Endoscopist-Directed Administration of Propofol: A Worldwide Safety Experience

Article Outline

• Abstract
• Materials and Methods
  • Review of Published Cases
  • Unpublished Cases
  • Estimation of the Added Cost of Using Anesthesia Specialists
  • Statistical Analysis
• Results
• Discussion
• References
• Copyright

Background & Aims

Endoscopist-directed propofol sedation (EDP) remains controversial. We sought to update the safety experience of EDP and estimate the cost of using anesthesia specialists for endoscopic sedation.

Methods

We reviewed all published work using EDP. We contacted all endoscopists performing EDP for endoscopy that we were aware of to obtain their safety experience. These complications were available in all patients: endotracheal intubations, permanent neurologic injuries, and death.

Results

A total of 646,080 (223,656 published and 422,424 unpublished) EDP cases were identified. Endotracheal intubations, permanent neurologic injuries, and deaths were 11, 0, and 4, respectively. Deaths occurred in 2 patients with pancreatic cancer, a severely handicapped patient with mental retardation, and a patient with severe cardiomyopathy. The overall number of cases requiring mask ventilation was 489 (0.1%) of 569,220 cases with data available. For sites specifying mask ventilation risk by procedure type, 185 (0.1%) of 185,245 patients and 20 (0.01%) of 142,863 patients required mask ventilation during their esophagogastroduodenoscopy or colonoscopy, respectively (P < .001). The estimated cost per life-year saved to substitute anesthesia specialists in these cases, assuming they would have prevented all deaths, was $5.3 million.

Conclusions

EDP thus far has a lower mortality rate than that in published data on endoscopist-delivered benzodiazepines and opioids and a comparable rate to that in published data on general anesthesia by anesthesiologists. In the cases described here, use of anesthesia specialists to deliver propofol would have had high costs relative to any potential benefit.

Abbreviations used in this paper: ASA, American Society of Anesthesiologists, EDP, endoscopist-directed propofol sedation, EGD, esophagogastroduodenoscopy, MAC, monitored anesthesia care

The use of propofol for sedation during endoscopic procedures has increased in recent years,¹ because of its favorable pharmacokinetic profile compared with traditional endoscopic sedation with benzodiazepines and opioids.², ³, ⁴ In the United States, propofol is generally administered by anesthesia specialists,¹ despite evidence that endoscopists can administer or supervise the administration of propofol sedation safely without the involvement of an anesthesia specialist.⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹, ⁵² The administration of propofol by anesthesia specialists for routine endoscopic procedures is controversial because it adds significantly to the cost of endoscopic procedures⁵³ without an established improvement in outcomes.⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹, ⁵² The administration of propofol by endoscopists or supervision of its administration by endoscopists is controversial because anesthesiologists claim that it is unsafe.⁵⁴, ⁵⁵, ⁵⁶ Concerns about the safety of endoscopist-directed propofol (EDP) have been voiced almost exclusively by the anesthesia community,⁵⁴, ⁵⁵, ⁵⁶ who often cite the warning contained in the package insert that propofol should be given only by persons trained in the administration of general anesthesia.⁵⁴, ⁵⁵ The package insert was written before evidence accumulated that nonanesthesiologists could administer propofol safely for endoscopic procedures. Whether EDP is allowed to proceed should be based on evidence about efficacy and safety. A related issue that is relevant to whether endoscopists should sedate their own patients, as has been standard practice in the United States, is whether sedation performed by anesthesia specialists for routine endoscopic cases has acceptable costs compared with other health care practices.

In this report, we describe the safety of EDP for endoscopic procedures, and, on the basis of this safety experience, we estimate the cost of substituting anesthesia specialists for endoscopists in the delivery of sedation for routine endoscopic procedures.

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Materials and Methods 

Review of Published Cases 

The following databases were searched: Ovid MEDLINE and PubMed (1966–November Week 1 2008), EMBASE (1980–2008 Week 45), CINAHL (1982–November Week 1 2008), Cochrane Database of Systematic Reviews (3rd Quarter 2008), and Cochrane Central Register of Controlled Trials (4th Quarter 2008).

The medical subject heading for propofol was combined with all subject headings for medical specialties, specialism, nursing, nursing care, nursing services, nurse's role, health personnel, hospital units, and digestive system endoscopy (or their equivalents in EMBASE and CINAHL). Keyword variants were also added for endoscopist, gastroenterologist, and nonanesthesiologist.

