A Study Comparing Propofol Auto-coinduction and Standard Propofol Induction in Patients Undergoing General Anesthesia Without Midazolam Pretreatment: A Prospective Randomized Control Trial.

BACKGROUND: Propofol has emerged as an induction agent of choice over the past two decades due to its quick, smooth induction and rapid recovery. The main concern for an anesthesiologist is the hemodynamic instability caused by the standard induction dose of propofol (2-3 mg/kg). AIM: We aim to study the efficacy of propofol auto-coinduction technique in comparison to the standard propofol induction technique in terms of the total induction dose requirement of propofol, the incidence of hemodynamic side effects and pain on injection, and the incidence of fentanyl-induced cough (FIC) in the absence of a synergistic agent like midazolam.
MATERIALS AND METHODS: This was a prospective, observer-blinded, randomized controlled trial. The study was initiated after obtaining the institutional ethics committee approval and is registered in the Clinical Trials Registry India. Eighty American Society of Anesthesiology Physical Status I and II patients, of either sex, aged between 18 and 55 years, and scheduled for elective surgeries under general anesthesia were randomized into two equal groups. Patients allocated to Group I (auto-coinduction) received 20% of the calculated dose of injection propofol 2 mg/kg (i.e., 0.4 mg/kg) as the priming dose followed by injection fentanyl 1 μg/kg after 1 min and the remaining propofol was administered in titrated doses till loss of verbal response after 2 min. In Group II (control), patients received injection fentanyl 1 μg/kg followed by single bolus dose of injection propofol up to 2 mg/kg till loss of verbal response. Midazolam was not used for premedication or induction. Intubation was carried out only after ensuring achievement of optimum depth of anesthesia using bispectral index scale. The total dose of propofol administrated for induction, occurrence of pain on injection, severity of cough after fentanyl administration, hemodynamic parameters, and apneic episodes were recorded. STATISTICAL ANALYSIS: All data were expressed as mean ± 2 standard deviation. For statistical analysis, SPSS software version 16 (SPSS Inc., 2007, Chicago, IL, USA) was used.
RESULTS: The mean dose of injection propofol required for induction was significantly lower in Group I (67.0 ± 17.9 mg) when compared with Group II (111.3 ± 17.6 mg) (P < 0.01). The mean heart rate was significantly higher (P < 0.01) and the mean blood pressure was significantly lower in Group II (P < 0.01) when compared to Group I at 1 min postinduction, immediately after intubation, and 5 min after induction. The incidence of complications such as hypotension, pain on injection, and FIC was higher in Group II (50%) as compared to Group I (18%).
CONCLUSION: In our study, we found that the induction dose requirement of propofol was significantly lower in the auto-coinduction group when compared to the conventional induction group. The auto-coinduction technique offered a stable hemodynamic profile, reduced pain on injection, and less incidence of FIC as compared to the conventional propofol induction technique.

INTRODUCTION

Propofol has emerged as an induction agent of choice over the last two decades due to its smooth induction and rapid recovery.[1] Compared with the conventional induction agents such as thiopentone and ketamine, propofol offers better intubating conditions and superior airway integrity with the added advantage of airway reflex suppression.[1] However, the main concern for an anesthesiologist is the hemodynamic instability caused by the standard induction dose of 2–3 mg/kg and the pain during drug injection.[23] “Auto-coinduction” is a technique where we administer a precalculated dose of the induction agent before administering the full dose of the same agent.[456] In our study, we proposed to study the efficacy of propofol auto-coinduction technique as compared to the conventional propofol induction technique in patients who are not pretreated with midazolam. We aim to study the total induction dose requirement of propofol, the incidence of hemodynamic side effects and pain on injection, and the incidence of fentanyl-induced cough (FIC) between the auto-coinduction technique and the conventional induction technique.

MATERIALS AND METHODS

The study was a prospective, observer-blinded, randomized controlled trial, initiated after obtaining institutional ethics committee approval and registering in the Clinical Trials Registry India Registry. Eighty American Society of Anesthesiology (ASA) Physical Status I and II patients, of either sex, aged between 18 and 55 years, and scheduled for elective surgeries under general anesthesia were included in the trial after obtaining informed written consent. Patients who refused consent to be part of the trial, individuals with known allergy to propofol, patients with deafness, obesity (body mass index >35 kg/m2), uncontrolled hypertension, and ischemic and valvular heart disease, patients in whom rapid sequence induction was indicated, and pregnant and lactating women were excluded from the study. Patients were randomized into two equal groups: Group I (auto-coinduction) and Group II (control) using computer-generated randomization chart and closed envelope method.

