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Sedation and Monitoring in Endoscopy

Introduction

Sedation is regularly used to facilitate the performance of endoscopic procedures. Sedation practices have noticeably changed over the past decade, with a shift from no or moderate sedation to monitored anesthesia care (MAC) for gastrointestinal (GI) endoscopy.

Sedation during an endoscopic procedure helps in two ways; first, by decreasing procedural pain, thereby making the patient more comfortable, and second, by decreasing any untimely patient movements, thereby reducing complications. Both these factors affect the overall quality and safety of endoscopic procedures.

Sedation is associated with its own potential problems. Sedation-related complications, such as aspiration, oversedation, hypoventilation, and airway obstruction, make up more than half of all reported endoscopic complications.

Sedation use requires additional monitoring and recovery, and therefore has implications in the form of time, cost, and staffing. Due to these issues, some prior studies have advocated for the use of unsedated endoscopy ; however, the rate of use of unsedated endoscopy remains very low in the United States. The main reason for that is unpredictable patient tolerability during the endoscopic procedures. Several studies have shown that even though patients agree to undergo the procedure without sedation initially, the need for sedation later in the procedure causes significant delays in procedure completion when compared to patients who are sedated throughout the procedure.

The length and complexity of procedures and the comorbidities of the patient are the most important factors for sedation use. These factors may influence the choice of sedative, the level of sedation, and the need for an anesthesiologist during the procedure. Patients also vary in their sensitivity to sedation and their tolerance of endoscopy. The American Society of Anesthesiologists (ASA) defines the level of sedation on a spectrum of four recognizable levels, from minimal sedation to general anesthesia ( Table 7.1 ). The most commonly used level in endoscopic procedures is moderate sedation, wherein the patient demonstrates purposeful response to visual or tactile stimuli. This level of sedation can be achieved with a benzodiazepine alone or combined with an opiate. Due to the increased use of MAC, propofol use to target balanced propofol sedation (concurrent use with midazolam and/or fentanyl) is being increasingly used for mild to moderate sedation and is associated with improved patient outcomes.

TABLE 7.1
Levels of Sedation
From Bryson HM, Fulton BR, Faulds D: Propofol: an update of its use in anesthesia and conscious sedation. Drugs 50(3):513–559, 1995.
Level 1: Minimal sedation Drug-induced state, during which patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are unaffected
Level 2: Conscious sedation Drug-induced depression of consciousness, during which patient responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Patent airway is maintained without help. Spontaneous ventilation is adequate, and cardiovascular function is usually maintained
Level 3: Deep sedation Drug-induced depression of consciousness, during which patient cannot be easily aroused but responds purposefully to repeated or painful stimulation. Patient may require assistance maintaining an airway. Spontaneous ventilation may be inadequate, and cardiovascular function is maintained
Level 4: General anesthesia Patient is not able to be aroused even by painful stimuli. Patient often requires assistance in maintaining patent airway. Positive-pressure ventilation may be required owing to respiratory depression or neuromuscular blockade. Cardiovascular function may be impaired

This chapter focuses on all aspects of sedation and patient safety. Patient evaluation and risk assessment, presedation preparation, patient monitoring during sedation, sedation providers, sedation in high-risk populations, and issues of consent are discussed. The attributes of commonly used sedative drugs are discussed in the context of level of sedation and monitoring required.

Patient Evaluation, Preparation, and Risk Stratification

The risk of adverse outcomes can be reduced by appropriate preprocedural evaluation of the patient's history and physical findings. The clinicians responsible for sedation should familiarize themselves with specific and relevant aspects of the medical history, including abnormalities of major organ systems, previous adverse experience with sedation and analgesia, current medications and drug allergies, time of the last oral intake, and history of alcohol or recreational drug use. A thorough physical examination should be done, particularly to assess the heart and lungs, in addition to assessing the airway anatomy. It may be useful to consider the patient in terms of the ASA status classification ( Table 7.2 ), as increasing number and severity of comorbidities are associated with an increased incidence of cardiopulmonary unplanned events. Patients undergoing sedation should be informed of the benefits, risks, and limitations associated with sedation and possible alternatives. This should be completed as part of the patient consent.

TABLE 7.2
Definition of American Society of Anesthesiologists Status
Class 1 Patient has no organic, physiologic, biochemical, or psychiatric disturbance. Pathologic process for which operation is to be performed is localized and does not entail systemic disturbance
Class 2 Mild to moderate systemic disturbance caused either by the condition to be treated surgically or by other pathophysiologic processes
Class 3 Severe systemic disturbance or disease from whatever cause; it may be impossible to define degree of disability with finality
Class 4 Severe systemic disorders that are already life-threatening, not always correctable by operation
Class 5 Moribund patient who has little chance of survival but is submitted to operation in desperation

Patients undergoing sedation should be stratified according to the risk for sedation-related complications to receive either moderate sedation or MAC. The Stratifying Clinical Outcomes Prior to Endoscopy score (the SCOPE score) is a validated score that can be used to predict difficult moderate sedation for endoscopy based on several factors. The purpose of the risk stratification is to reduce the incidence of sedation-related adverse events.

Procedural Monitoring

Patients should have continuous monitoring while undergoing endoscopic procedures and also before, during, and after the administration of sedative agents. Standard monitoring procedures include electrocardiography, pulse oximetry, blood pressure measurement, and capnography. Monitoring should be discontinued only when the patient is fully awake. According to the ASA guidelines, it is recommended that continuous recording of the patient's level of consciousness, respiratory function, and hemodynamics reduces the risk of sedation-related adverse outcomes. Close monitoring helps in early detection of adverse events induced by sedatives, such as apnea, hypoxemia, hypotension, and arrhythmias, which allows for early intervention to prevent any life-threatening complications. Each of the monitored parameters is addressed in the following sections.