All original studies that used propofol sedation [alone or in combination with other agents(s)] for endoscopic procedures were eligible for inclusion, provided that propofol was administered without the involvement of an anesthesia specialist. We define an anesthesia specialist as either an anesthesiologist or certified registered nurse anesthetist. All of the endoscopists performing endoscopy and administering or directing EDP were gastroenterologists, except for the Australian group (where the endoscopists were gastroenterologists and the anesthetists were primary care physicians) and the Italian group (where the endoscopists were pediatric gastroenterologists and the anesthetists were general pediatric residents). When available, the type of procedure performed [esophagogastroduodenoscopy (EGD), colonoscopy, combined EGD plus colonoscopy, endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography] was documented. We eliminated earlier reports if patients were included in multiple summaries over time,³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹ or if they concerned non–anesthesiologist-administered propofol with the use of computer-assisted personalized sedation device.⁵² If uncertain, we contacted the investigators to make sure no patients were counted twice.

Unpublished Cases 

The senior author (D.K.R.) contacted all groups performing EDP that were known to us and invited them to participate in this safety review. These included investigators of previously published studies and abstracts, trainees of 2 teaching programs for EDP in the United States, and all others whom we became aware of through discussion or who contacted us because of awareness of our interest in EDP. All contacted physicians who we reached or who contacted us agreed to submit and did submit their data on safety. Four groups outside the United States with previous publications either could not be reached (n = 2) or had no additional data beyond their most recent publication (n = 1) or the physician had moved to a different country and was no longer using propofol (n = 1). One group in the United States reported to us that they had no additional data since their publication because their program was terminated by the anesthesia group at their institution. However, they confirmed that their patients receiving propofol had no complications. All the participating centers were able to assert that they have kept prospective databases on safety since the inception of their use of propofol except one,³² which generated its database retrospectively. A total of 28 centers (academic and private practice) contributed unpublished safety data. Seventeen centers were from the United States, 2 were in Japan, and 2 were in Germany. Single centers were in each of the following countries: Switzerland, Australia, Peru, the islands of the Bahamas, Italy, Saudi Arabia, and Canada. Data on endotracheal intubations, neurologic injuries, and deaths were available on all 646,080 endoscopic cases included in the study. Cases listed in both Table 1, Table 2 represent patients rather than procedures; ie, patients undergoing 2 procedures in 1 day are counted as one case. Neurologic injuries included stroke, transient ischemic attack, and anoxic encephalopathy. The complications were not mutually exclusive, and more than one complication could have occurred in the same patient. We tallied data on mask ventilation by procedure type (EGDs versus colonoscopies), when data were available.

Table 1. Publications (Papers and Abstracts) From Our Literature Search for Endoscopist-Directed Propofol Sedation

N/A, not available.

Table 2. Unpublished Data of Safety for Endoscopist-Directed Propofol Sedation^a

Estimation of the Added Cost of Using Anesthesia Specialists 

To estimate the added cost of using anesthesia specialists to administer sedation for all 646,080 cases, we did a simple “back-of-the-envelope” analysis,⁵⁷ in which we considered only the direct cost of an anesthesia specialist and assumed the following items. (1) Involvement of an anesthesia specialist would have prevented all 4 deaths without permanent sequelae. (2) Involvement of an anesthesia specialist would not have been associated with fatal complications or permanent sequelae in any of the remaining 646,076 patients. (3) The average cost of an anesthesia specialist to deliver sedation for an endoscopic procedure is $286.⁵³ (4) The life expectancy of the 70-year-old with widely metastatic cancer was 1 month. The life expectancy of the 68-year-old with mental retardation was 12 years. The life expectancy of the 58-year-old with severe alcoholic cardiomyopathy was 22 years. The life expectancy of the 68-year-old man with pancreatic cancer and hemorrhage was 1 year. (5) We did not attribute lost wages to the cost of EDP, because none of the patients who died was employed. In a simple sensitivity analysis, we further assumed that (1) anesthesia specialists were used only for patients with American Society of Anesthesiologists (ASA) class III or higher, who were estimated to comprise 10% of the study population,⁵⁸ and (2) the 4 patients who died would have lived to 85 years.

Statistical Analysis 

The incidence of mask ventilation during upper endoscopic versus colonoscopy procedures was compared with the use of the chi-square test.

