Efficacy of Propofol Sedation for Endoscopic Submucosal Dissection (ESD): Assessment with Prospective Data Collection

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1 ORIGINAL ARTICLE Efficacy of Propofol Sedation for Endoscopic Submucosal Dissection (ESD): Assessment with Prospective Data Collection Taku Yamagata, Dai Hirasawa, Naotaka Fujita, Takashi Suzuki, Takashi Obana, Toshiki Sugawara, Tetsuya Ohira, Yoshihiro Harada, Yuki Maeda, Yoshiki Koike, Kenjiro Suzuki and Yutaka Noda Abstract Objective The indications for endoscopic treatment in early stage cancer of the digestive tract are expanding with the emergence and technical development of endoscopic submucosal dissection (ESD). ESD requires longer term stable sedation than conventional endoscopic procedures due to the necessity of meticulous control of the devices during the procedure. Propofol has a very short half-life and can be administered continuously, which is advantageous for long-term sedation. Propofol, thus, is likely to be useful for sedation during ESD. Methods Fifty consecutive patients who underwent ESD for early gastric cancer with propofol sedation (Group P) and those with midazolam sedation (Group M) were included in this study. Cardiorespiratory suppression rate and the condition of arousal were compared between the groups. A questionnaire survey on the satisfaction of endoscopists, anesthesiologists, endoscopy nurses, and ward nurses with the use of propofol was also carried out. Results Respiratory suppression was observed in 50% in Group M and in 20% in Group P (p). Hypotension was seen in 14% and 36% in Groups M and P, respectively (p). No sedation-related complications were encountered in either of the groups. Arousal rates 1 hour and 3 hours after the procedure were 23% and 60% in group M and 86% and 100% in Group P (p). As for the questionnaire survey, most respondents, in particular the ward nurses, supported the use of propofol. Conclusion Our data suggest that propofol is safe and useful during ESD as compared with midazolam. Key words: propofol, ESD, early gastric cancer (Intern Med 50: , 2011) () Introduction With the widespread use and technical development of endoscopic submucosal dissection (ESD), the indications for endoscopic treatment in early stage cancer of the digestive tract are expanding (1-4). As a result, the number of cases treated with ESD, which require a lengthy procedure time, such as those with broad lesions and lesions associated with ulcer scars, are increasing (5, 6). As ESD consists of fine complicated maneuvers and any patient movement during the procedure can result in complications such as perforation, intraoperative management of the patient s general condition is very important to achieve safe ESD. Sedation during endoscopic procedures has long been carried out with benzodiazepine. Recently, an increasing number of papers have been published on the use of propofol (7-14). Propofol has an immediate onset (30-60 sec) and a half-life of minutes, which is much shorter than those of benzodiazepine and advantageous for introduction Department of Gastroenterology, Sendai City Medical Center, Japan Received for publication October 2, 2010; Accepted for publication March 23, 2011 Correspondence to Dr. Taku Yamagata, yamagatataku @yahoo.co.jp 1455

2 and recovery from sedation. Furthermore, propofol can be administered continuously, which enables constant maintenance of the depth of sedation. On the other hand, propofol has a narrower safety range compared with other sedatives as to cardiopulmonary suppression (15, 16). Thus far, there have been a few reports on the use of propofol for the sedation of patients undergoing ESD. We herein report on our comparative study of propofol and midazolam as a sedative during ESD and discuss the usefulness and problems of propofol administration during ESD. Patients and Methods This study was approved by the institutional review board of the hospital and informed consent of this study was obtained from all the participating patients. Patients Fifty consecutive patients with early gastric cancer who underwent ESD under propofol sedation (September 2005 to February 2006) were included in this study (group P). Another 50 consecutive patients with early gastric cancer who underwent ESD under midazolam sedation just before the introduction of propofol (February 2005 to August 2005) were also included as controls (group M). Dosing strategy for sedation In group M, 5-10 mg of midazolam was initially given intravenously, essentially 5 mg for patients with a body weight 70 kg and 10 mg for those whose body weight was greater than 70 kg. Additional administration (2-5 mg) was carried out according to patient movement. Patient movement was defined as that necessitating discontinuance of the procedure