Level of Consciousness

Alteration in the level of consciousness while under sedation serves as a guide to the depth of sedation the patients. With a decrease in level of consciousness being associated with a loss of reflexes that normally protect the airway and prevent hypoventilation, it is important to assess patient response to commands during sedation (see Table 7.1 ). Verbal responses also provide information indicating that the patient is breathing. In procedures where verbal responses are impossible, such as upper GI endoscopy, nonverbal responses such as hand movements, finger squeezing, toe wiggling, etc., should be sought. A lack of response to verbal or tactile stimuli suggests a higher depth of sedation and should be managed accordingly.

Pulse Oximetry

A common noninvasive method of measuring oxygen saturation is pulse oximetry, which uses a light signal transmitted through tissue and takes into account the pulsatile volume changes that occur. The pulse oximeter measures the pulsatile signals across perfused tissue at two distinct wavelengths: the infrared band, which corresponds to oxyhemoglobin, and the red band, which corresponds to reduced hemoglobin.

However, the sole use of pulse oximetry is inadequate for detecting alveolar hypoventilation in patients undergoing endoscopy. This is demonstrated by the oxyhemoglobin dissociation curve. A high oxyhemoglobin concentration is preserved despite a decrease in partial pressure of oxygen in the blood (Pa o 2 ) until the Pa o 2 falls below 60 mm Hg, at which point the pulse oximeter reading reflects the decreasing Pa o 2 with a rapid decrease in oxygen saturation. Therefore, alveolar hypoventilation is detected earlier with the use of capnography (described later) than pulse oximetry.

Pulmonary Ventilation

Respiratory depression in the form of transient hypoxemia is not uncommon with sedation use and is usually trivial. It is also encountered in unsedated procedures. Extended periods of hypoxemia, however, can cause tachycardia and coronary ischemia. Therefore, respiratory monitoring is very important to reduce the risk of adverse outcomes.

Direct observation of respiratory movement or direct pulmonary auscultation is the simplest way to monitor ventilator function. A noninvasive method for measuring arterial carbon dioxide is transcutaneous carbon dioxide monitoring (PtCO 2 ), which entails placing a heated electrode on the skin, causing the microcirculation to “arterialize.” The eventual production of carbonic acid due to diffusion of carbon dioxide into an electrolyte solution provides a pH reading by using the Henderson-Hasselbalch equation, which allows for calculation of the arterial carbon dioxide level. The use of this technique was validated by Nelson et al (2000), who demonstrated significantly more CO 2 retention in patients with standard monitoring than those with standard monitoring coupled with PtCO 2 monitoring in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP).

Capnography is the gold standard for respiratory monitoring. It works by measuring the CO 2 indirectly by virtue of light absorption in the infrared region of the electromagnetic spectrum. CO 2 retention is identified as an early event on capnography and is a sign of ventilation compromise. It serves as a qualitative method for detection of CO 2 levels in nonintubated patients undergoing endoscopy, as the exact measurement of CO 2 is inaccurate unless the breathing system is a closed circuit, such as in intubated patients. There have been several studies that have demonstrated that use of capnography detects significantly more hypoxemia in patients undergoing GI endoscopy than standard monitoring. However, a 2016 trial did not demonstrate any reduction in the incidence of hypoxemia events in healthy individuals undergoing routine endoscopy targeting moderate sedation.

Bispectral index (BIS) monitors are often used in the operating room to assess the adequacy of the depth of anesthesia while under a general anesthetic in patients undergoing surgical procedures. However, the BIS monitor has significant overlap of scores across sedation levels when it is used to detect deep sedation, resulting in an overall lower accuracy rate.

Hemodynamic Measurements

Hemodynamic complications, such as hypotension, arrhythmias, and cardiovascular response to stress, are some of the mild direct effects of sedative agents and analgesics that may happen during sedation. Regular measurements of pulse and blood pressure can help detect these changes, which may represent responses to hypoxemia, oversedation, or possibly patient distress to procedure-induced pain. Although no evidence shows that blood pressure monitoring during endoscopy influences morbidity and mortality, it has been recommended that both regular blood pressure measurements and pulse be monitored throughout procedures performed under sedation. Continuous electrocardiogram (ECG) monitoring should be considered in high-risk patients, such as patients with known disturbances in cardiac rhythm, cardiomyopathies, or ischemic heart disease. The requirement for ECG monitoring has not been evaluated in clinical trials.

Supplemental Oxygen

Supplemental oxygen administered via nasal cannulas or a mask has been shown to reduce the incidence of desaturation during endoscopy performed under sedation and hence it should be given to all patients receiving sedation. However, as supplemental oxygen may delay the onset of hypoxemia in sedated patients with decreased pulmonary ventilation, it is essential not to rely solely on pulse oximetry to monitor ventilation but to employ additional techniques, such as capnography or a BIS monitor.

Intravenous Access

Intravenous access should be maintained throughout the procedure until the patient is no longer at risk from cardiopulmonary or respiratory depression. It facilitates the immediate availability of vascular access in the event of oversedation for administration of reversal agents or for using emergency drugs in the event of cardiopulmonary compromise. In patients who are receiving sedatives via nonintravascular routes (e.g., pediatric patients undergoing endoscopic procedures), intravenous access should also be obtained if the likelihood of any cardiopulmonary depression is high.