All study participants were kept fasting as per the ASA guidelines of 6 h for solids and 2 h for clear fluids; nonsedative anxiolytic tablet alprazolam 0.25 mg and tablet ranitidine 150 mg were given orally on the night before surgery. On the day of surgery, the patients were shifted to the operating room and intravenous access was obtained with an 18-G cannula under local anesthesia with 2% lignocaine, preferably in the forearm. Both groups received injection glycopyrrolate 0.04 mg/kg and injection metoclopramide 10 mg intravenously, 15 min before induction. All patients were monitored with electrocardiogram, pulse oximeter (SpO2), noninvasive blood pressure (NIBP), and bispectral index scale (BIS). Baseline heart rate (HR), blood pressure (BP), SpO2, and BIS values were also recorded. Patients allocated to Group I received 20% of the calculated dose of injection propofol 2 mg/kg (i.e., 0.4 mg/kg) as the priming dose followed by injection fentanyl 1 μg/kg after 1 min. Two minutes after the priming dose, the remaining propofol was administered in titrated doses till loss of verbal response. In Group II, patients received injection fentanyl 1 μg/kg followed by a single bolus dose of injection propofol up to 2 mg/kg till loss of verbal response. In both groups, the injection propofol used was 1% w/v, long-chain triglyceride (LCT) propofol at an injection rate of 30 mg over 10 seconds, and all patients received injection lignocaine 10 mg, 15 s before propofol injection. Injection suxamethonium 2 mg/kg was administered to facilitate tracheal intubation only after attaining a target BIS of 40–45. An observer, blinded to the patient group, recorded the total dose of propofol administrated for induction, occurrence of pain on injection, severity of cough after fentanyl administration, hemodynamic parameters, and apneic episodes. Pain during propofol injection was recorded with verbal response of the patient or behavioral signs such as withdrawal of arm, grimacing, and tears. Hemodynamic parameters recorded included HR and BP before and after induction and 1 min and 5 min after induction. A fall in mean BP (MBP) of >20% from baseline or <90 mmHg was defined as hypotension, and the incidence of such episodes was noted. The severity of cough was graded as none (grade 0), mild (grade 1–2), moderate (grade 3–4), or severe (grade 5 or more). Apneic episodes were defined as any clinically noticeable episode of apnea lasting >30 s.

Statistical analysis

We calculated that 40 patients in each group would be required to detect difference in drug dosage at a significance level of 80% power and an alpha value of 0.05 and the recruitment was done accordingly. Data were collected with the help of a prestructured pro forma. All data were expressed as mean ± 2 standard deviation. For statistical analysis, SPSS software version 16 (SPSS Inc., 2007, Chicago, IL, USA) was used. Student's t-test and Chi-square test were used for comparison of demographic parameters, propofol dosage, and side effects as appropriate. Two-way ANOVA was used for comparison of vital parameters within each group and between two groups. A P < 0.05 was considered statistically significant and P < 0.01 was considered highly significant.

RESULTS

The demographic profile including age, gender, and weight was found to be comparable between the two groups with no statistically significant difference [Table 1]. The mean dose of injection propofol required for induction was significantly lower in Group I (67.0 ± 17.9 mg) when compared with Group II (111.3 ± 17.6 mg) (P < 0.01) [Table 2].

Table 1

Comparing the demographic parameters between the two groups

Table 2

Comparing the mean propofol induction dose between the two groups

The hemodynamic parameters were compared just before induction, 1 min after induction, immediately after intubation, and 5 min after induction. Baseline HR was comparable between two groups (P = 0.36). The mean HR was significantly higher in Group II (P < 0.01) at 1 min after induction and continued to remain significantly high at all time points up to 5 min postinduction (P < 0.01) as shown in Graph 1. Baseline systolic BP (SBP) was comparable in both the groups (P = 0.07). The mean SBP, mean diastolic BP (DBP), and MBP of Group II were significantly lower than Group I at 1 min after induction (P < 0.01), immediately after intubation (P < 0.01), and 5 min after induction (P < 0.01) [Graphs 2 and 3].

