documented at baseline among subjects of all 3 groups and the mean value was found to be 104 in Group A, 102 in Group B and 101 in Group C which was comparable with no statistical significance. Mean arterial pressure was taken at baseline among subjects of all 3 groups and the mean value was found to be 82 in Group A, 81.5 in Group B and 82.3 in Group C which was comparable with no statistical significance.

Table 5: Total dose requirement of Propofol

The induction dose was compared and found to be least in Group C (1.2mg/kg) as compared to Group A (1.8mg/kg) and Group B (1.4mg/kg). The additional doses of Propofol administered was recorded and the total amount of drug administered was found to be 98.45mg in Group A, 88.24 mg in Group B and 76.32mg in Group C. This difference was found to be statistically significant (p<0.05). Incidence of movement or bucking at the time of laryngoscopy was seen to be the highest in Group A (29.7%) and least in Group C (2.7%). This was found to be a highly significant.

Table 6: Rescue doses of Propofol

The induction dose was compared and found to be least in Group C (1.2mg/kg) as compared to Group A (1.8mg/kg) and Group B (1.4mg/kg).

Table 7: Heart rate of the 3 groups at different time intervals at induction

The heart rate (HR) was also found to be comparable between the groups A and B in the induction period. However, when compared to Group A and B,Group C was shown to have least fluctuations in heart rate with statistical significance as seen in table 9 and Graph 6 (p values<0.05).

Table 8: Mean Arterial Pressure at different time intervals at induction

Mean arterial pressure was compared between the groups during induction. While the baseline values between the three groups showed no statistical significance, compared to Group A and B, Group C had least fluctuation in MAP with statistical significance.

Table 9: Mean arterial pressure in the intraoperative period

Table 10: Heart rate in the intraoperative period

Hemodynamic parameters were monitored every 5 mins after induction during the intraoperative period. It was noted that administration of Propofol 3 minutes after fentanyl had more stable hemodynamics compared to Group A. Furthermore, Group C which received Propofol 5 minutes after administration of fentanyl had even better hemodynamic parameters compared to both groups A and B. Beyond 35 minutes however, all 3 groups had similar hemodynamics with no statistical significance (p>0.05).

Table 11: Adverse effects

Incidence of bradycardia was highest in Group C(8.1%) compared to other two groups. Whereas incidence of hypotension was least in Group C(12.6%). There were no occurrences of arrhythmias noted in any of the study groups.

The aim of this study was to establish if there exists a significant reduction in required Propofol dose for induction and if it further decreases the associated side effects of Propofol and to find out the temporal relationship of administration of Propofol and Fentanyl.

Pharmacokinetic and pharmacodynamic studies of Fentanyl by Peng PW et al7 have found that the lag time between change in its plasma concentration and effect ranged from 3 to 5 min. Therefore, in our study we used Fentanyl 1mcg/kg, which is commonly used clinically in cancer patients and if any changes in Propofol dose and effect on hemodynamic stability were observed after allowing 3-5 min time interval between Fentanyl and Propofol. Following an IV dose of 2–2.5 mg/kg of Propofol, loss of consciousness occurs in less than a minute and can last for approximately five minutes. Furthermore, hypnosis can be maintained by Propofol concentrations of 1.5–6 μg/mL in the presence of N2O/O2 (60:40 ratio) or other anesthetic agents to produce satisfactory anesthesia with haemodynamic stability, rapid recovery and without major adverse effects.1

 In our study, recording of heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) was done every minute from the start of induction and hypotension (fall of blood pressure >20% of baseline) was watched for mean arterial pressure was compared between the groups during induction. While the baseline values between the three groups showed no statistical significance, compared to Group A and B, Group Chad least fluctuation in MAP and HR which received Propofol 5 minutes after Fentanyl. This finding had a statistical significance of p=0.048 in our study. This was in agreement with the separately published data of Aken et al6, Darlong V et al8, Arora V et al9 and Sawano Y et al10 who found that Propofol administered in a dose immediately after Fentanyl with 3mcg/kg had significant drop in arterial pressure, cardiac output and heart rate in patients. In our study however, we had similar findings at a far lesser dose of 1mcg/kg body weight.

This was also in agreement with a study by Kumar et al4 who in their study assessed the attenuation of hemodynamic response to laryngoscopy and tracheal intubation with Fentanyl, lignocaine nebulization and a combination of both and found that IV Fentanyl 2 μg/kg administered 5 min pre-induction was found to be the most effective in attenuating the hemodynamic response. Similarly, Bansal S et al have also reported that dose of Propofol required for induction of anesthesia was significantly reduced when administered after Fentanyl in patients with supratentorial tumors.11

Requirement of additional Propofol boluses in case of bucking, movement or vocalization at the beginning of check ventilation were found to be least among subjects of Group C (p<0.00001) which was a highly significant statistical finding further substantiating the synergism of Fentanyl on Propofol.3 Similarly, Smith et al5 have demonstrated that arterial concentrations of Propofol required for loss of response to verbal command and skin incision was significantly less when co-administered with Fentanyl (63% and 89% reduction in Propofol with Fentanyl concentration 1 and 3 ng/ml, respectively). Some authors such as Bhattarai R et al have found Ketamine to be equally efficacious as an adjuvant to Propofol. However in debilitated patients such as those with cancer, haemodynamic parameters may be unpredictable and recovery time significantly higher with Ketamine-Propofol.12