Sedation and Consent

There are a couple of important things to keep in mind when it comes to consent and sedation. First and foremost, the patient should be fully informed of the indications, risks, and alternatives to sedation before he or she consents to the procedure. The second important issue is whether a patient, while under sedation, can withdraw consent for the procedure. If a sedated patient indicates during endoscopy that he or she wishes to have the procedure stopped, should the endoscopist stop or complete the procedure, bearing in mind that it would be in the patient's best interests to complete it? A study from the United Kingdom researched this issue and found that 88% of gastroenterologists stated that they would only stop after repeated requests by the sedated patient, and only 45% of gastroenterologists thought patients were capable of making rational decisions while under sedation. When looked at from the patient's perspective, the study found that opinion was evenly divided into terminating the procedure immediately or completing it.

Staffing Levels and Training

Adequate patient monitoring during sedation is difficult for a clinician performing the procedure. There should be additional individuals available to monitor the patient's status in terms of level of consciousness, ventilatory function, and hemodynamic parameters. The presence of another individual is likely to improve patient comfort and satisfaction. Several areas of expertise are required while managing sedated patients, including knowledge of administered drugs and management of adverse events. All staff members administering sedative drugs should be made familiar with the pharmacology of all drugs used prior to their involvement. Particularly, staff members should be aware of the basics such as the time to onset of action, elimination half-life, interactions, adverse reactions, contraindications, and pharmacology of appropriate antagonists.

Individuals monitoring sedated patients should be able to recognize complications associated with the sedative drugs. Since most of the complications associated with sedatives are cardiopulmonary in nature, at least one individual should be familiar with advanced airway and ventilation management. Guidelines recommend an advanced resuscitation provider be immediately available in the event of an emergency. Resuscitation equipment should be readily available and must include a cardiac defibrillator, advanced airway and positive-pressure ventilation equipment, and all the appropriate drugs, including sedative antagonists ( Box 7.1 ).

Box 7.1
From American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists: Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 96(4):1004–1017, 2002.
Appropriate Emergency Equipment to Have Available When Using Sedative or Analgesic Drugs Capable of Causing Cardiorespiratory Depression

Appropriate emergency equipment should be available whenever sedative or analgesic drugs capable of causing cardiorespiratory depression are administered. The following lists should be used as a guide, which should be modified depending on the individual practice circumstances. Items in brackets are recommended when infants or children are sedated.

Intravenous Equipment

  • Gloves

  • Tourniquets

  • Alcohol wipes

  • Sterile gauze pads

  • Intravenous catheters [24–22-gauge]

  • Intravenous tubing [pediatric “microdrip” (60 drops/mL)]

  • Intravenous fluid

  • Assorted needles for drug aspiration, intramuscular injection (intraosseous bone marrow needle)

  • Appropriately sized syringes [1-mL syringes]

  • Tape

Basic Airway Management Equipment

  • Source of compressed oxygen (tank with regulator or pipeline supply with flowmeter)

  • Source of suction

  • Suction catheters [pediatric suction catheters]

  • Yankauer-type suction

  • Face masks [infant/child]

  • Self-inflating breathing bag-valve set [pediatric]

  • Oral and nasal airways [infant/child-sized]

  • Lubricant

Advanced Airway Management Equipment (for practitioners with intubation skills)

  • Laryngeal mask airways [pediatric]

  • Laryngoscope handles (tested)

  • Laryngoscope blades [pediatric]

  • Endotracheal tubes

    • Cuffed 6.0, 7.0, 8.0 mm ID

    • [Uncuffed 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 mm ID]

  • Stylet (appropriately sized for endotracheal tubes)

Pharmacologic Antagonists

  • Naloxone

  • Flumazenil

Emergency Medications

  • Epinephrine

  • Ephedrine

  • Vasopressin

  • Atropine

  • Nitroglycerin (tablets or spray)

  • Amiodarone

  • Lidocaine

  • Glucose, 50% [10% or 25%]

  • Diphenhydramine

  • Hydrocortisone, methylprednisolone, or dexamethasone

  • Diazepam or midazolam

ID, internal diameter.

Postprocedural Monitoring

The patients remain at risk of sedative-related complications even after completion of the procedure. The risk of upper airway obstruction and hypoxemia after significant moderate sedation for ERCP seems to be greatest immediately after removal of the endoscope. Monitoring of the patient should be continued until the patient has reached an acceptable level of consciousness, with normal ventilation, oxygenation, and hemodynamic parameters. Before discharging the patient, it should be recognized that there may be a prolonged period of amnesia with impairment of cognition and judgment, even though the patient's conscious level may appear normal. Patients may also be mildly dehydrated, especially after colonoscopy, and fluid replacement should be addressed before discharge planning.

After an outpatient procedure, the following instructions should apply for at least 24 hours after discharge:

  • Patients should not drive.

  • Patients should not operate heavy or dangerous machinery.

  • Patients should not sign any legally binding documents.

  • Patients should be given written instructions regarding “warning signs and symptoms” of any adverse outcomes of the procedure and contact numbers for 24-hour advice.

In addition to the previous points, patients should arrange for a ride home beforehand, and that should be confirmed with the patient before starting the procedure.

In a placebo-controlled study, flumazenil use was shown to augment recovery from sedation and amnesia without any apparent risk for resedation. Although use of flumazenil adds to the costs of the procedure, it still may be preferable for some patients. Use of flumazenil does not preclude the need for postprocedural monitoring, and there is currently not enough evidence to support its routine use.

