Hemodynamic status during induction of anesthesia may modify the amount of propofol needed to induce loss of consciousness (LOC). This study was aimed to evaluate the effect of antispasmodic-induced tachycardia on the concentration of propofol at the effect-site for inducing LOC when deep sedation was executed for colonoscopy.
One hundred and sixteen adult patients were randomly assigned to receive either 20 mg of the antispasmodic Buscopan intravenously (Buscopan group; n = 58) or normal saline (control group; n = 58) for colonoscopy. After administration of Buscopan, the antispasmodic or normal saline, propofol was given by means of target-controlled infusion to induce LOC. We recorded patient characteristics, hemodynamic profiles, effect-site propofol concentration upon LOC, total propofol dosage for colonoscopy, and colonoscopy outcomes.
There were no significant differences in the characteristics between the two groups. Although the patients receiving Buscopan had a higher heart rate than those of the control group (101 ± 15 beats/minute vs. 77 ± 13 beats/minute; p < 0.001), we found no significant difference between two groups in the effect-site propofol concentration for inducing LOC (3.9 ± 0.6 μg/mL vs. 3.8 ± 0.6 μg/mL; p = 0.261) nor total propofol dosage required for colonoscopy (3.2 ± 1.4 mg/kg vs. 3.1 ± 1.1 mg/kg; p = 0.698). Both groups had comparable colonoscopy outcomes, including percentage of patients completing the procedure and total procedure time.
The hemodynamic responses to intravenous Buscopan neither affected the effect-site propofol concentration needed to induce LOC, nor the total propofol dosage required for colonoscopy in this study. There is no need to modify the dosage of propofol in patients subject to Buscopan premedication in colonoscopy.
Colonoscopy is the best available method of detecting colonic polyps, the precursor lesions of colorectal carcinomas. However, misdiagnosis rates of polyps in colonoscopy are reported to range between 2.1% and 26%, depending on the size of polyps.1 The use of an antispasmodic agent during colonoscopy may reduce colonic spasm and improve visualization of the mucosal surface, which may therefore decrease the rates of the polyp misjudgment, especially in patients with a moderate to marked degree of colonic spasm.2 In fact, some endoscopists routinely administer antispasmodic medication to their patients receiving colonoscopies.3
Propofol is a hypnotic commonly used for sedation during colonoscopy in our institute. Previously, several studies had demonstrated that changes in cardiac output might modify the pharmacokinetics of propofol in animal studies.4, 5, 6 Clinical studies, too, had suggested that cardiac output7 and even heart rate8, 9, 10 might influence the propofol requirement to induce anesthesia. Premedication with an antispasmodic drug, which can block the muscarinic receptor and exert a parasympatholytic action, has been associated with a significant increase in heart rate.3, 11, 12 The use of antispasmodic premedication may affect the efficacy of sedation used, but how it affects the sedation requirements is unknown. In addition, some studies, examining the benefit of an antispasmodic agent for colonoscopy in patients receiving light-to-moderate sedation, have reported conflicting results.11, 12, 13, 14 The primary objective of our study was to evaluate the effect of antispasmodic-induced tachycardia on sedative requirements (propofol). As a secondary objective, we aimed to evaluate the benefit of an antispasmodic agent in patients receiving deep sedation for colonoscopy.
2. Materials and methods
This prospective study was carried out in a single institution from October 2009 to October 2010. We recruited patients aged between 18 years and 75 years who were to receive planned colonoscopies. We excluded patients with a history of colonic resection or any other intra-abdominal surgery, a history of hypertension or antihypertensive drug treatment (e.g., β-blockers), glaucoma, obstructive uropathy, autonomic dysfunction, use of anticholinergic medication, a predicted difficult airway, or an allergy to propofol. We also excluded patients with insufficient bowel preparation (large amounts of solid fecal material found or <90% of mucosa seen as graded by the endoscopists)15 and those with cardiac diseases (e.g., cardiac arrhythmia). The protocol for this study was approved by the research ethics committee of Chang Gung Memorial Hospital (981554A3), and written informed consent was obtained from all patients.