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Results 

Of the 28 centers providing previously unpublished cases, all had formal training programs in EDP. Twenty-three centers had didactic training sessions, and 13 required physicians and nurses performing EDP to pass a written test. Twenty-seven centers required trainees to do hands-on supervised administration of propofol, and one used a simulator for training in administration. All centers included training in airway assessment and management, and 5 centers included sessions with an anesthesiologist, sometimes in the operating room. All 28 centers required physicians and nurses to have Advanced Cardiac Life Support certification or an equivalent certification outside the United States. All centers monitored intermittent blood pressure, continuous heart rate, electrocardiography, and pulse oximetry. Two of the 28 centers used capnography routinely. Among the unpublished cases, 4 centers performed systematic telephone follow-up at 30 days on 19,566 cases. Sixteen centers, representing 309,724 cases, had systematic follow-up by telephone call on the working day after the procedure. Eight centers (including 93,134 cases) had follow-up only until discharge from the endoscopy unit on the day of the procedure.

We identified 646,080 (223,656 published and 422,424 unpublished) endoscopic cases performed by nonanesthesiologists using propofol (Table 1, Table 2). There were 11 cases in which endotracheal intubation was performed, and 4 of these patients died. The other 7 patients who underwent endotracheal intubation recovered completely. There were no patients with permanent neurologic sequelae, although one patient had a tonic-clonic seizure, and one had a transient ischemic attack (blindness), both of which resolved without sequelae.

Each of the 4 deaths occurred among the previously unpublished cases and during or after an upper endoscopic procedure. One patient was a 70-year-old man with widely metastatic pancreatic cancer and 2 areas of duodenal obstruction on barium studies. He underwent enteroscopy with fentanyl, midazolam, and propofol, with successful placement of 2 enteral stents. Shortly after completion of the procedure, he became cyanotic. He was mask ventilated and intubated and placed on a ventilator. There was no evidence of aspiration, and his chest x-ray remained clear. However, he required high concentrations of inspired oxygen to maintain adequate oxygen saturation. A pulmonary consultant thought the most likely diagnosis was pulmonary embolism. The family declined investigation or treatment and requested that life support be withdrawn.

A second patient who died was a 68-year-old man with severe mental retardation. He underwent successful percutaneous endoscopic gastrostomy placement with propofol alone. In the recovery area, he awoke from sedation but subsequently developed shortness of breath and hypoxemia for unclear reasons. He was successfully resuscitated and intubated and placed on a ventilator. There was no evidence of aspiration, but his caregiver requested that life support be withdrawn.

A third death occurred in a 58-year-old man with a history of alcoholism, polysubstance abuse, and alcoholic cardiomyopathy. He was on permanent disability. He had previously undergone successful endoscopic dilation of an esophageal stricture with the use of EDP. He was sedated with meperidine, midazolam, and propofol, in anticipation of placement of a removable plastic stent in his esophageal stricture. Shortly after administration of sedation, he suddenly became asystolic, despite oxygen saturation and ventilatory effort that were normal until the moment of collapse. Normal sinus rhythm was restored several times but could not be sustained, and his family requested that the resuscitation effort be stopped. An autopsy showed abnormal levels of several substances that were not revealed to the endoscopy team and severe cardiomyopathy.

The fourth death occurred in a 68-year-old man who presented with hematochezia of 2 days duration and hemoglobin 8.6 g/100 mL. Upper endoscopy with midazolam and propofol showed a large duodenal ulcer with arterial spurting. The patient appeared to aspirate gastric contents, the procedure was stopped, and he was intubated prophylactically. Immediately before intubation the oxygen saturation was 91%, heart rate was 102, and blood pressure was 95/68 mm Hg. Endoscopy was repeated after intubation, but the bleeding could not be stopped with injection and hemoclip. Emergent surgery showed pancreatic cancer eroding into the duodenal bulb. Ligation of the duodenal artery was unsuccessful, and the patient died 5 days later in hemorrhagic shock.

On the basis of a simple back-of-the-envelope analysis, we estimated that the added cost to use an anesthesia specialist for all 646,080 procedures would be $184,778,880 (646,080 × $286/procedure) and would have prevented loss of 35.08 years of life, such that the cost for each life-year saved is $5.3 million. If used routinely on all patients, irrespective of ASA class, the cost of anesthesia specialist services would have to be between $2.70 and $5.40 to be cost-effective (at $50,000–$100,000 per life-year saved). In sensitivity analyses, under the assumption that all 4 decedents would have lived until age 85 (resulting in 72 life-years saved), the cost per life year saved is $2.6 million. When we further assumed that anesthesia specialists would be used only for ASA III patients (an estimated 10% of all patients),⁵⁸ the cost per life-year saved was $527,000. When both assumptions are considered simultaneously (ie, all 4 decedents living to age 85 years and an anesthesia specialist providing assistance for only 10% of all patients) the added cost per life-year saved would be $257,000. Under these conditions, the cost of using an anesthesia specialist would have to cost $56–$111 per procedure to make the cost of each life-year saved between $50,000 and $100,000.