Graph 1

Graph comparing the mean heart rates between the two groups

Graph 2

Graph comparing the systolic blood pressure between the two groups

Graph 3

Graph comparing the mean blood pressure between the two groups

We observed that nine patients (18%) in Group I and 20 patients (50%) in Group II had developed adverse events [Table 3]. Eight patients (20%) in Group II had hypotension as compared to only two (5%) in Group I [Table 3]. Clinically noticeable apnea (>30 s) was seen in three patients (7.5%) in Group II and only in one patient (2.5%) in Group I [Table 3]. Only two patients (5%) had pain on injection of propofol in Group I as compared to five patients (12.5%) in Group II [Table 3]. FIC occurred only in one patient (2.5%) in Group I when compared to 4 (10%) in Group II [Table 3].

Table 3

Comparing the incidence of adverse effects in both the groups

DISCUSSION

Induction of anesthesia is the most important and eventful time frame during the entire course of general anesthesia. Among the intravenous agents, propofol is preferred due to its rapid onset and offset time and suppression of airway reflexes.[1] However, the major concern for the anesthesiologist with the use of propofol is the hemodynamic instability and pain on injection caused by the conventional induction dose of 2–3 mg/kg.[23] Propofol induction elicits a biphasic response from the cardiovascular system. Phase I is characterized by a decrement in mean arterial pressure due to reduction in the systemic vascular resistance followed by a reflex tachycardia mediated by the carotid baroreceptors.[7] Phase II sets in after 2 min postinduction with a reduction in the HR and MBP despite a normal systemic vascular resistance due to the resetting of the baroreceptors.[7] To avoid these adverse effects, multiple studies were done evaluating propofol coinduction strategies with benzodiazepines.[4568] All these agents due to their synergistic effects result in excess sedation and cardiorespiratory depression, thereby offsetting the advantages offered by propofol induction.[69]

To overcome this, we decided to study the efficacy of propofol auto-coinduction technique versus the standard propofol induction technique in the absence of a synergetic agent like midazolam. In our study, we found that the auto-coinduction group had approximately 40% reduction in the induction dose requirement of propofol compared to the conventional induction group. The depth of anesthesia achieved was clinically comparable in both the groups as reflected by the comparable BIS values in the range of 40–45 in both the groups. This significant reduction in the dosage may be attributed to the unique pharmacokinetic and pharmacodynamic mechanisms of propofol. Cardiac output plays a small, yet significant predictive role in determining the hypnotic dose of propofol.[10] It is noted that for a given dose of propofol, the effective plasma concentration is higher in a patient with low cardiac output than the one with a high cardiac output.[10] Patient anxiety and pain are the main contributors to increased cardiac output state during the induction phase of anesthesia.[11] In auto-coinduction, the initial priming dose of propofol produces anxiolytic and amnestic effects. This results in reduced cardiac output during induction, and thus, an increased effective plasma-site concentration is achieved with a significantly lower dose of propofol.[10]

Our results were comparable to that of Kumar et al., who studied the effects of a priming dose of propofol versus the conventional propofol induction in patients pretreated with injection midazolam. They found that the total induction dose requirement in priming group was 27% lower than the conventional group as compared to our study which had shown 40% reduction in auto-coinduction group, that too in the absence of midazolam pretreatment.[8] Kataria et al. studied the efficacy of propofol auto-coinduction versus propofol midazolam coinduction. They found that even though midazolam coinduction group had a significantly reduced induction dose of propofol when compared to the auto-coinduction group, it did not offer hemodynamic stability in the peri-intubation period.[6] Their findings were similar to that of Kumar et al. and Cressey et al., who found that midazolam pretreatment reduces the induction dose requirements of propofol.[812] Midazolam has synergistic effects with propofol by its action on the GABAA receptors, thereby masking the actual priming effect and priming dose requirement of propofol in these studies. This has been proven by findings of our study where the auto-coinduction group obtained comparable results to these prior studies in terms of anesthesia endpoints. Our study showed that both clinically and electrophysiologically (BIS) comparable anesthetic depths were achieved with a reduced dose of propofol in the auto-coinduction group. Our findings also concurred with that of Djaiani et al., who compared the feasibility of propofol auto-coinduction with midazolam coinduction in patients presenting for ambulatory surgery.[4]

