Different anesthetic techniques and drugs can be used for esophagogastro-duedonal endoscopy. However, the scientists are still searching for appropri-ate drugs and protocols for sedation during esophagogastroduedonal endos-copy. The aim of this review is to discuss the topics related with sedation and esophagogastroduedonal endoscopy in the light of literature. Today standard procedure for diagnostic esophagogastroduedonal endoscopy usually con-sists of topical pharyngeal anesthesia, minimal sedation or anxiolysis, which may be complemented with analgesia when needed. When a prolonged, com-plex, or particularly troublesome or painful examination is foreseen, deeper sedation with multiple drugs and in closed observation of a staff may be required.

Keywords: Endoscopy; Gastrointestinal Endoscopy; Sedation

Introduction

Esophagogastroduodenal Endoscopy EGDE is a disturb-ing procedure. Even sedation is not required to perform a technically adequate EGDE; it has been accepted as a standard practice for decades. The primary aim of using sedation is to increase the comfort both for the patient and endoscopist and decrease the duration of the pro-cedure by easing the endoscopy course and increasing patient cooperation and willingness for future EGDE’s by diminishing the memory of the event. However, the use of sedation for endoscopic procedures varies widely throughout the world and there is still no consensus on sedation types for EGDE [1].It is important to examine current practice for increasing the quality of EGDE and sedation techniques. We have much experienced in rigid EGDE than colonos-copy. So the purpose of this review is to summarize the characteristics of drugs used for rigid EGDE and to pres-ent an outline for endoscopist. There is also a contro-versy on the specialty of staff that performs sedation we did not criticize any suggestions on this issue.BackgroundSedation is a continuum of progressive impairment in consciousness that has been roughly divided into four different levels, ranging from anxiolysis or minimal seda-tion to general anesthesia [2].Sedation levels according to the American Society of Anesthesiology (ASA) were shown in table 1.

Preprocedural Preparation and Assessment

Endoscopist will have to assess patient and procedural-related factors before reaching a decision on what specific type of endoscopic sedation and drug (if any) to use. These factors should include medical his-tory of the patient, review of drug and food (egg, soy) allergies, current medications (history of antidepressant, neuroleptic or cardiologic agent), potential drug inter-actions, history of adverse reaction to sedation or an-esthesia, preoperative fasting (time and nature of last oral intake). History of tobacco, alcohol, or substance us-age should also be evaluated. In addition, all women of childbearing age should be queried about the possibility of pregnancy.The preprocedural airway assessment is the most criti-cal aspect of safe sedation practice [3]. In order to predict which patients may be more likely to show difficulties re-garding airway, the following should be considered: History of problems with previous anesthesia, presence of sleep apnea, snoring; facial dimorphism; oral cavity abnormali-ties (mouth opening smaller than 3 cm, protruding incisors, high-arched palate, macroglossia, tonsillar hypertrophy or nonvisible uvula (Mallapati III-V), inability to bite upper lip by lower incisors, neck abnormalities (morbid obesity, short neck, limited neck extension, endothoracic goiter, neck mass, reduced hyoid-mental distance (< 3 cm)]; patients with man-dibular abnormalities (micro-retrognatia,). Patients who were not in good health (ASA>3-4) or had risk factors for the development of airway complica-tions or possible airway management problems should be excluded.

How to Perform an Unsedated Endoscopy?

Selected older patients, male gender, patients who are not anxious, may have better tolerance of upper endoscopy pa-tients may be able to undergo EGDE without sedation by use of topical pharyngeal anesthesia (TPA) [4]. However, first time examinees with high scores for trait anxiety poorly tolerate insertion of the endoscope. In order to perform an unsedated endoscopy the traditional techniques consist fol-lowing steps.1. Asking to pa-tient whether he or she prefer spray or gargling before appli-cation of TPA.2. Observing pharyngeal sensitiv-ity during application of TPA. (Encouraging patient to say “aah” is not recommended because this might expose the larynx to the anesthetic agent and inhibits the cough reflex. )3. Observing patient after first puff for any adverse events. (Patients may swallow the anesthetic after a while.)Maximum dose of lidocaine (1-1.5 mg/kg ) (7-10pufs) should be kept in mind. A high trait-anxiety score during local anes-thesia application usually points out a difficult EGDE.