Drugs for Sedation

An ideal sedative agent should have the following characteristics:

  • Rapid onset of action

  • Practical means of delivery

  • Short half-life with rapid recovery

  • Safe with predictable sedative response (pharmacodynamics)

  • Minimal or no cardiovascular or respiratory effects

  • Effective in producing a calm, pain-free, cooperative patient

The most commonly used class of drugs are benzodiazepines, which are used alone or in combination with an opiate. It is vital that clinicians are familiar with a few specific sedatives (e.g., midazolam or fentanyl). Most recently, propofol has become the agent of choice to induce deep sedation. Midazolam and diazepam are also frequently used and have been shown to have similar efficacy when compared to each other. Midazolam is an attractive agent for endoscopy owing to its rapid onset of action, short half-life, and amnestic properties.

Fentanyl and meperidine are the most frequently used opiates, with fentanyl being preferred and commonly used because of its rapid action and absence of nausea.

The use of a benzodiazepine and an opiate is the most frequently utilized combination in endoscopic procedures, although this concurrent use may lead to an increased incidence of sedation-related complications. Combination therapy in colonoscopy and upper GI endoscopy, however, does not seem to improve pain and tolerance when compared with individual agents.

The safest method of administration is by giving small incremental doses until the desired level of sedation is attained, rather than giving a single bolus dose based on patient weight.

Droperidol used to be used in the sedation of agitated patients; however, due to its numerous side effects, it is not widely utilized anymore. Nitrous oxide has also been infrequently used as a form of patient-controlled analgesia in several studies involving colonoscopy. Potential benefits of its use include an absence of sedation-related risks and a rapid recovery. However, studies utilizing nitrous oxide were inconsistent and showed minimal to no benefit compared with traditional sedation.

Propofol and Deep Sedation

In certain circumstances, standard moderate sedation is not sufficient, and patients may require a higher level of sedation. These circumstances include patients who are not tolerant of endoscopy under moderate sedation and in procedures that are painful, longer, or complex, such as ERCP, endoscopic ultrasound (EUS), balloon enteroscopy, and endoscopic submucosal dissection (ESD). Deep sedation can be achieved with benzodiazepine and narcotic combinations. Fentanyl, remifentanil, and meperidine all have been combined with benzodiazepines and narcotics to accentuate sedative effects to achieve deep sedation.

Propofol is a popular drug that is frequently used for GI endoscopy because of its highly favorable pharmacokinetics. Its short half-life, rapid onset of action, rapid recovery times, and attainable depth of sedation make an attractive agent for endoscopic procedures. It has no analgesic properties. Patients who regularly use sedatives and narcotics are often insensitive to standard benzodiazepine sedation and may benefit from propofol sedation. There are several disadvantages associated with propofol use. Propofol has to be continuously titrated to maintain sedation due to its short half-life. The narrow therapeutic window between moderate sedation, deep sedation, and anesthesia necessitates close monitoring. As a result of peripheral vasodilation and impairment of cardiac contractility, propofol may cause profound hypotension. Propofol causes apnea more readily than midazolam, so managing the airway and pulmonary ventilation is more critical if propofol is used.

Newer Agents

Remimazolam is the latest drug innovation in anesthesia. It is an ester-based benzodiazepine designed to be used for short-duration sedation. It has an organ independent metabolism and is rapidly hydrolyzed by tissue esterases without producing any active metabolites. The sedation effect is shorter than midazolam, and frequent dosing may be required for procedure completion. Preliminary studies have suggested that the recovery time is similar to midazolam, although remimazolam recovery times lack the long outliers seen with midazolam sedation.

Fospropofol is a prodrug that is enzymatically converted to propofol in the liver with a delayed onset of action (4–8 min) and extended duration of action (20–30 min). It may decrease the need for frequent administration, which is often seen with propofol; however, because it needs to be converted to propofol, it has a decreased clinical effect compared to propofol. Fospropofol failed to gain popularity due to several inaccuracies that were reported in the published fospropofol pharmacokinetic-pharmacodynamic data. This led to the retraction of six studies, and correct data is yet to be made available.

Dexmedetomidine is an α 2 -adrenoreceptor agonist with sedative, anxiolytic, and analgesic effects. Its effects on respiratory system are minimal, and it does not cause clinically significant respiratory depression. It can be administered either intranasally or intravenously, although the latter is preferred. Dexmedetomidine is delivered as an initial bolus infusion of 1 µg/kg over 10 min followed by continuous infusion of 0.6 µg/kg per hr that may be titrated between 0.2 to 1.0 µg/kg per hr. Dose modification is often necessary in elderly or critically ill patients. Side effects include bradycardia and a biphasic change in blood pressure (high then low) with administration of increasing concentrations. Dexmedetomidine alone or dexmedetomidine with meperidine and midazolam has shown to have less respiratory depression and higher patient satisfaction scores for routine endoscopy and more advanced procedures (e.g., ERCP) than midazolam alone or midazolam with meperidine. Dexmedetomidine causes less respiratory depression even when administered with propofol as compared to propofol administered with sufentanil, meperidine, or midazolam.

Sedation Providers

In the United States, moderate sedation is usually administered by an endoscopist, whereas anesthesiologists are the ones managing sedation for MAC or general anesthesia. There are several alternative methods of sedation for endoscopy, which include patient-controlled sedation (PCS), automated delivery using methods such as the SEDASYS system (Ethicon Endosurgery, Inc., Somerville, NJ), and nonanesthesiologist-administered sedation using centrally acting agents such as propofol.

