Sedation plays an integral part in endoscopy. By achieving patient comfort, it allows for a better examination and enhances patient satisfaction. Various medications have been used, propofol being the current favorite. With emphasis on patient safety and quality of endoscopy, various new medications in different combinations are being used to achieve adequate sedation and not escalate the cost of the procedure. With the advent of newer medications and newer modalities to administer these medications, there is need for more specialized training for the endoscopist to feel comfortable while using these medications.
Key points
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Endoscopic sedation has evolved substantially over the past decade.
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Patient safety and comfort remain the center of focus.
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Even though a formal curriculum has been developed, there has not been, to the authors’ knowledge, a competency-based sedation training program that has been implemented for endoscopic procedural sedation.
Introduction
According to the standards of practice committee of the American Society for Gastrointestinal Endoscopy (ASGE), “sedation is defined as a drug-induced depression in level of consciousness.” Sedation is a fundamental aspect of gastrointestinal endoscopy (GIE) because it reduces anxiety and patient discomfort and also allows for better examination during endoscopy, thereby improving patient outcomes. The goal of sedation is to achieve a balance between the comfort aspects while preserving patient safety. Although sedation improves a patient’s tolerance, it also increases both the cost and the risks of complications. Sedation itself is responsible for about 50% of all GIE complications. Sedation can be divided into 4 levels, ranging from minimal sedation to moderate, deep, and general anesthesia. Differences between various stages of sedation are described in Table 1 . The most commonly used form of sedation in GIE is moderate sedation, also known as “conscious sedation.” Some of the most commonly used agents for sedation and their antagonists in GIE are listed in Boxes 1 and 2 , respectively. The targeted level of sedation depends on various factors like the type of examination, patient comorbidities, and the American Society of Anesthesiology (ASA) disease classification ( Table 2 ). Although the gastroenterology community is well versed in traditional sedation methods, the authors would like to put forth recent advances in endoscopic sedation, newer anesthesia medications, or combination methods that might be of use in the future of GIE, current aspects of sedation training available, and quality assessment of sedation during GIE.
| Minimal Sedation | Moderate Sedation | Deep Sedation | General Anesthesia | |
|---|---|---|---|---|
| Responsiveness | Normal response to verbal stimulation | Purposeful response to verbal or tactile stimulation | Purposeful response after repeated or painful stimulation | Unarousable even with painful stimulus |
| Airway | Unaffected | No intervention required | Intervention may be required | Intervention often required |
| Spontaneous ventilation | Unaffected | Adequate | May be inadequate | Frequently inadequate |
| Cardiovascular function | Unaffected | Usually maintained | Usually maintained | May be impaired |
- 1.
Dexmedetomidine
- 2.
Diazepam
- 3.
Diphenhydramine
- 4.
Droperidol
- 5.
Fentanyl
- 6.
Meperidine
- 7.
Midazolam
- 8.
Propofol
Naloxone: Fentanyl, Meperidine
Flumazenil: Diazepam, Midazolam
| PS1 | Normal healthy patient | No organic, physiologic, or psychiatric disturbance; excludes the very young and very old; healthy with good exercise tolerance |
| PS2 | Patients with mild systemic disease | No functional limitations; has well controlled disease of 1 body system; controlled hypertension or diabetes without systemic side effects; cigarette smoking without COPD; mild obesity; pregnancy |
| PS3 | Patients with severe systemic disease | Some functional limitation; has controlled disease of >1 body system or 1 major system; no immediate danger of death; controlled CHF, stable angina, previous heart attack, poorly controlled hypertension, morbid obesity, chronic renal failure, bronchospastic disease with intermittent symptoms |
| PS4 | Patients with severe systemic disease that is constant threat to life | Has at least 1 severe disease that is poorly controlled or at end stage; possible risk of death; unstable angina, symptomatic COPD, symptomatic CHF, hepatorenal failure |
| PS5 | Moribound patients who are not expected to survive without operation | Not expected to survive >24 h without surgery; imminent risk of death; multiorgan failure, sepsis syndrome with hemodynamic instability, hypothermia, poorly controlled coagulopathy |
| PS6 | A declared brain-dead patient whose organs are being removed for donor purposes | — |
Introduction
According to the standards of practice committee of the American Society for Gastrointestinal Endoscopy (ASGE), “sedation is defined as a drug-induced depression in level of consciousness.” Sedation is a fundamental aspect of gastrointestinal endoscopy (GIE) because it reduces anxiety and patient discomfort and also allows for better examination during endoscopy, thereby improving patient outcomes. The goal of sedation is to achieve a balance between the comfort aspects while preserving patient safety. Although sedation improves a patient’s tolerance, it also increases both the cost and the risks of complications. Sedation itself is responsible for about 50% of all GIE complications. Sedation can be divided into 4 levels, ranging from minimal sedation to moderate, deep, and general anesthesia. Differences between various stages of sedation are described in Table 1 . The most commonly used form of sedation in GIE is moderate sedation, also known as “conscious sedation.” Some of the most commonly used agents for sedation and their antagonists in GIE are listed in Boxes 1 and 2 , respectively. The targeted level of sedation depends on various factors like the type of examination, patient comorbidities, and the American Society of Anesthesiology (ASA) disease classification ( Table 2 ). Although the gastroenterology community is well versed in traditional sedation methods, the authors would like to put forth recent advances in endoscopic sedation, newer anesthesia medications, or combination methods that might be of use in the future of GIE, current aspects of sedation training available, and quality assessment of sedation during GIE.