for patient safety. When cardiopulmonary suppression was observed, the amount of drip infusion and flow volume of oxygen were increased. When ineffective, an antagonist of midazolam was administered. In group P, propofol was administered slowly as a drip infusion approximately 10 mg/kg/hr, with monitoring of the patient s level of consciousness and movement. After achieving a suitable sedation level for ESD, continuous drip infusion (1-5 mg/kg/hr) using a syringe pump was performed to maintain the depth of sedation. When a patient moved much, a bolus injection of 5-10 mg of propofol, depending on the reaction to gradual injection, was performed. An increase in the amount of drip infusion and the volume of oxygen inhalation, as well as a decrease in the amount of propofol drip infusion, were carried out depending on patient movement and cardiopulmonary suppression. An analgesic (pentazocin, mg) was given intravenously at the beginning of sedation in both groups and further injection was performed if the patient exhibited pain with movement. We evaluated the level of sedation following the ASA (American Society of Anesthesiologist) classification and maintained it at a moderate to deep level (15, 16). Intraoperative management Electrocardiography, an automated blood pressure meter, and pulse oximetry were used for intraoperative monitoring. Oxygen was given to the patient with a nasal cannula, without intratracheal tubing, at a flow rate of 2 L/min, which was controlled by monitoring the serum oxygen saturation rate. An overtube (Flexible overtube, Sumitomo Bakelite, Tokyo, Japan) was used to avoid aspiration pneumonia. An intermittent pressure device for the lower extremities was used to prevent deep venous thrombosis. ESD was performed by a team composed of an endoscopist, a physician dedicated to the control of sedation, an assistant technician, and a nurse. Management of sedation was performed by gastroenterologists who had undergone 10 cases each of hands-on training for propofol sedation by anesthesiologists along with anesthetic chart reviews. Procedure of ESD The scope used for ESD was a GIF Q260J (Olympus Optical Co., Ltd., Tokyo, Japan) with a transparent hood (D , Olympus) attached at the tip of the scope. ESD was performed as described by Oyama et al (24) using a Hook knife and an electrocautery unit (ICC200, ERBE, Tubingen, Germany). All procedures were performed by skilled endoscopists with more than 5 years of experience in performing therapeutic GI endoscopy. Outcome measurement The prevalence and timing of cardiorespiratory suppression and recovery from sedation were compared between the two groups. Clinical data was collected prospectively. A questionnaire survey for medical staff was also administered. Respiratory suppression was defined as a decrease in blood oxygen saturation to 92% or less. Circulatory suppression was defined as a decrease in systolic blood pressure to 90 mmhg or less. The first 10 minutes was defined as the introductory phase and the following period as the maintenance phase. The incidence of cardiorespiratory suppression was also evaluated in each phase. We visited the patient one and three hours after ESD to evaluate the consciousness status utilizing the Ramsay score (23). Patients with a Ramsay score of 2 were categorized as awake and the others as drowsy. The questionnaire survey included endoscopists, physicians dedicated to the control of sedation, assistant technicians, and ward nurses. At the end of this study, the medical staff members were asked questions regarding their comfortableness with and ease of endoscopic treatment, sedation control, intraoperative assistance, and postoperative care. They chose their answer from the following 3 options propofol is superior, propofol and midazolam are equal, and midazolam is superior. Statistics Statistical analyses were carried out using computer soft- 1456

3 Table 1. Patient Characteristics M group P group p value Number of patients Gender(male/female), n 36/14 39/ Mean age(±sd), years 68± ± BMI 23.5± ± ASA classification ASA 1 ASA ASA 3,4 0 0 Location in stomach 0.86 U M L Histology 0.51 tub por or sig 4 6 Size of specimen, mm 41.7± ± Procedure time, minutes 95.4± ± ASA, American Society of Anesthesiologists BMI, body mass index SD, Standard deviation U, Upper third; M, middle third; L, lower third tub, tubular adenocarcinoma por, poorly differentiated adenocarcinoma sig, signet-ring cell carcinoma 31 8 ware Stat Mate III version 3.14 (ATMS Co. Ltd., Tokyo, Japan). The T-test was used for continuous variables and the chi-square test was applied to categorical variables. A p value of was considered significant. Results As for patient characteristics of the two groups, the male/ female ratio, mean age, body-mass index, ASA classification, mean size