Topical Pharyngeal Anesthesia (TPA)

Main indication for TPA is to suppress vomiting re-flex. Vomiting reflex during insertion of the endoscope and its operation in the upper gastrointestinal tract may cause changes in hemodynamics, oxygen saturation and au-tonomic nervous activities, and even induce lethal dis-rhythmia or sudden death [5, 6, 7 ].In clinical practice, topical anesthesia is used during unsedated EGDE. It is more beneficial for younger pa-tients who are anxious or undergoing EGDE for the first time without sedation [8]. TPA can be applied either by spraying or gargling. Even patient’s preferences among TPA is favored on gargling, spray application may be more feasible for the proce-dure because the anesthetic agent can be applied to the posterior pharyngeal wall visually. During administration of TPA, observing the presence of a strong gag reflex strongly correlates with pharyngeal sensitivity as a “real-life” clinical practice [9]. Some patients may dislike its taste, the burning sensa-tion that accompanies anesthesia and the anesthetic feeling itself [10]. Lidocaine, benzocaine, and tetracaine are the most commonly used topical local anesthetics in the endoscopy suites [11]. Traditionally spraying poste-rior pharyngeal wall with 1-1.5 mg/kg lidocaine provides sufficient TPA. Commercial lidocaine sprays contains 10 mg lidocaine per puff. Lidocaine is relatively poorly ab-sorbed (much is swallowed) from the nasopharynx. It is well tolerated in the elderly patients with co morbidities. However, lidocaine is irritant and can cause complete airway obstruction due to laryngospasm [12]. Lidocaine lollipops are promising form of local oropharyngeal an-esthesia for EGDE.Risks of TPA: The potential complications of TPA are mainly laryngospasm, anaphylactic reactions, systemic toxicity (methemoglobinemia) to topical anes-thetics, and aspiration pneumonia [13].Because up to 25% of patients receiving pharyngeal an-esthesia showed radiologic evidence of aspiration, TPA should not be used in cases with predisposing factor for aspiration [14,15]. It should be kept in mind that the an-esthetic effect of TPA can last for more than 30 to 40 minutes after the procedure. Patients should be strictly advised not to take any oral food and/or beverage (fast for about an hour) after EGDE. Methemoglobinemia should be considered in patient who develops cyanosis after TPA especially with benzo-caine [16]. Supplemental oxygen and Methylene blue, 1–2 mg/kg should be administered over 5 min after, arterial blood gases analyses with co-oximetry. Patients with a glucose-6 phosphodiesterase deficiency require transfu-sion or dialysis for treatment [17].

Intraprocedural Monitoring

During EGDE, patients routinely positioned on side lying or prone and a mouth adaptor and an endo-scope in the mouth that narrows airway and restricts air flow. Because hypoxemia and hypoten¬sion are the major reasons of major complications during EGDE, pa-tients should be monitored for hemodynamic and respi-ratory status. Baseline readings should be obtained at least four times; prior to sedation, during procedure, dur-ing recovery and before discharge. Patients should be monitored with continuous electro-cardiogram (ECG) during moderate sedation and blood pressure should be chequed by intervals.The respiratory cycle of oxygenation and ventilation are related, but completely separate, physiologic processes. Human body has reserves that hold on and provides oxy-gen for several minutes. If sedation is deep enough to compromise breathing, body begins to consume these reserves while chest continues to move up and down and breathing efforts of patient moves dead space air only. SpO2 begins to drop after body oxygen reserves con-sumed.From this point of view, it is not logical to expect the accurate level of ventilation and oxygenation breath to breath by pulseoximeters. To date the most pertinent in-formation about frequency and adequacy of breathing during sedation is provided by capnography [18, 19, 20]. During endoscope introduction waveforms diminishes due to gag reflex. The waveform should return once the scope has advanced. However, a fall in SpO2 does not occur during introduction of endoscope.Supplemental OxygenThe ASA Task Force recommends supplemental oxygen for moderate and deep sedation unless specifi-cally contraindicated. However, giving supplemental oxy-gen may cause long apnea periods in heavily sedated pa-tients. and may result in higher rates of cardiopulmonary unplanned events [21]. An average 6 minutes of apnea is required before a healthy adult desaturates to less than 90% [22], and 2 to 4 minutes for healthy children [23, 24, 25].

Sedation and Analgesic Agents Used for Endoscopy

Before deciding the appropriate agent and application way of sedation, it is of paramount importance to decide the type of endoscopic procedure (diagnostic, therapeu-tic), the degree of pain associated with it, and the length of total procedure time. Diagnostic and uncomplicated therapeutic upper endoscopy can be performed under moderate sedation. More complicated, lengthy proce-dures and patients with special conditions may require deep levels of sedation. Sedation monitoring and rescue equipment should be available in the room.