| Minimal Sedation | Moderate Sedation | Deep Sedation | General Anesthesia | |
|---|---|---|---|---|
| Responsiveness | Normal response to verbal stimulation | Purposeful response to verbal or tactile stimulation | Purposeful response after repeated or painful stimulation | Unarousable even with painful stimulus |
| Airway | Unaffected | No intervention required | Intervention may be required | Intervention often required |
| Spontaneous ventilation | Unaffected | Adequate | May be inadequate | Frequently inadequate |
| Cardiovascular function | Unaffected | Usually maintained | Usually maintained | May be impaired |
- 1.
Dexmedetomidine
- 2.
Diazepam
- 3.
Diphenhydramine
- 4.
Droperidol
- 5.
Fentanyl
- 6.
Meperidine
- 7.
Midazolam
- 8.
Propofol
Naloxone: Fentanyl, Meperidine
Flumazenil: Diazepam, Midazolam
| PS1 | Normal healthy patient | No organic, physiologic, or psychiatric disturbance; excludes the very young and very old; healthy with good exercise tolerance |
| PS2 | Patients with mild systemic disease | No functional limitations; has well controlled disease of 1 body system; controlled hypertension or diabetes without systemic side effects; cigarette smoking without COPD; mild obesity; pregnancy |
| PS3 | Patients with severe systemic disease | Some functional limitation; has controlled disease of >1 body system or 1 major system; no immediate danger of death; controlled CHF, stable angina, previous heart attack, poorly controlled hypertension, morbid obesity, chronic renal failure, bronchospastic disease with intermittent symptoms |
| PS4 | Patients with severe systemic disease that is constant threat to life | Has at least 1 severe disease that is poorly controlled or at end stage; possible risk of death; unstable angina, symptomatic COPD, symptomatic CHF, hepatorenal failure |
| PS5 | Moribound patients who are not expected to survive without operation | Not expected to survive >24 h without surgery; imminent risk of death; multiorgan failure, sepsis syndrome with hemodynamic instability, hypothermia, poorly controlled coagulopathy |
| PS6 | A declared brain-dead patient whose organs are being removed for donor purposes | — |
Training in sedation for endoscopy
Given the recent advances in GIE sedation, training forms the cornerstone of successful sedation practices for the current and future gastroenterologist. The Multisociety Sedation Curriculum for Gastrointestinal Endoscopy (MSCGE) outlines a detailed, systemic approach for sedation describing pharmacology, informed consent, periprocedural assessment, levels of sedation, and anesthesiologist assistance for endoscopic procedure. This curriculum is beneficial for both the training individual and the practicing gastroenterologist to boost their knowledge and skills. The American Association for the Study of Liver Diseases, the American College of Gastroenterology, the American Gastroenterological Association, Society for “Gastroenterology Nurse and Associates”, and the ASGE all contributed to this MSCGE. Representatives from these societies helped in forming this curriculum, keeping in mind the utmost importance of research based on ethics, humanism, and professionalism.
The endoscopist must have a complete understanding of sedation agents, including pharmacokinetics and pharmacodynamics, adverse effects, and drug interactions. As the main focus is the comfort and safety of the patient during the procedure, the patient’s detailed medical history, medications, intubation assessment, anxiety, and pain intolerance should be reviewed. Benzodiazepines and opioids were previously commonly used agents, but, with time, newer sedation agents have been used. In most cases, moderate sedation is used, but a trainee should be knowledgeable in titrating the agents to produce the required level of sedation.