All patients were instructed to take a standard colon preparation agent the day prior to the examination. Patients were attending on the day the elective colonoscopy was scheduled to be performed. Once a patient gave (his or her) consent, an anesthesia nurse, who was not involved in the sedation procedures, collected demographic data and took a history of the patient's prior experiences with colonoscopies. Immediately after this interview, the assigned nurse inserted a 22-gauge IV catheter into the patient's right forearm. Saline infusion (0.9%) was running to keep the intravenous line patent, after which, each patient opened a sealed envelope containing a computer-generated code indicating whether he or she would receive 20 mg of scopolamine butylbromide3 (Buscopan; Boehringer Ingelheim, Yamagata, Japan) (Buscopan group) or an equivalent volume of normal saline (control group) intravenously. Five minutes before the patient was brought to the operating room, the Buscopan or normal saline was administered by a nurse managing the endoscopy. No other medication was administered prior to sedation. Patients, endoscopists, and anesthesiologists were blinded to which group the patients belonged.
All patients were monitored using electrocardiograms, continuous pulse oximetry, and noninvasive blood pressure measured at 5-minute intervals. After baseline hemodynamic profiles were obtained, the patient was placed in the left-lateral position. Supplemental oxygen (6 L/minute) was administered through a face mask. Patients received supplemental intravenous alfentanil 10 μg/kg as analgesic premedication. Lidocaine (40 mg) was administrated intravenously to reduce the pain that might be caused by the injection of propofol. Propofol was administered intravenously using the Base Primea system (Fresenius, Brezins, France). This delivery system displays effect-site concentrations (drug concentration at site of action) estimated by Schneider's pharmacokinetic model,16 which is based on the patient's age, sex, weight, and height.
A previous study reported the half maximal effective concentration (EC50) for effect-site propofol concentration at loss of consciousness (LOC) to be 4.14 μg/mL.17 In the current study, the propofol infusion was started with an initial effect-site concentration of 3 μg/mL and increased in increments of 0.5 μg/mL every 4 minutes until the patient had lost eyelash reflex and exhibited no response to a verbal command. This clinical endpoint was defined as LOC and was assessed every 15 seconds during the induction of anesthesia. The effect-site concentration of propofol required for LOC was recorded. After LOC was achieved, the colonoscopy procedure was started. The goal in the current study was to achieve deep sedation, deﬁned as a level of sedation whereby patients lose consciousness and are unable to respond to the stimulus from colonoscopy.18 If the desired sedation level was not achieved during colonoscopy (indicated by such signs a purposeful muscular movement or eye opening), the target effect-site concentration was increased by 0.5 μg/mL step by step. If no purposeful muscular movement or cardiopulmonary depression (e.g., SpO2 (arterial O2 saturation) < 90%; systolic blood pressure < 20% of the baseline or <90 mmHg) was found, the target effect-site concentration was decreased by 0.5 μg/mL stepwise.
To reduce interindividual variability in the assessment of the level of sedation, an anesthesiologist, blinded to the hemodynamic profiles of patients, was solely entrusted to shoulder the anesthetic procedures to provide deep sedation for all patients. Audible tones of monitors were silenced or turned away to avoid the possibility that the anesthesiologist or the endoscopist might be aware of whether the patient was receiving Buscopan or the normal saline. Another anesthesiologist, who was not involved in the anesthetic procedures, was responsible for monitoring the safety of the patient. If any signs of airway obstruction or respiratory depression arose, a simple jaw thrust or chin lift was performed. Positive pressure ventilation was performed as required in the event of hypoxemia (SpO2 < 90%). Ephedrine (8 mg) was administered intravenously if the systolic blood pressure fell to <20% of the baseline level or <90 mmHg.