Nearly all endoscopic procedures in the United States are completed with some form of sedation, whereas nearly three-fourths of all endoscopies performed in Europe and Asia are completed without sedation. The percentage of patients undergoing endoscopic procedures (simple or advanced) with MAC or deep sedation in the United States continues to rise. A national survey in 2006 concluded that roughly 75% of patients undergoing endoscopic procedures in the United States received moderate sedation and 25% received deep sedation. Presently, the regions with the highest anesthesiologist-administered sedation rates are the South and Mid-Atlantic states. Cooper et al (2013) showed that from 2000 to 2009, anesthesia services were used in 40% of the total endoscopies performed in the northeastern United States.

SEDASYS

In 2013, the US Food and Drug Administration (FDA) approved the SEDASYS system (Ethicon) for minimal to moderate sedation in ASA class 1–2 patients who are at least 18 years old and have a body mass index (BMI) less than 35 for elective esophagogastroduodenoscopy (EGD) and colonoscopy with a requirement that an anesthesiologist be “immediately available” in case of any complications. It was designed to be used with an initial fentanyl dose, followed by a propofol bolus delivered over 3 to 5 minutes, and then an adaptable propofol infusion. It had shown promise when compared with moderate sedation for endoscopy in low-risk patients, with better recovery times and greater satisfaction with SEDASYS among patients and clinicians. There is no direct comparison between SEDASYS and anesthesiologist-delivered sedation in the current literature. A very limited number of hospitals in the United States adopted SEDASYS. As a result, in May 2016, the manufacturer (Johnson & Johnson, New Brunswick, NJ) decided to remove it from the market due to a lack of popularity.

Patient-Controlled Sedation (PCS)

PCS uses the same hardware as patient-controlled analgesia with drugs (propofol, opioid, and/or benzodiazepines) chosen by the endoscopist. PCS has been shown to be successful in several small studies of both simple and advanced endoscopic procedures. Anesthesiologist-administered propofol and PCS have equal satisfaction for ERCP but with shorter recovery times and less frequent use of minor airway interventions, such as chin lifts, in the PCS group. In one study, anesthesiologist intervention was required to complete ERCP in 7% of PCS cases.

Gastroenterologist-Directed Propofol Sedation

Worldwide, gastroenterologists favor using propofol as a sedative for endoscopic procedures over traditional sedatives. In Switzerland, gastroenterologists administer propofol in both hospital and private practice settings, reflecting successful implementation of nonanesthesiologist-administered propofol-based sedation in other countries. A 2014 large German study of 24,441 endoscopic procedures with gastroenterologist-directed propofol sedation in ASA class 1–3 patients with BMI less than 40 and without obstructive sleep apnea (OSA) (ASA class 3 patients with cardiac issues were also excluded) concluded that the incidence rate for major adverse events (such as apnea or laryngospasm requiring mask ventilation or intubation) was only 0.016%, with the incidence of minor adverse events being just 0.46%. All affected patients made a full recovery. Anesthesia was titrated between moderate to deep sedation.

The latest guidelines of the European Society of Gastrointestinal Endoscopy for the administration of propofol for GI endoscopy by nonanesthesiologists consist of involving an anesthesiologist in high-risk patients, such as those with an ASA classification of 3 or higher, with a Mallampati score of 3 or higher, with conditions that put them at risk for airway obstruction, chronically receiving significant amounts of narcotics, or for whom a lengthy or a complicated procedure is anticipated.

The FDA regulations on propofol state, “For general anesthesia or MAC sedation, Diprivan Injectable Emulsion (Fresenius Kabi USA LLC, Lake Zurich, IL) should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure.” This statement has grossly limited the use of propofol by nonanesthesia providers in the United States.

A fairly large 2017 meta-analysis found no difference in rates of overall complications between endoscopist-directed propofol administration and nonendoscopist-directed propofol administration.

Sedation in Different Patient Populations

Endoscopy in Patients With Cirrhosis

Chronic liver disease is one of the most common indications for emergent endoscopy. Liver dysfunction reduces both the clearance of the drugs eliminated by hepatic metabolism and plasma protein binding. It is also associated with a reduction in drug-metabolizing enzyme activities such as the Cytochrome P450 (CYP450) enzymes. Therefore, in patients with advanced liver disease, it is imperative to adjust the dose of those drugs eliminated by renal excretion.

A 2015 meta-analysis concluded that propofol provided more prompt sedation and recovery from EGD than midazolam in cirrhotic patients, with no difference in incidence of side effects.

Endoscopy Without Sedation

Unsedated endoscopy is facilitated by use of ultraslim endoscopes (<5.9 mm in diameter). The transnasal route of EGD has a higher patient acceptance rate and is preferred by more patients as compared to conventional EGD with or without sedation. However, the disadvantages of the transnasal EGD are the inferior image and the smaller biopsy samples.

Endoscopy and Pregnancy

Endoscopic procedures in pregnant patients are rarely required and should only be done for the most convincing indications, such as significant GI bleeding, severe nausea and vomiting, dysphagia, and severe diarrhea (all of which may impact maternal and fetal nutrition), as well as biliary pancreatitis or cholangitis. The procedures should be deferred to the second trimester whenever possible to decrease the impact of anesthesia drugs on fetal development.

Both the mother and fetus are at risk for adverse events with endoscopy and, more significantly, anesthesia. A comprehensive discussion of the risks to the fetus and mother with a preoperative obstetrician consultation should be compulsory during the informed consent process for endoscopy. Monitoring of fetal heart rate may be performed during the endoscopy or before and after the procedure.

The left lateral position is recommended for the procedure to avoid compression of inferior vena cava or aorta and prevent compromise of the fetal circulation. Any exposure to radiation should absolutely be avoided. If an ERCP is required, patient position should be appropriate with a lead apron shielding the uterus. An expert should perform the procedure and preferably use a nonfluoroscopy technique.