of tumor, and procedure time were comparable, as shown in Table 1. The mean dose of midazolam in group M was 17.5+/-7.0 mg, and that of propofol in group P was 431+/-274 mg. The prevalence of respiratory suppression was 50% in group M and 20% in group P (p) (Table 2). The prevalence of circulatory suppression was 14% in group M and 36% in group P (p) (Table 3). The prevalence of respiratory suppression during the introductory phase was 34% (17/50) in group M and 18% (9/ 50) in group P (p=0.07). The prevalence of respiratory suppression during the maintenance phase was 16% (8/50) in group M and 2% (1/50) in group P (p=0.01) (Table 4). As for circulatory suppression, its incidence during the introductory phase was 4% (2/50) in group M and 20% (10/50) in group P (p=0.01), and that during the maintenance phase was 10% (5/50) in group M and 20% (10/50) in group P (p=0.16) (Table 5). During the maintenance phase, respiratory suppression occurred more frequently in group M. On the other hand, circulatory suppression occurred more frequently in group P during the introductory phase Table 2. Prevalence of Respiratory Suppression in Both Groups respiratory suppression group M, n group P, n respiratory depression: SpO 2 below 92 % Table 3. Prevalence of Circulatory Suppression in Both Groups Circulatory suppression group M, n 7 43 group P, n Circulatory suppression: blood pressure below 90 mmhg The rate of a state of consciousness 1 hour and 3 hours after the procedure was 23% and 60%, respectively in group M, and 86% and 100%, respectively in group P (p and p) (Table 6). Five endoscopists, 5 physicians dedicated to the control of sedation, 11 assistant technicians, and 28 ward nurses answered the questionnaire (Fig. 1). Three out of the 5 endoscopists rated propofol superior to midazolam due to less movement of patients, enabling them to concentrate on the procedure. One endoscopist assessed midazolam as being superior to propofol. As for the anesthesiologists, 40% assessed propofol to be superior and the others rated propofol and midazolam equally. Ninety-one percent of the technicians rated propofol as being superior to midazolam due to less movement and few indications of patient pain, while the others expressed the opposite opinion. All of the ward nurses favored propofol because there was no delay of recovery from sedation, resulting in the disappearance of urinary incontinence, falling, and wandering of patients. Some respondents supporting midazolam pointed out that there were no antagonists against propofol and midazolam was more familiar than propofol. Complications Although there were some cases showing transient cardiorespiratory suppression, which was successfully treated with oxygen administration or drip infusion, no serious complications necessitating discontinuance of the procedure were encountered. As for ESD, post ESD bleeding was seen in 2 cases in group M, which was successfully treated by endoscopic hemostasis without blood transfusion. There were no serious complications such as perforation requiring surgical therapy. 1457

4 Table 4. Prevalence of Respiratory Suppression in Both Groups Introductory phase respiratory depression group M, n group P, n 9 41 Maintenance phase respiratory depression group M, n group P, n 1 49 Table 5. Prevalence of Circulatory Suppression in Both Groups Introductory phase circulatory suppression group M, n group P, n Maintenance phase circulatory suppression group M, n group P, n Table 6. Arousal Rate 1 after procedure arousal rate after 1 hour group M, n group P, n after procedure arousal rate after 3 hour group M, n group P, n 50 0 Patients with a Ramsay score of 2 were categolized as consciousness and the others as drowsy Discussion The usefulness of ESD for early stage cancer of the digestive tract has now been accepted (1-4). As ESD requires fine complicated maneuvers, the risk of perforation is higher than that in other endoscopic procedures. With the expansion of its indications, furthermore, the significance of stable long-term intraoperative sedation to achieve safe ESD is increasing. Benzodiazepins, especially midazolam, which has a short half-life with a clear on-off of its effect, have long been used as sedatives for endoscopy (7, 9, 10, 12, 13). ESD, however, requires a longer procedure time than other endoscopic interventions. Use of midazolam tends to necessitate repeated intravenous administration during the long procedure time, and the sedative status is not constant, re- 1458