Our study gains more relevance as recent studies have shown that perioperative benzodiazepine administration is a major risk factor for postoperative cognitive dysfunction (POCD).[13] This is of importance as midazolam propofol coinduction techniques are routinely used in the elderly population and in patients with cardiac dysfunction to overcome the hemodynamic instability caused by conventional standard propofol induction. These patients are already at risk for POCD and the perioperative use of midazolam will further aggravate this.[1314]

We evaluated the effects of auto-coinduction technique on the hemodynamic parameters during the induction phase of anesthesia. HR was higher in the control group at 1 min after induction, just before intubation, immediately after intubation, and 5 min after induction, when compared with the auto-coinduction group. This could be attributed to the higher dose of propofol in the control group causing a fall in BP, thus eliciting reflex tachycardia. The SBP, MBP, and DBP at all time points postinduction were significantly lower in the control group with concurrent tachycardia. Also, the incidence of hypotensive episodes was significantly lower in the auto-coinduction group. These observations show that hemodynamic fluctuations are minimal when propofol auto-coinduction is practiced as it will help in overcoming the biphasic response elicited in the conventional induction technique. Prior studies by Claeys et al. and Fairfield et al. have shown that magnitude of hemodynamic disturbances is directly related to the dose of propofol administered.[23] Thus, auto-coinduction could be advantageous in patients with compromised end-organ blood supply such as coronary artery disease and ischemic stroke in whom hemodynamic instability caused by standard propofol induction and propofol midazolam coinduction could be detrimental. In auto-coinduction technique, the anxiolytic priming dose is administered in the presence of the anesthesiologist and under standard monitoring unlike benzodiazepines premedication administered in the preoperative period. There was no incidence of apnea in our auto-coinduction group unlike the priming group studied by Kumar et al., which had 2% incidence of apnea. This could be due to the pretreatment of the priming group with midazolam.[8]

In our study, the incidence of pain on injection of propofol in auto-coinduction group was lower than in the control group. Although the mechanism is unclear, the study by Liljeroth et al. showed that priming with propofol can effectively reduce pain during bolus injection of propofol.[15] This could be beneficial as studies have shown that up to 70% of the patients perceive propofol-mediated pain and it is one of the major drawbacks in clinical anesthesia practice.[15] Although nonsignificant, the incidence of FIC was lower in the auto-coinduction group as compared to the control group. Our results were similar to that of Firouzian et al., who concluded that a low dose of propofol priming can effectively suppress FIC during induction of anesthesia.[16] FIC is commonly observed after intravenous injection fentanyl administration, and the incidence is as high as 28%–80% of cases.[16] Auto-coinduction reduces the incidence of FIC in patients with raised intracranial pressure and cervical spine injury in whom the cough would be detrimental.

Thus, we found that propofol auto-coinduction technique attains comparable anesthestic depth of anesthesia during induction with a significantly lower dose when compared to the conventional propofol induction, with a stable hemodynamic profile, reduced pain on injection, and less incidence of FIC. This technique is also cost-effective, easy to practice, and safe as the patient is under constant supervision of the anesthesiologist.

However, there are a few limitations to our study; the first being a single center trial, our institutional practice of general anesthesia induction may have contributed to these results which may differ to that of other institutes practicing different induction methodologies. The use of an invasive arterial BP monitoring, instead of NIBP, could have helped in a more accurate measurement of hemodynamic variables. We did not study the effect of auto-coinduction and its subsequent effect on the incidence of postoperative nausea and vomiting, which is a unique advantage of propofol-based regimens. Further, we used 1% propofol v/w LCT preparation, so the results cannot be extrapolated to the incidence of pain on injection with the use of propofol of different concentrations such as the 2% medium-chain triglycerides–LCT preparation. Pain on injection of drug was assessed by a subjective method rendering it difficult to be assessed as patients can have variable pain thresholds. Future studies with larger number of participants may help in refining the dose and technique of auto-coinduction with propofol.

CONCLUSION

In our study, we found that the induction dose requirement of propofol was significantly lower in the auto-coinduction group when compared to the conventional induction group. The auto-coinduction technique offered a stable hemodynamic profile, reduced pain on injection, and less incidence of FIC as compared to the conventional propofol induction technique.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.