Anesthesiology services are recommended to be involved during endoscopic procedures involving pregnant patients. There is an increased risk for aspiration in pregnant patients due to elevated intraabdominal pressure and decreased lower esophageal sphincter tone. Maternal hypoxia and/or hypotension may result in reduced uterine blood flow and affect fetal viability.

To summarize, endoscopic procedure time should be minimized, special attention must be paid to the indication for the procedure and patient positioning, fetal monitoring should be made a priority and, if possible, all procedures should be deferred to at least the second trimester.

Endoscopy in Obese Patients

Obese patients are at risk for OSA and adverse cardiovascular events during endoscopic procedures. These patients can be stratified into groups at high and low risk for OSA using the STOP-BANG ( S noring, T iredness, O bserved apnea, blood P ressure, B ody mass index, A ge, N eck circumference, and G ender) screening tool. The STOP-BANG score may help in predicting sedation-related adverse events in obese patients undergoing advanced, but not routine, endoscopic procedures.

EGD can be safely performed with moderate sedation in most patients with a Roux-en-Y gastric bypass unless the coexisting medical conditions necessitate anesthesia monitoring. In a comparison with those without a bypass, patients with Roux-en-Y gastric bypass required higher doses of fentanyl and midazolam during EGD. The dose of drugs required for sedation increased after gastric bypass despite the resulting weight loss.

Sedation for Different Endoscopic Procedures

Standard Endoscopic Procedures

Propofol has been compared with traditional sedative agents such as midazolam, meperidine, and fentanyl in several trials during standard endoscopic procedures.

Propofol was shown to be safer and more effective than traditional sedative agents for maintaining an adequate level of sedation during endoscopy, resulting in better titration of the level of sedation and a shorter recovery time. A 2017 meta-analysis of 27 studies did not find any difference in cardiopulmonary complications between propofol and traditional sedative agents for GI endoscopy.

Balanced propofol sedation targeted to induce moderate sedation in patients undergoing upper GI endoscopy was also shown to result in better patient satisfaction and a shorter recovery time than standard sedation alone.

Propofol Use in Complex Endoscopic Procedures

The use of propofol in complex and prolonged procedures has also been investigated extensively. Patients undergoing ERCP are increasingly using MAC instead of moderate sedation. Most of these procedures are performed today without any need for endotracheal intubation. Studies have evaluated the use of balanced propofol sedation in patients undergoing ERCP, with recovery times being longer than in patients undergoing sedation only with propofol. In addition, deep biliary cannulation rates for moderate and deep sedation have shown to be similar.

In Europe, gastroenterologists have transitioned to using propofol sedation in patients undergoing EUS. Recently, a study from Spain (2012) concluded that nonanesthesiologist-administered propofol-based sedation for upper EUS in high-risk and average-risk patients had a low rate of minor complications and no major complications. General anesthesia use assists in EUS-guided fine-needle aspiration of pancreatic masses by decreasing patient movement and resulting in an increased diagnostic yield.

ESD is an emerging procedure in the United States. Unlike standard endoscopy, ESD is associated with pain throughout the procedure, such as during the incision and dissection phases, as well as the distension and endoscope movement required to perform the procedure. Therefore, deep sedation is a prerequisite for these patients. MAC without endotracheal intubation in patients undergoing esophageal or gastric ESD reduces body movement and provides a safer treatment environment in these difficult and prolonged cases. A 2015 comparison of two sedation protocols, moderate sedation with analgesic supplementation (MSAS) and analgesia-targeted light sedation (ATLS), showed that ATLS did not affect the ESD performance while producing a lower incidence of desaturation events and decreased incidence of aspiration pneumonia. Propofol-remifentanil infusion regimens were used in this study to achieve the desired level of sedation.

Pharyngeal Anesthesia in Sedation

Topical anesthetic agents are frequently used to suppress the gag reflex in upper endoscopy in addition to sedation. The most commonly used agents are lidocaine, benzocaine, and tetracaine, administered as an aerosol spray to the pharynx. Pharyngeal anesthesia in conjunction with intravenous or intramuscular sedation during upper endoscopy was shown to improve ease of endoscopy and patient tolerance in a meta-analysis. Topical anesthetics have been associated with severe adverse effects such as aspiration, anaphylaxis, or methemoglobinemia and hence should be used cautiously.

Management of Oversedation

Sedative agents have been associated with more than 50% of all endoscopy-related complications, the most common being oversedation, hypotension, and respiratory depression. Studies have shown that the expected mean desaturation during all endoscopic procedures is approximately 3% from baseline during sedation. The availability of reversal agents for sedative drugs (i.e., benzodiazepines and opioids) are associated with a reduced risk of sedation-related adverse events. The specific antagonists that are available are flumazenil for benzodiazepines and naloxone for opioids.

However, no such antagonists exist for propofol and that is the biggest disadvantage of using this drug. Even though its short half-life may lead to a rapid reversal of sedation, cardiopulmonary compromise in the interim may prove to be disastrous in the absence of an anesthesiologist.