Benzodiazepins

The most commonly used benzodiazepines are midazolam and diazepam. The efficacy of sedation with these 2 benzodiazepines is comparable [26]. However, there is a known favor on midazolam due to minimal risk of venous irritation and phlebitis resulting in painless İ.V. injection, strong anterograde amnesia and an existing antidote flumazenil [27].Midazolam has a longer interval to peak effect (8–12 min versus 2–5 min) and almost 3.5 times more potent than diazepam. The anti-anxiety and sleep effects are generally manifested 1–2 min after intravenous in-jection of 5 mg dose and anterograde amnesia effect becomes evident after 4 min, continuing up to 30 min after injection.Standard i.v. dose for sedation induction is 0.06-0.07 mg/kg. Esophageal intubation could successfully be per-formed after 30 seconds and patients will not remember the procedure [28]. When the sedative state 30 s after i.v. midazolam is insufficient, appropriate additional doses should be administered [28]. It should be kept in mind that benzodiazepines are lipid-soluble (particularly mida-zolam) and repeated doses may accumulate into the adi-pose tissue and after subsequently releasing, prolongs recovery. Benzodiazepine combinations: Because midazolam does not exhibit any analgesic effects, sole use for conscious sedation does not suppress sympathic stimulation due to esophageal intubation [29]. In order to reduce the harm-ful effects of sympathic stimulation benzodiazepines are usually combined with opioids. The obvious disadvan-tage of benzodiazepine-opioid combination is respirato-ry depression due to synergistic effect by flattening the carbon dioxide (CO2) response curve of the respiratory center. When given with fentanyl, only about 25% of the ED50 dose of midazolam and 25% of the ED50 dose of fentanyl were necessary to produce unresponsiveness. In past midazolam usually combined with pethidine. How-ever, it has a slower onset of action that delays the start of endoscopy, longer duration of action that prolongs the recovery and produces more postprandial nausea and fatigue when compared with newer opioids. Nowadays, it is not realistic to use it while more suitable drugs like fentanyl were still exists. 

Propofol

Propofol is the most studied sedative agent for gastro-intestinal endoscopy. It is pure sedative/hypnotic without analgesic properties. It has a rapid onset and offset ef-fect time. When used for GI endoscopy, 40 to 60 mg bo-lus doses are typically produce sedation in normal adults within 40 seconds ie, “1 arm-brain circulation”. Subse-quent doses should be administered after assessment of responses to the initial dose, but typically given in 10- to 20-mg increments every 1 to 2 minutes. Dose reduction is necessary in patients with cardiac dysfunction and in the elderly as a result of decreased clearance.Therapeutic index (the difference between the doses for moderate and deep sedation) of propofol is very narrow. This means that patients may quickly slip from moder-ate to deep sedation or to general anesthesia. Therefore, vigilant monitoring is necessary. It is a pregnancy category B drug and should be used with caution during lactation [30]. Vials are labeled for single-use only; unused portions should be discarded within 6 hours to decrease the risk of contamination.Two preparations exist; one is prepared as an oil/water emulsion consisting of 1% propofol, 10% soybean oil, 2.25% glycerol, and 1.2% egg lecithin. It is contraindicated in pa-tients with propofol allergy or hypersensitivity to eggs or soybean. The other preparation has bisulfates; and it is con-traindicated in patients with, allergies/reactions to bisul-fates. Propofol is superior to other sedatives in terms of recovery time, physician and patient satisfaction and psychomotor testing during discharge [31]. However, a benefit in this re-gard over traditional benzodiazepine/narcotic combinations has not been uniformly demonstrated [32].The total dosage needed to perform EGDE is slightly higher than for colonoscopies with an accompanying increased risk of apnea [33, 34]. Nevertheless, the short procedure time corresponds very well with the action of the drug. After an adequate level of sedation has been reached, most EGDE’s could be performed without further additional doses. It is concluded that propofol concentration which suppresses the somatic response to EGDE was higher than the concentration that suppresses a response to verbal command [35]. However, dose-related side effects such as hypotension, hypoventilation, or bradycardia are relatively frequent, when large doses are administered [36].