Informed consent for endoscopic sedation is an obligation for the physician, from both ethical and legal standpoints. A trainee should be well versed with the process of informed consent. Periprocedure assessment is another important part of endoscopic sedation, which includes the medical and sedation history of the patient while keeping the risks of sedation in mind. Before the procedure, a trainee should be able to assess the patient according to the ASA physical status classification (see Table 2 ). The patient’s airway should be evaluated, which covers the structure of the neck, hyoid mental distance, cervical spine, and oropharyx. The trainee should understand the anatomy of the oral cavity, which facilitates endotracheal intubation, and keep in mind the modified Mallampati classification, which has 4 grades (grade 1 means a complete visibility of the soft palate, uvula, and tonsils, and grade 4 means only the hard palate is visible). The trainee should be able to recognize whether anesthesiologist assistance is required for the procedure that needs general anesthesia or deep sedation. The trainee must be facile with intraprocedure and postprocedure assessment, including physiologic parameters and levels of sedation.
The trainee should be well prepared to rescue the patient in the event of a deeper sedation than what was targeted. Usually, opioids and benzodiazepines are used to achieve moderate sedation, but propofol can be used with other agents for moderate sedation and alone for deep sedation. An endoscopist should precisely identify arrhythmias and take proper measures to manage them. A trainee should have an Advanced Cardiac Life Support (ACLS) certificate or have had training in an Advanced Trauma Life Support course and should have experience in airway training; the indications for the use of naloxone and flumazenil are also required.
Postprocedure assessment is a continuation of intraprocedure monitoring and evaluates the physiologic recovery of the patient. The trainee should be familiar with the Post Anesthetic Discharge Scoring System (ie, vital signs, activity, mental status, pain, nausea, vomiting, bleeding) or the Aldrete Score (ie, respiration, oxygen saturation, consciousness, circulation; Box 3 ). The patient procedure should be accompanied by an adult and should not drive.
Respiration
2 = Able to take deep breath and cough
1 = Dyspnea/shallow breathing
0 = Apnea
Oxygen saturation
2 = Maintains >92% on room air
1 = Needs O 2 inhalation to maintain O 2 saturation >90%
Consciousness
2 = Fully awake
1 = Arousable on calling
0 = Not responding
Circulation
2 = BP ± 20 mm Hg preprocedurally
1 = BP ± 20 to 50 mm Hg preprocedurally
0 = BP ± 50 mm Hg preprocedurally
Activity
2 = Able to move 4 extremities
1 = Able to move 2 extremities
0 = Able to move 0 extremities
Total score is 10.
Patient scoring ≥8 and returned to similar preoperative status are fit for transition to phase II recovery.
The assessment of competency is of utmost importance in endoscopic sedation and should be tested clinically and in written examinations. Trainees should work on simulators (if available) before they start in the procedure room. Simulator-based training using a full-scale patient simulator as an adjunct to practical courses may improve the skills of trainees. MSCGE curricula recommend the use of such simulator programs. Simulation-based sedation training includes both technical and human performance aspects of managing adverse events; it also allows training in pharmacology, appropriate selection of sedative drugs for use in endoscopic procedures, pertinent monitoring techniques, and management of complications of intravenous sedation, including basic to advanced life support and recovery care. One study performed during a training course for sedation during endoscopy showed significant improvement in examination test scores of attendees at the end of 3 hours of training that included hands-on management on a full-scale patient simulator compared with those before training. It provides trainees with the specified knowledge and skills during a condensed period.
According to the American Board of Internal Medicine, evaluations should be transparent and based on the trainee’s medical knowledge, ACLS protocols, patient care, practice-based learning and system-based learning, interpersonal and communication skills, and feedback from nurses, patients, and technicians.
Currently published guidelines emphasize all endoscopists and endoscopy nurses using nonanesthesia provider-administered propofol (NAAP) to have the appropriate education and practical training. The ASGE recommends that training courses include theoretical and practical parts, followed by an examination and certified documentation of the training. An endoscopist using NAAP must be trained in ACLS, and nurses should, at least, be trained in basic life support.
As of now, not many fellowship training programs have a dedicated training time that is devoted toward endoscopic sedation training. The authors think there should be a graded curriculum of teaching endoscopic sedation in fellowship programs. Training programs are encouraged to use simulator-based training to train fellows in an initial period of training, followed by training under direct supervision of a staff physician. Curriculum should be designed to move from conscious sedation to AAP to NAAP. The training program should assess competency of fellows in sedation at regular intervals during their training.