In patients who have received both a benzodiazepine and an opioid, flumazenil reverses sedation but not respiratory depression. Similarly, naloxone monotherapy has not been shown to reverse respiratory depression induced by opioid and benzodiazepine combinations. In the setting of combination therapy-induced respiratory depression, it is recommended that naloxone is given in addition to flumazenil. At the time of reversal or before reversal, the following should be done:

  • Perform basic airway management

    • Clear airway including suction (if appropriate)

    • Jaw thrust maneuver

    • Guedel airway if necessary

  • Administer supplemental oxygen or increased oxygen

  • Encourage or stimulate deep breaths

  • Administer positive-pressure ventilation if spontaneous ventilation is inadequate

Flumazenil and naloxone were previously reserved only for treatment of oversedation and respiratory depression. However, the long recovery times experienced with benzodiazepine use have prompted some research into the feasibility of routine use of flumazenil with potential cost savings. The cost-effectiveness of this routine use is still under investigation.

Review of Specific Drugs

Benzodiazepines

Benzodiazepines are central nervous system (CNS) depressants that induce sedation, hypnosis, amnesia, and anesthesia. The mechanism of action seems to intensify the physiologic inhibitory mechanisms mediated by γ-aminobutyric acid (GABA).

Midazolam

Pharmacology.

Midazolam is a short-acting benzodiazepine with an intravenous peak onset of action of 2 to 5 minutes depending on the dose given and level of consciousness attained. If given with an opioid, the onset of action is more rapid (1.5 minutes), sedation is deeper, and a dose reduction of 30% is recommended. At doses sufficient to induce sedation, midazolam decreases the ventilatory response to increased CO 2 in normal patients and in specific patients with chronic airway limitation. The pharmacokinetic profile of midazolam is linear, over 0.05 to 0.4 mg/kg, lending predictable dosage titration. The elimination half-life is 1 to 2.8 hours with a large volume of distribution. The drug is metabolized rapidly to 1-hydroxymethyl midazolam in the liver, conjugated, and secreted in the urine. The elimination half-life is increased in elderly patients and patients with renal failure.

Administration.

Midazolam should be titrated in doses of 0.5 to 2 mg at intervals of 2 to 3 minutes to a total dose of 5 mg. Higher doses may be required but should be used with caution.

Precautions and adverse reactions.

When given with an opioid analgesic, there is an increased sedative effect necessitating administration in small incremental steps and a usual requirement of a 30% reduction in dose. Sensitivity increases with age. Caution is required when using midazolam in elderly patients, patients with hepatic or renal impairment, and patients with airflow limitation. Owing to a reduced rate of plasma clearance, patients with heart failure eliminate midazolam more slowly. Paradoxic reactions may occur with restlessness, agitation, and disinhibition. Hypotension is a recognized association of midazolam, particularly if given with an opioid.

Contraindications.

Midazolam should not be given to patients with myasthenia gravis, alcohol intoxication, or narrow-angle glaucoma.

Interactions.

The sedative effects of midazolam are enhanced by other CNS depressants, including neuroleptics, alcohol, tranquilizers, antidepressants, analgesics, antiepileptics, and anxiolytics. The effects of midazolam are attenuated by drugs that induce cytochrome P450 (rifampicin, carbamazepine, and phenytoin) and enhanced by inhibitors (erythromycin, diltiazem, antiviral agents, and fluconazole). In particular, midazolam should be given with care in patients receiving combination antiretroviral therapy.

Diazepam

Pharmacology.

Diazepam is metabolized in the liver to the active metabolites temazepam, nordiazepam, and oxazepam, all of which are renally excreted. Plasma concentrations of diazepam and its active metabolites exhibit considerable interpatient variation. The intravenous plasma time curve is biphasic, with an initial rapid increase with a half-life of up to 3 hours and a second elimination phase with a half-life of 20 to 70 hours. The elimination half-life is increased in elderly patients and in patients with renal and hepatic impairment.

Administration.

Diazepam should be titrated in doses of 2 to 4 mg to a total of 10 to 20 mg in some circumstances.

Precautions and adverse reactions.

Caution is required in patients with renal, hepatic, and cardiopulmonary impairment. Hypotension occurs rarely. Other precautions, contraindications, and drug interactions are similar to midazolam.

Opioid Analgesics

Fentanyl

Pharmacology.

Fentanyl is a synthetic opioid with an estimated 80-fold greater potency than morphine. In contrast to other opioids, fentanyl does not induce histamine release. After intravenous injection, fentanyl reaches peak analgesic effects within 1 to 2 minutes, with a duration of 30 to 60 minutes. Serum concentrations decrease rapidly within 5 minutes to 20% of peak concentrations, followed by a slow decrease over 30 minutes. The drug is metabolized in the liver to active metabolites, all of which are excreted in the urine.

Administration.

A dose of 50 to 100 µg should be given before administering a benzodiazepine to enable accurate sedative dose titration.

Precautions and adverse reactions.

Fentanyl causes respiratory depression for periods extending beyond the analgesic effect. In light of the route of elimination, a reduced dose should be used in hepatic and renal impairment. In view of the marked respiratory depression that can occur with its use, caution is required in patients with pulmonary disease.

Contraindications.

Fentanyl may cause severe bronchospasm and is contraindicated in patients with asthma. Fentanyl may cause severe muscle rigidity and is contraindicated in patients with myasthenia gravis.

Interactions.

The sedative effect of fentanyl is enhanced by other CNS depressants, such as other opioids, benzodiazepines, alcohol, neuroleptics, and tranquilizers. In particular, fentanyl has been associated with hypotensive adverse events with monoamine oxidase inhibitors and neuroleptics.

Meperidine

Pharmacology.

Meperidine is a synthetic opioid with sedative and analgesic properties. Similar to other narcotics, meperidine causes respiratory depression and suppresses the cough reflex. The sedative and analgesic effects of meperidine after intravenous dosing occur within 2 to 4 minutes, and the analgesic effects can last 4 hours. The elimination half-life is 3.2 hours, and metabolism is predominantly hepatic conjugation. Meperidine elimination is prolonged in patients with hepatic impairment.