Propofol combinations

Due to the mentioned lack of analgesic effect of propofol it is logical to use it in conjunction with a pain-relieving drug (balanced anesthetic technique) [37]. In accordance with this data, nowadays propofol-opioid combination became an al-ternative to the traditional benzodiazepine-opioid combina-tion. More precise dose titration is possible with smaller bo-lus doses of propofol (5-15 mg) and the potential for partial pharmacologic reversibility by naloxone [38,39]. Propofol-Pethidine Combination: Pethidine prolongs the re-covery time compared with alfentanil [40].Propofol Benzodiazepine Combination: This regimen was not superior in terms of sedation and was associated with longer recovery times [41]. In fact it eliminates the advan-tage of using propofol because both drugs are sedative and combining two same class drugs does not produce an effect that each one has.Propofol-ketamine Combination: The combination of propo-fol with subhypnotic, analgesic dosages of ketamine im-proves patient comfort, suppress the need for supplemen-tal opioids, reduces total propofol dose, and (in contrast to benzodiazepines) do not have cardiorespiratory depressant actions [42]. Guit et al. [43] reported that propofol-fenta-nyl combination depressed hemodynamics, but propofol-ketamine combination resulted in stable hemodynamics. Therefore Propofol-Ketamine may be an effective combina-tion during EDGE’s of patients with limited cardiac reserves. Propofol-Ketamine combination was associated with more patient satisfaction and amnesia and a reduced need for restraint during fiberoptic bronchoscopy [43]. This suggests that the level of sedation was deeper with the PK combination. Propofol-remifentanil Combination: Remifenta-nil is an ultra-short acting mu-opioid receptor agonist with zero-order kinetics and provides dense analgesia. However, it has no hypnotic or amnestic properties and it is not suitable for patients with high anxiety levels. It should be used under closed supervision of anesthetist [44]. There are now two different strategies in using propofol for EGDE. First one is to use propofol as a routine seda-tive for all EGDE’s in outpatient settings due to its rapid re-awakening and metabolism even without an anesthe-sia staff [33, 34, 45]. However, propofol use by nonanes-thesiologists remains a contraindication in the package insert of propofol in most countries. In fact there are some economic aspects of this tradition. These are the costs of anesthesia staffs and rather expensive cost of propofol. The supporters of second strategy thought that propofol is primarily an anesthetic agent and should be reserved for prolonged and difficult endoscopic procedures [46, 47, 48]. Sedation guidelines produced by the American Society of Gastroenterology partially contradict those produced by the American Society of Anesthesiologists for sedation by non-anesthesiologists, whereas the Ger-man guidelines were developed with anesthesiologists involved. In accordance with ASA, it’s our belief that propofol is an ideal agent for short diagnostic EDGE’s. However, it should be used with closed observation of an anesthetist during long lasting therapeutic EDGE’S while this enables gastroenterologists to get pleasure of performing endoscopy without concerning of what is happening to the patient.

Pediatric Endoscopy

Diagnostic and therapeutic pediatric upper gastrointes-tinal endoscopy procedures have dramatically increased during last decades. Gastrointestinal endoscopy in an uncooperative child is very risky and may be associated with perforation of the gastrointestinal tract. Effective and safe sedation is crucial for this procedure. The goals of anesthetic sedation regimens for pediatric gastrointestinal endoscopy are to ensure pa-tient safety, immobility, comfort, successful completion, and amnesia of the procedure. Other goals are to maxi-mize efficiency and contain costs [49]. The method of se-dation is a matter of choice after careful consideration of a number of factors including the patient’s condition, ASA classification, the type of procedure, the parents’ and patient’s preference, and the level of cooperation of the patientWith proper patient selection, intravenous se-dation is a safe and effective method for sedation in pe-diatric endoscopy [50,51]. General anesthesia should be considered necessary for highly complicated procedures and for patients at high risk for cardiovascular complica-tions. Airway of infants and children requires a sound understanding and knowledge of the variations in anato-my, physiology, and pathology in a wide age range of pa-tients. Each case, depending on the presenting problem, may require a different approach to anesthesia.