Rates of bag-mask ventilation were available for 569,220 cases. Of these, bag-mask ventilation was reported in 489 cases (0.1%). There were procedure-specific rates of mask ventilation available for 328,108 patients. The mask-ventilation rate was 185 (0.1%) among 185,245 upper endoscopic procedures and 20 (0.01%) of 142,863 during lower endoscopic procedures (P < .001, chi-square test). In the remaining patients requiring mask ventilation, the type of procedure was not specified.

No centers used a laryngeal mask airway in any patient. Nasopharyngeal airways were placed in one or more patients at 6 centers (number of patients = 2, 2, 6, 6, and 2 centers did not track the number of placements). There was substantial overlap in patients who had nasopharyngeal tube placement and bag-mask ventilation at these centers. Two centers used oropharyngeal tubes either occasionally (n = 2 patients) or routinely in patients undergoing prolonged procedures.

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Discussion 

In this report, we summarize published literature and previously unpublished cases about the safety of EDP for endoscopic procedures. Our results indicate that the safety record of propofol administration by endoscopists is superior to the published safety record of opioids and benzodiazepines by endoscopists for gastrointestinal endoscopy.⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³ Specifically, the overall death rate for EDP that we identified was 1 per 161,515 cases. By comparison, earlier published death rates for nonanesthesiologist administration of opioids and benzodiazepines range from 1 in 1000 to 1 in 11,000,⁵⁹, ⁶⁰, ⁶¹, ⁶² and a single report of no deaths in 73,000 cases.⁶³ A more recent retrospective evaluation of 324,737 cases sedated by endoscopists in the Clinical Outcomes Research Initiative of the American Society for Gastrointestinal Endoscopy, using opioids and benzodiazepines, reported 39 deaths (11 per 100,000), including 28 cardiopulmonary deaths (8 per 100,000).⁵⁸ These results for EDP also compare favorably to the published rates of anesthesia-related deaths for general anesthesia. Although some studies have estimated death rates for general anesthesia as low as 1 in 100,000 to 1 in 250,000,⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹ other more recent studies have estimated anesthesia-related deaths during general anesthesia at 1 in 10,000 to 1 in 50,000.⁷⁰, ⁷¹, ⁷², ⁷³ A review of a 30-year period found that the incidence of anesthesia-related death has remained unchanged at 1 in 10,000.⁷⁴ We were unable to identify published death rates for monitored anesthesia care (MAC), which is generally considered more dangerous than general anesthesia by anesthesia experts.⁷⁵

MAC is unlikely to be cost-effective, even under assumptions that the use of MAC would have prevented the 4 deaths and not caused any other deaths. Using a simple back-of-the-envelope model, we found that the added cost of MAC per life-year saved was more than $5 million, which substantially exceeds the accepted cost-effectiveness threshold of $50,000–$100,000 per life-year saved.⁷⁶ This finding, although based on a simple model, was not sensitive to the number of life-years that could have been saved, the proportion of endoscopy requiring use of an anesthesia specialist, or anesthesia cost per procedure.

The current controversy surrounding performance of EDP and the cost of anesthesia specialists for endoscopy is focused on average-risk patients undergoing routine procedures. The deaths in this series occurred in patients and procedures that were neither routine nor average risk. Patient factors almost certainly contributed to the deaths in these patients. Anesthesiologist-administered propofol for truly routine procedures in average-risk patients would be very costly, because we observed no deaths or permanent sequelae among such patients or procedures.

The 4 deaths in this large cohort of patients undergoing EDP occurred in patients with ASA III or higher status, who were undergoing nonroutine medical procedures. Three of the patients had serious underlying illnesses. The results might be interpreted to suggest that such patients should be sedated by anesthesiologists; however, nonanesthesiologists have successfully used propofol for patients with higher ASA classes,³⁹ despite the higher risk associated with sedating these patients. In addition, there is no evidence that resuscitation efforts in these patients were delayed or ineffective because of lack of skill on the part of the endoscopist. Thus, conclusions about the appropriateness of EDP in these cases are difficult to draw.