Singh SA et al too noticed that unlike Fentanyl, ketamine increased the recovery time. Thus, they concluded that Fentanyl was a better additive to Propofol than ketamine in reducing the total dose of Propofol without affecting recovery parameters which further substantiates our favour towards Fentanyl as a superior adjuvant.13 Bradycardia or arrhythmias were rarely noticed in our study population which is indicative of hemodynamic stability of both Propofol as well as Fentanyl when administered in titrated doses. This is in agreement with studies by Vuyk J et al who evaluated the cardiovascular effects of Propofol by the induction dose of 2-2.5mg/kg and found that it produced a 25%-40% reduction in systolic blood pressure and diastolic blood pressure due to decrease in cardiac output, stroke volume and systemic vascular resistance. They were also of the opinion that premedication with opioids markedly reduced the necessary induction dose through their synergistic action with Propofol and helped improve haemodynamic stability as seen in our study.2,3

Our study compared the efficacy of varying time intervals between Fentanyl and Propofol administration on requirement of Propofol dose for induction of anesthesia. We also evaluated the effects of Propofol given at different time intervals on hemodynamic stability following Fentanyl administration. We used Fentanyl 1mcg/kg, and noted any changes in Propofol dose and effect on hemodynamic stability after allowing 3-5 min time interval between Fentanyl and Propofol. Our study found that Propofol administered after 5 min of Fentanyl 1mcg/kg was most effective in attenuating the hemodynamic response to laryngoscopy as well as skin incision. We also found that additional doses of Propofol required for induction of anesthesia was significantly reduced when administered 5 minutes after Fentanyl. There was no significant respiratory depression, bradycardia, oxygen desaturation or respiratory complications in any of the groups. There were no serious complications encountered in our study. Thus, we conclude by our finding that least dose of Propofol for induction in cancer patients was noted when Propofol was administered after 5 min of administration of Fentanyl when compared to administering Propofol 1 min and 3 min after administration of Fentanyl and thus Propofol and Fentanyl exhibits synergism and safety profile.

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2.       Vuyk J, Sitsen E, Reekers M. Intravenous anesthetics. In: Miller R, Eriksson L, Fleisher L, Wiener-Kronish J, Cohen N, Young W, editors. Miller’s Anaesthesia. Elsevier Saunders; Philadelphia, USA 9th ed. 2019: p. 638-679.

3.       Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions. Acta anaesthesiologica belgica. 2001 Jan 1;52(4):445-51.

4.       Kumar A, Seth A, Prakash S, Deganwa M, Gogia AR. Attenuation of the hemodynamic response to laryngoscopy and tracheal intubation with fentanyl, lignocaine nebulization, and a combination of both: A randomized controlled trial. Anesthesia Essays and Researches. 2016 Sep 1;10(3):661-6.

5.       Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith LR, Glass PS. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology. 1994 Oct 1;81(4):820-.

6.       Van Aken H, MEINSHAUSEN E, PRIEN T, BRÜSSEL T, HEINECKE A, LAWIN P. The influence of fentanyl and tracheal intubation on the hemodynamic effects of anesthesia induction with propofol? N2O in humans. Anesthesiology (Philadelphia). 1988;68(1):157-63.

7.       Peng PW, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999 Feb 1;90(2):576-99.

8.       Darlong V, Som A, Baidya DK, Pandey R, Punj J, Pande A. Effect of varying time intervals between fentanyl and propofol administration on propofol requirement for induction of anaesthesia: Randomised controlled trial. Indian Journal of Anaesthesia. 2019 Oct 1;63(10):827-33.

9.       Arora V, Bajwa SJ, Kaur S. Comparative evaluation of recovery characteristics of fentanyl and butorphanol when used as supplement to propofol anaesthesia. International Journal of Applied and Basic Medical Research. 2012 Jul 1;2(2):97-101.

10.    Sawano Y, Miyazaki M, Shimada H, Kadoi Y. Optimal Fentanyl dosage for attenuating systemic hemodynamic changes, hormone release and cardiac output changes during the induction of anesthesia in patients with and without hypertension: a prospective, randomized, double-blinded study. J Anesth. 2013 Aug;27(4):505-11.

11.    Bansal S, Ramesh VJ, Umamaheswara Rao GS. Fentanyl co-administration decreases the induction dose requirement of Propofol in patients with supratentorial tumors and not in patients with spinal lesions. J Neurosurg Anesthesiol. 2012 Oct;24(4):345-9.

12.    Bhattarai R, Hamal PK. Comparison of Fentanyl -Propofol and Ketamine-Propofol Combination in Induction and Maintenance with Intravenous Anesthesia for Short Surgical Procedures at Moderate Elevations. J Nepal Health Res Counc. 2021 Jan 22;18(4):769-775.

13.    Singh SA, Prakash K, Sharma S, Dhakate G, Bhatia V. Comparison of Propofol alone and in combination with ketamine or Fentanyl for sedation in endoscopic ultrasonography. Korean J Anesthesiol. 2018 Feb;71(1):43-47.