All colonoscopies were carried out by two responsible endoscopists, each of whom performed >300 colonoscopies using a standard adult colonoscope (CF–230I, Olympus Optical Co., Tokyo, Japan). Electronic images, polypectomies, and biopsies were performed as indicated during the procedures. Each individual endoscopist documented cecal intubation based on the visualization of the ileocecal valve and appendiceal orifice. After the procedure, the endoscopist rated the degree of colonic spasm (spasm score; 1 = no spasm encountered; 5 = marked, long waiting and very difficult to examine)12 and difficulty of the procedure (difficulty score; 1 = easy; 5 = very difficult). We recorded the total procedure time, defined as the period between the time the colonoscope first touched the anus to the time it was withdrawn.
At the end of the procedure, we discontinued the infusion pump and recorded the total dosage of propofol required. We reckoned and recorded the time it took for the patient to regain consciousness, defined as the period between the time that the patient was first requested to open his eyes after discontinuing the infusion pump to the time the patient actually did. After the patient had fully recovered in the recovery room, an investigator who was blinded to group allocation recorded the willingness of the patient to attempt colonoscopy again (yes/no) and the patient's satisfaction score with the sedative technique using a five-point score of 1–5 (the higher the score, the greater the level of satisfaction). Patients were discharged from the post anesthesia care unit when they met with positive modified Aldrete score criteria.19
The primary outcome measurement was effect-site propofol concentration needed for LOC. Based upon our preliminary data, the effect-site propofol concentration at the LOC level without Buscopan premedication was 3.7 ± 0.6 μg/mL. One previous study reported that tachycardia from atropine premedication could lead to a difference of 10% in propofol dosage requirement (from 2.22 mg/kg to 2.45 mg/kg).10 Assuming that there can be 10% difference in effect-site propofol concentration following Buscopan premedication, we estimated that 56 patients per group were needed to reach a statistical power of 90%. To compensate for possible dropouts, we enrolled 58 patients per group. Categorical variables were analyzed using the Chi-square test or Fisher's exact test. Nonparametric data were analyzed using the Mann-Whitney U test. All normally distributed data were expressed as the mean (standard deviation), median (interquartile range) for nonparametric data or percent for number of patients (%). Significance was set at p < 0.05. Data were analyzed using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA).
During the study period, 42 of the 158 eligible patients were excluded, leaving 116 patients who could be randomly assigned to two distinct groups of 58 members each. All of these participants completed the study. Table 1 shows a summary of the patients' characteristics and hemodynamic profiles of two groups of patients prior to sedation. They were comparable in age, sex, weight, height, and previous colonoscopy history. They also had comparable systolic and diastolic blood pressures. Prior to sedation, the patients who received Buscopan premedication had a higher heart rate than those who did not, in the control group (101 ± 15 beats/minutes vs. 77 ± 13 beats/minute; p < 0.001).
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Table 2 shows the summary of sedation results and recovery times. The effect-site propofol concentration at LOC was 3.8 ± 0.6 μg/mL for the control group as opposed to 3.9 ± 0.6 μg/mL for the Buscopan group (p = 0.261). No significant differences were found between the two groups for total propofol dosage required for colonoscopy (3.1 ± 1.1 mg/kg vs. 3.2 ± 1.4 mg/kg; p = 0.698). Table 3 summarizes the colonoscopic outcomes. No significant differences were found between the two groups in percentage of patients who completed procedures, total procedure time, difficulty score, spasm score, or frequency of willingness to try colonoscopy procedures again. We found no side effects, except for tachycardia, with the use of Buscopan.
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In this study, we investigated how the use of an antispasmodic might affect the sedation requirement and colonoscopic outcomes of patients under deep sedation. We found that although the patients who received Buscopan premedication had a higher average heart rate than those in the control group (101 ± 15 beats/minute vs. 77 ± 13 beats/minute; p < 0.001), this hemodynamic effect of Buscopan did not relate to the effect-site propofol concentration for LOC (p = 0.261) or total propofol dosage used for colonoscopy (p = 0.698). We also found no significant differences in colonoscopy outcomes when deep sedation was used.