5 20% 20% 60% 60% 40% 9% 91% 100% propofol > midazolam propofol = midazolam propofol < midazolam Endoscopists Physicians dedicatet to Assistant technicians Ward nurses the control of sedation (n=5) (n=5) (n=11) (n=28) Figure 1. Results of the questionnaire survey. sulting in uncomfortable patient motion. During ESD, the operator has to focus on the maneuver and it is sometimes difficult to check the monitor. Therefore, it is mandatory to have an anesthesiologist on the team who is familiar with the agent for safe control of the depth of sedation. Propofol, which is classified as an agent for intravenous anesthesia, has a very short half-life and can be administered continuously by drip infusion. This characteristic is advantageous for long-term stable sedation and for lessening patient motion, which is quite favorable for sedation during ESD. Propofol has a relatively narrow safety range on cardiorespiratory suppression (15, 16). In this particular study, propofol tended to show weaker respiratory suppression and stronger circulatory suppression compared with midazolam. There were no cases in which ESD had to be discontinued due to such adverse events. The short life-time of propofol contributes to quick recovery from sedation as well. The questionnaire survey revealed that the involved staff, especially ward nurses, were in favor of the use of propofol. This is deemed to be due to the following reasons: Sedation with propofol had fewer negative effects as compared with midazolam, which 1) requires a long recovery time, 2) can cause a return to a drowsy state even after administration of an antagonist, and 3) can be followed by urinary incontinence, falling, or wandering of patients, after they return to the ward. Propofol, however, is known to have a narrow safety range. Therefore, it is mandatory for the doctors who are dedicated to the control sedation with propofol to have sufficient training before introduction of the sedation technique. Sedation with propofol tends to cause cardiorespiratory suppression at the time of introduction and with additional administration of the agent. Extensive care must be taken during such time periods. In some cases, the control of the level of sedation using the maximum dose of propofol may not be possible. In such cases, re-evaluation of the level of analgesia is considered important. Administration of analgesic is often effective in patients exhibiting pain along with body movement, which represents the importance of pain control during ESD, even under deep sedation. If we cannot control sedation even with additional administration of a painkiller, combined use of midazolam or dropoeridol is an option, although no cases required the additional use of these agents in this particular study. In our practice, we apply 2 mg of midazolam or 2.5 mg of droperidol on such an occasion in esophageal ESD. When ineffective, conversion to ESD under general anesthesia is the treatment of choice. As the incidence of complications relevant to sedative agents is closely related to the administered dose, several attempts to reduce the dose have been reported. Bispectral (BIS) monitoring is now available for the assessment of the depth of sedation, and some studies on its use during endoscopic procedures for the purpose of reducing the dose of propofol have been reported (17-19). Unfortunately, no study could succeed in reduction of the dose of propofol, although satisfaction of anesthesiologists and patients was improved. Introduction of a target-controlled infusion (TCI) system, which enables automatic control of the dose of propofol by computer-regulated anticipation of serum propofol concentration, is another attempt. Fanti et al utilized the TCI system in 205 consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and reported the safety and efficacy of administration of propofol with this system (20). The American Society for Gastrointestinal Endoscopy recommends the use of electrocardiography, blood pressure monitoring, and pulse oximetry for endoscopy (15, 16). There is, however, no consensus on the monitoring devices needed during ESD at present, and further studies on the use of special devices such as BIS monitoring and auditory evoked potential monitoring for achieving safe ESD are awaited (21, 22). This study had some limitations. First, the number of patients included was small. As it was not a randomized study, randomized prospective assessment of the usefulness and safety of sedation with propofol is necessary. In conclusion, our study suggests that propofol is useful for sedation during ESD, which requires long-term stable maintenance, and its safety is comparable with that of midazolam. The authors state that they have no Conflict of Interest (COI). References 1. Neuhaus H, Costamagna G, Devière J, et al. ESD of early gastric lesions using the R-scope. Endoscopy 38: , Yahagi N, Fujishiro M, Kakushima N, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (Thin type). Dig Endosc 16: 34-38, Oka S, Tanaka S, Kaneko I, et al. Advantage of endoscopic sub- 1459

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