Sedation agents
Over the years, various sedation agents have been tried and used for GIE. Box 1 presents a brief list of GIE sedation agents. Although midazolam and propofol remain the cornerstones of GIE sedation, various other newer agents are also being tested as feasible alternatives to the traditional agents. For the purpose of this review, the use of propofol is discussed in detail, and some of the newer agents are briefly touched upon.
Propofol
Propofol (2,6-diisopropylphenol) is currently the most common and popular hypnotic agent used for procedural sedation. It is an ultra-short-acting agent with sedative, amnestic, and hypnotic effects. Because of these properties, anesthesiologists and gastroenterologists all over the world have been increasingly using propofol to replace classical sedation over the last decade. Propofol rapidly crosses the blood-brain barrier and causes potentiation of the γ-aminobutyric acid-A receptor in the brain. It is 98% plasma protein-bound and is rapidly metabolized in the liver. Typically, the time from administration to its onset of action is 30 to 60 seconds, and its duration of effect is up to 4 to 8 minutes. It is now, essentially, the agent of choice for endoscopic sedation. In a recent nationwide US survey, 25.7% of gastroenterologist responders preferred propofol. Propofol also potentiates the central nervous system effects of narcotic analgesics and sedatives such as benzodiazepines, barbiturates, and others, thereby helping reducing the dose of these medications administered.
Some of the potential side effects of propofol include pain at the injection site, which can occur in up to in 30% of patients receiving the drug. It also causes a decrease in cardiac output, systemic vascular resistance, and a drop in blood pressure (BP). It also causes respiratory depression. All these effects can be reversed rapidly with a dose reduction or the interruption of infusion. As of now, there is no reversal agent for propofol. Propofol comes with a package warning that agent should only be given by persons trained in the administration of general anesthesia. The ASA released a directive stating propofol “must only be used by healthcare provider with specialized training in airway management.” This package warning has both medical and legal implications regarding patient safety issues. Secondary to the directive, the administration of propofol by nonanesthesiologists in the United States has waned popularity. Across the United States, propofol is now only administered by an anesthesiologist or a Certified Nurse Anesthetist who works with an anesthesiologist.
Studies have shown a higher after-procedure patient satisfaction with propofol versus conscious sedation agents for colonoscopy, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP), but not for esophagogastroduodenoscopy (EGD). It is also known that time to sedation and recovery is also shorter with propofol versus traditional sedation. Because of the above-mentioned reasons, new evidence has emerged in recent years regarding the use of NAAP and monitored anesthesia care (MAC) for GIE. NAAP refers to administration of propofol by either a gastroenterologist or a registered nurse under the supervision of the endoscopist.
A recent meta-analysis looked at the pooled results of NAAP and anesthesia provider-administered propofol (AAP) studies and reported the same rates of hypoxia and airway intervention in both arms. Several other significant studies, including a worldwide safety survey of 646,080 procedures with NAAP, concluded NAAP is safe to use for GIE.
Recently, a large prospective study was done in Sao Paulo, Brazil. In this prospective study, patients undergoing routine EGD and colonoscopies were enrolled in the study. Patients were divided into 2 groups: one NAAP group and another MAC group. A total of 2000 patients were enrolled in 2 groups with 1000 per group. The investigators reported that 12.8% of patients in the NAAP group experienced hypoxemia compared with 11.2% in MAC group. The investigators concluded that there were no notable differences in any outcomes between the 2 groups. In another study from Australia, a retrospective chart review was done, in which a total of 33,539 NAAP procedures were identified. Complications were recorded based on medical emergency team calls during those procedures. A total of 23 calls were noted, and patients were discharged the same day with no intervention in 16 of the calls, whereas 7 calls led to endotracheal intubation, of which 2 patients died (and both patients were either ASA III or ASA IV).
Based on the current mounting evidence on the safety and efficacy of NAAP, the European Society of Gastrointestinal Endoscopy and the European Society of Gastroenterology and Endoscopy Nurses and Associates released joint guidelines for the use of NAAP. They recommended that, for patients undergoing NAAP, health care professionals should assess the patient’s ASA classification, physical status, age, body mass index (BMI), Mallampati classification, and the risk factors for obstructive sleep apnea (OSA) before the procedure. They also indicate that any patient with an ASA class II or lower and Mallampati class less than 3 may undergo NAAP, and patients with an ASA classification at or above III or any severe comorbidity, an anesthesiologist should be involved in the procedure. They also suggest considering the use of capnography during NAAP, especially in long procedures and in patients with significant comorbidities. Regarding the administration of propofol, they recommend using intermittent bolus infusion or perfusion systems, including target-controlled infusion. Regarding the discharge of patients after NAAP, they recommend using a postanesthetic discharge scoring system (PADSS) to determine which patient can be discharged. The group also recommends that patients in ASA class II or higher should, upon discharge, be accompanied by a caregiver and refrain from driving, drinking alcohol, operating heavy machinery, or engaging in legally binding decisions for 24 hours.