The use of deep sedation for colonoscopy, a potentially uncomfortable invasive procedure, is reported to be not only capable of enhancing patient tolerance and satisfaction, but also to increase the willingness of a patient to return for a successive examination.20 In addition, more advanced lesions may be found21 and more patients are likely to undergo comprehensive colonoscopies22 under deep sedation. Therefore, our hospital routinely uses propofol to achieve deep sedation for individuals receiving colonoscopies. All of our patients in the Buscopan group (100%) and most of our patients in the control group (96.6%; Table 3) had undergone comprehensive colonoscopies (cecal intubation), an actuality consistent with that of one previous report.23
It is well known that there is great interindividual variability in the concentration of propofol required to achieve LOC.24 This variability can be due to a patient's age, sex, or body weight. Cardiac output has also been reported to influence the pharmacokinetics of propofol4, 5, 6 and be a determinant of propofol requirement for induction of anesthesia.7 After the administration of a single dose of propofol, the plasma concentration of propofol will be thinner in patients with a high cardiac output than that in those with a low cardiac output.7 This suggests that patients with a higher cardiac output will require a larger dosing of propofol to achieve LOC. Even an increase in heart rate prior to anesthetic induction has been reported to require a significant increase of propofol dose to achieve LOC.8, 9, 10
Takizawa et al10 reported a 10% difference in propofol dosage between the atropine group and the control group (2.45 mg/kg vs. 2.22 mg/kg, respectively; p = 0.014) for inducing hypnosis. Although there was a significant increase in heart rate, we did not find a different effect-site propofol concentration with the use of the antispasmodic Buscopan. This inconsistency may be related to the fact that heart rate is only one determinant of cardiac output. For example, cardiac output may also be influenced by patient position.25, 26 Colonoscopy is often performed with the patient in the left lateral position, and the cardiac output can be decreased significantly by shifting the patient from the supine position to the left lateral position.26 Another influential factor is dehydration, which can occur after the use of bowel preparation regimens.27 Dehydration can also influence cardiac output. Therefore, these factors, although possible in both groups, may confound correlations between heart rate and cardiac output, and may lead to inconsistencies in the results of our study.
In this study, Buscopan did not have a significant beneficial effect for colonoscopy, a finding consistent with those in two earlier studies.12, 13 Although in theory, the procedure time, difficulty of procedure, and degree of colonic spasm may be reduced with the use of antispasmodics, the current literature has not substantiated this proposal. There may be other factors that interfere with the benefits of antispasmodics for colonoscopy. These might be related to the skill levels of the endoscopists3 or the quality of cleansing the bowel in preparation. Anxious patients who are not sedated or who are under light sedation may not cooperate well with the endoscopists. This lack of cooperation may also bias evaluating the outcome parameters during colonoscopy.28 Although deep sedation for colonoscopy may minimize the effect of anxiety or discomfort on the outcomes of colonoscopy, we did not find the use of the antispasmodic Buscopan to have any significant beneficial effect on colonoscopy.
There are several limitations in our study. First, the lack of cardiac output and arterial propofol concentration measurements makes it difficult to further investigate the causes of our conflicting results. Secondly, we only used the clinical endpoint to monitor the depth of anesthesia. The use of the bispectral index in the current study may make our results more convincing. Another limitation is that we did not collect data on the frequency of adverse events during deep sedation for colonoscopy. Previous studies have reported that these adverse sedation-related events are uncommon during colonoscopy and most of them are transient.23, 29
In conclusion, we found that the effect of Buscopan-induced tachycardia did not increase the sedative requirements for LOC in patients who intend to receive deep sedation for colonoscopy. It is not necessary to modify the dosage of propofol for deep sedation in patients receiving Buscopan premedication.