Precautions and adverse reactions.

Care should be taken when giving meperidine concurrently with other neurodepressants. The most common adverse reaction is respiratory depression. Meperidine may also result in profound hypotension. One active meperidine metabolite, normeperidine, has convulsant properties, and elimination is prolonged in patients with renal impairment and elderly patients. In these patients, high doses of meperidine may lead to convulsions, agitation, irritability, and tremors.

Administration.

Meperidine should be given at an intravenous dose of 25 to 50 mg. Higher doses are more likely to result in adverse events.

Drug interactions.

The sedative effects of neurodepressants all are potentiated by meperidine. In addition, when given with phenothiazines, CNS toxicity and hypotension may occur. Interactions with monoamine oxidase inhibitors may be fatal and result in excitation, sweating, rigidity, hypertension or hypotension, and coma.

Propofol

Pharmacology

Propofol is distributed rapidly and induces sedation within 30 to 60 seconds. The context-sensitive half-life is only 2 to 8 minutes. Metabolism is by hepatic conjugation with renal excretion of inactive metabolites. Propofol is a centrally acting neural depressant without any analgesic properties and rapidly crosses the blood-brain barrier to potentiate GABA activity.

Contraindications

Propofol is contraindicated in patients with known allergy to propofol.

Precautions and Adverse Reactions

The most important effects to be monitored with propofol are respiratory depression and apnea, occurring frequently with deep sedation. Hypotension is also common. Patients with ASA class 3 or higher, elderly patients, and patients using sedatives or opioid agents are at particular high risk for developing these cardiorespiratory complications. Apnea and hypotension can occur in 75% of patients. In endoscopic trials using propofol, ventilatory support was necessary in 10% of patients, although incidence of respiratory depression necessitating support was far greater in complex procedures requiring a cooperative patient. Excitatory phenomena such as tremors, twitches, hypertonus, and hiccups can occur in 14% of patients. Rarely, pulmonary edema, hypertension, cardiac arrhythmias, bronchospasm, and laryngospasm have occurred. Pain at the injection site is the most frequent local complication and occurs in 5% to 50% of patients.

Administration

Propofol has been given in endoscopic studies by repeated bolus injections or as an infusion. Propofol is usually administered as an initial bolus dose of 20 to 40 mg followed by maintenance doses of 10 to 20 mg to attain the required level of sedation. Alternatively, propofol can be infused at a dose of 0.5 to 1.0 mg/kg over 1 to 5 minutes to induce deep sedation, followed by maintenance infusion at a dose of 1.5 to 3 mg/kg per hr. For anything other than very short procedures, administration of propofol as an infusion is preferable because this produces better steady-state levels and more stable operating conditions.

Interactions

The sedative effect of propofol is enhanced by other sedative agents and analgesics.

Flumazenil

Pharmacology

Flumazenil is an imidazobenzodiazepine and antagonizes benzodiazepines through competitively inhibiting central receptors. Its effects are rapid, within 30 to 60 seconds, and it has an elimination half-life of 53 minutes. Clearance is entirely hepatic, where it is conjugated to form inactive metabolites.

Contraindications

Flumazenil should not be given to patients with known sensitivity to flumazenil.

Precautions and Adverse Reactions

Care should be taken when administering flumazenil to patients with known benzodiazepine dependence because this may precipitate withdrawal or convulsions. Consideration should be given to the possibility of resedation and respiratory depression following the use of flumazenil. Patients should be monitored for an appropriate period based on the dose and duration of effect of the benzodiazepine used. Despite the use of reversal agents, patients should still be given postprocedural warnings, as previously described. Flumazenil is not recommended in epileptic patients taking benzodiazepines because this may give rise to convulsions. Seizures have been reported in patients with epilepsy and hepatic impairment.

Interactions

Flumazenil also blocks the effects of nonbenzodiazepines acting on benzodiazepine receptors such as zopiclone.

Administration

The recommended initial dose is 0.2 mg administered intravenously over 15 seconds. This dose can be repeated using 0.1-mg doses every 60 seconds to achieve reversal to a total dose of 2 mg.

Naloxone

Pharmacology

Naloxone is a competitive antagonist at opiate receptor sites and can reverse the sedative and respiratory effects of opiates. The effects of intravenous naloxone are apparent within 2 minutes, and a single dose from an ampule of 0.2 mg lasts 20 to 30 minutes. The effects of meperidine and other opioids last longer than this, therefore repeated doses of naloxone may need to be given. Naloxone is conjugated in the liver with renal excretion of the metabolites. Elimination half-life is 60 to 90 minutes.

Contraindications

Naloxone should not be administered to patients with known hypersensitivity to this medication.

Precautions and Adverse Reactions

Care is required in patients who are dependent on opiates because naloxone can precipitate withdrawal syndrome. A rapid reversal of opioids can induce catecholamine release and cause excitation, ventricular arrhythmias, hypotension, pulmonary edema, convulsions, and death. Care should be used in patients with preexisting cardiac abnormalities.

Administration

Naloxone can be given intravenously or intramuscularly at an initial dose of 0.4 to 2 mg. Doses can be repeated at 2- to 3-minute intervals until a total dose of 10 mg is reached.

Acknowledgement

We would like to thank Drs. Matthew R. Banks, George J.M. Webster, and Liang H. Wee for their valuable book chapter on the same topic in the previous edition of Clinical Gastrointestinal Endoscopy. The framework from their excellent chapter was used to write the current version of this book chapter.

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