These results confirm previous findings that the risk of complications during EDP is greater during upper endoscopic procedures than during colonoscopy.⁷ Indeed, there is still not a single report of death in the literature from EDP for colonoscopy. The reasons why ventilatory support is needed more often during upper endoscopy are unclear. Possible explanations include a deeper average level of sedation, or a higher incidence of coughing and laryngospasm during upper endoscopy with EDP.

Most of the cases described in this report were performed with single-agent propofol; however, propofol can be titrated to moderate sedation when it is given in combination with low doses of opioids or benzodiazepines or both.⁸, ¹² Propofol used in this fashion can result in moderate sedation more reliably than the use of opioids and benzodiazepines alone.⁸, ¹² Furthermore, there are few disadvantages for patient satisfaction or discharge from the endoscopy unit.⁴⁴ Anesthesia specialists have stated that combination regimens increase the risk of oversedation and cardiopulmonary complications.⁷⁷ This position is incorrect for propofol, because moderate sedation for endoscopy with single-agent propofol is not feasible, although combination therapy is essential to and enables titration of propofol to moderate sedation.⁸, ¹², ⁴⁴ On the basis of this report, both the single-agent model of EDP and combination therapy are safe.

Because there were 4 deaths in this experience, we anticipate that some anesthesia specialists will claim that EDP is unacceptable. This position is inappropriate for several reasons. Deaths occur during sedation by endoscopists using opioids and benzodiazepines,⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³ during general anesthesia by anesthesiologists,⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴ and during MAC.⁷⁸ Forbidding EDP on the basis of reported deaths is an inconsistent policy because the published safety record of EDP is superior to that of endoscopist-administered opioids and benzodiazepines, the traditional standard of care for endoscopic sedation. MAC performed by anesthesiologists has been associated with a number of deaths and malpractice claims,⁷⁸ and one-quarter of claims about MAC-related oversedation by anesthesiologists involved endoscopic procedures.⁷⁵, ⁷⁸ EDP is a service that is equivalent in function to MAC. Finally, it is obvious that patient factors contributed to deaths in this experience. Patient factors are an acknowledged cause of deaths associated with anesthesia,⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³ and in previous studies are often not counted as anesthesia-related deaths.⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³

This study had several limitations. First, the reliability of the data depended on self-reporting by the individual participating centers and not all of the centers collected their safety data prospectively (one center collected the data retrospectively). Although this is a potential weakness of our study, we do not believe that it negates our findings because most other case series reporting on sedation or anesthesia risk have also been heavily reliant on self-reporting.⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴ Second, centers typically did not track late-occurring sedation complications such as pulmonary infections. However, immediate adverse events related to oversedation should have been accurately tracked, because they invariably occur during the procedure or the immediate postprocedure recovery period. Third, the assumptions in our cost calculations could be incorrect. However, we heavily weighted the assumptions to favor anesthesia specialist delivery of propofol. Given that each of the deaths occurred in patients with ASA III or higher status, we could not identify any benefit to offset the cost of using anesthesia specialists for routine endoscopic procedures in ASA class I and II patients. Next, our only end points were death and other safety end points. We did not evaluate potentially important end points of EDP such as patient satisfaction, efficiency, adherence to colorectal cancer screening, adenoma detection, etc. Finally, we are unable to offer conclusions about the ideal method of EDP. Examination of Table 1, Table 2 shows substantial variation between centers in absolute rates of mask ventilation. These differences may reflect use of single-agent propofol compared with combination therapy, different target levels of sedation, differing thresholds of apnea duration before intervention different methods of monitoring of ventilation, and/or different methods or amounts of training before EDP. Although some of these potential explanations have been the subject of previous studies⁵, ¹², ¹³, ²⁸, ³⁹, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁵⁰, ⁵¹ and each is deserving of investigation, differences in mask ventilation rates do not alter the conclusion that EDP was safe with regard to the critical outcomes of death and permanent sequelae across a range of practices.

In conclusion, EDP is as safe or safer than endoscopist-administered opioids and benzodiazepines, based on the available literature. Further, our findings on the safety of endoscopist-administered sedation show that the use of anesthesiologists for sedation for endoscopic procedures is costly. It is reasonable for health care planners to doubt the wisdom of spending scarce resources on anesthesiologists to assist in endoscopic procedures, particularly those in low-risk patients. Our results support the endorsement of propofol use for endoscopy by trained nonanesthesiologists by organizations in the United States,³, ⁷⁹ Canada,⁸⁰ and Europe.⁸¹ We recommend that all individuals involved in the administration of propofol sedation receive appropriate training before using propofol.³, ⁷⁹, ⁸⁰, ⁸¹

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