Alternative Sedation Agents
Propofol has been the leader in sedation for GIE in the last decade. Given that the administration of propofol is done primarily by an anesthesiologist, the cost of the procedures involving propofol has been driven increasing. This increased cost is a driving factor to find an alternative sedative that is safe and can be administered by an endoscopist without compromising patient comfort, safety, and quality of the procedures. Various medications in different combinations have been explored, and some of them are reviewed in this article.
Dexmedetomidine
Dexmedetomidine (DEX) is a potent, selective α2-adrenoceptor agonist. Its specificity for α2-adrenoceptor is 8 times that of clonidine. Its other advantages include anxiolysis and analgesia without respiratory depression. DEX use during MAC has been evaluated in few studies. More recently, its safety profile has been assessed in various cardiology procedures. Its use as a sole sedative agent is still not accepted, because concrete evidence in this regard is still lacking.
Remifentanil
Remifentanil is an opioid with potent analgesic properties. It has a short half-life and time-independent context-sensitive half-time. Remifentanil carries a risk of respiratory depression. A group in France studied the use of remifentanil as a solo agent for sedation. The study had 91 patients, each receiving target-controlled infusion, with an initial target of 2 ng/mL. Thirty-seven percent of patients reported short-duration respiratory depression, which is a concerning finding, if the patient is in the care of practitioners untrained or unfamiliar with airway management. Remifentanil, given its nonhepatic metabolic clearance, can be safely used in patients with hepatic dysfunction. Few other studies have looked at the use of remifentanil in GIE. Bouvet and colleagues recommended the use of remifentanil as an alternative to propofol. Also, when remifentanil was used in combination with an etomidate infusion, the combination showed a similar cardiovascular safety profile as propofol for use during colonoscopy.
Ketamine
Ketamine is a phencyclidine derivative that acts on various receptors, including N -methyl- d -aspartate, dopamine 2, and noradrenalin. Ketamine also has a short half-life, and, like remifentanil, it also has a time-independent context-sensitive half-time. The biggest advantage of ketamine over other sedatives (including propofol) is its ability to provide analgesia without apnea or respiratory depression. Ketamine does not cause depression of the airway reflexes. There are limited data on the use of ketamine as a single agent or in combination with midazolam in GIE. It is used more commonly in the pediatric population because it causes less apnea. Nevertheless, despite its lack of effects on the respiratory system, ketamine has not gained popularity because of the emergence phenomenon, especially in adults. Some people advocate using midazolam in conjunction with ketamine to obliterate some of the effects of emergence.
Ketofol is a combination of ketamine and propofol that has also gained attention recently. Usually, the dose can be mixed in a 1:1 ratio or can be given sequentially. There is no evidence in GIE that ketofol is better than either agent alone; it has been used with some success in the emergency department, though.
Fospropofol
Fospropofol is one of the newer agents approved in 2008 by the US Food and Drug Administration. It is essentially a prodrug formulation of propofol. Because of this, it does not cause side effects like burning at the injection site, although it can cause pruritus or perineal paresthesia. Investigations are ongoing to study its use in GIE. So far, published literature regarding fospropofol use in GIE has not indicated a higher risk of adverse events for fospropofol.
Remimazolam
Remimazolam (CNS7056) is a new drug emerging in the field of sedation and anesthesia and is a combination of midazolam and remifentanil, 2 of the most well-studied drugs in GIE. It acts on the same receptors as midazolam: γ-aminobutyric acid. It has an organ-independent elimination similar to remifentanil. So far, 4 clinical trials have evaluated remimazolam for GIE. Pambianco and colleagues studied the use of remimazolam versus midazolam for colonoscopies. The investigators did use fentanyl for pain relief as needed in addition to remimazolam during the procedure. The study group showed a rapid onset of action that resulted in earlier and deeper sedation when compared with midazolam. The recovery times were short and similar for both groups. Adverse events between both the groups were similar. Discharge times between both study groups did not differ. More than 900 patients across 4 phase II clinical trials have been exposed to remimazolam with no additional reported safety concerns than previously expected with conscious sedation. Phase III clinical trials are needed to achieve a label similar to midazolam.
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