The Infant Airway

The larynx is anatomically higher. Tongue is closer to the roof of the mouth and can easily obstruct the airway. Larynx is more superior so visualization of laryngeal structures in infants is more difficult. The epiglottis is omega shaped, stiffer and tilted posteriorly, resulting in more difficulty in visualization of the vocal cords. Addi-tionally, the trachea is more compliant than adults and more sensitive to dynamic compression. The cricoid car-tilage is the narrowest part of the airway. It is nonex-pendable and airway edema owing to instrumentation may easily obstruct the airway. Oxygen reserves in the infant are low and oxygen consumption is high. Hypox-emia occurs very rapidly and many times worsens by gastric distention.Unlike adult patients who can receive minimal or moder-ate sedation, the pediatric patient requires deep seda-tion or general anesthesia [52]. Administration of seda-tive medications should be weight based and titrated by response after allowing adequate time to assess the effects of each dose. However, there is no standard prac-tice for anesthesia in children undergoing gastrointesti-nal endoscopy. Communication between the endoscopist and the anesthesiologist is the cornerstone of successful endoscopy. Propofol in conjunction with a short acting benzodiaz-epine such as midazolam and a narcotic such as fentanyl or remifentanyl may be titrated in small increments for intravenous sedation.Ketamine with propofol and midazolam provides effec-tive sedation in pediatric patients. However this regimen has more side effects such as cough, dizziness, vomiting, and diplopia. Small doses of ketamine largely spares the upper airway muscle tone and laryngeal reflexes Non-per-OS Guidelines for pediatric patients: Non-per-OS guidelines are set forth by the ASA as well as the American Academy of Pediatrics in 1992, which require fasting for solids and breast milk 4 hours for infants younger than 6 months, 6 hours for those 6 to 36 months, and 8 hours for those older than 36 months.

Endoscopy in Pregnancy

Endoscopy is rarely required during pregnancy. If neces-sary the procedure should be performed with the lowest possible dose of category B and C drugs or if possible, without any sedation [53]. Category D drugs may be used when the benefit clearly outweighs the risks safely.

Benzodiezepines (category D)

Prolonged use of diazepam during early pregnancy has been associated with cleft palate and other congenital abnormalities. Although there are no data on the use of intravenous diazepam for sedation for endoscopy, it is best avoided. Midazolam is a category D drug, but there are no reports of congenital abnormalities.Pethidine (category B): There is no reported evidence of teratogenicity [54].Topical lidocaine: Topical lidocaine is appears to be safe during pregnancy [55].The potential risks associated with endoscopy during pregnancy:1. Oversedation may cause maternal hypotension and hypoxia, which in turn may lead to fetal hypoxia, with potentially fatal consequences.2. The fetus may be exposed to potentially terato-genic drugs and radiation.3. Care must be taken with maternal positioning to avoid inferior vena caval compression by the pregnant uterus, which can lead to decreased uterine blood flow and fetal hypoxia.Because of these known risk factors the following fac-tors should be chequed.(1) A strong indication, particularly in high-risk pregnan-cies.(2) Defer endoscopy to the second trimester whenever possible.(3) Try to use the lowest dose of sedative medication.(4) Wherever possible, use category A or B drugs.(5) Minimize procedure time.(6) Pregnant patients should be positioned in left pelvic tilt or left lateral position to avoid vena caval or aortic compression.(7) Fetal heart sounds should be confirmed before during and after sedation.(8) Obstetric support should be available in the event of a pregnancy-related complication.(9) Endoscopy should be avoided during obstetric com-plications such as placental abruption, imminent deliv-ery, ruptured membranes or pre-eclampsia.

Nurse-Administered Sedation

The propofol dose must be carefully titrated according to the individual patient’s response. Factors influenc-ing dosage include age, ASA class, patient’s height and procedure duration. Propofol’s primary risk is its narrow therapeutic range which necessitates careful patient monitoring. The endoscopy team should take the respon-sibility of recussitation of the patient when necessary.

Patient-Controlled Sedation (PCS)

The combination of propofol with an anesthetic agent has likewise been repeatedly shown as practical for PCS during colonoscopy [56]. The typical self-administered bolus con-sists of 4.8 mg propofol and 125 μg alfentanil [40]. However there is lack of data for PCS during EDGE. Furthermore the concept of PCS depends on patient reaction to an unpleas-ant sensation necessitating patients to be sedated at levels that first permit to experiences pain than control the pain. This technique provides an individually tailored sedation and may only be applicable to convenient patients who can take responsibility for their own sedation.

Complications of Esophagogastroduedonal Endoscopy

The complication rate of EGDE is about 0.1% with cardiopulmonary events predominating [57].The majority of complications are due to oversedation, hypoventilation, vasovagal episodes, airway obstruction and aspiration [58]. Ascending ASA physiologic classification, age >60 years, in-patient status, the use of supplemental oxygen, and the in-volvement of a trainee in the procedure are the independent risk factors for CPC’s [4].Aspiration: The risk of aspiration is minimal during diagnos-tic endoscopy. Aspiration is particularly likely when protec-tive reflexes are blunted by excessive sedation or coexisting diseases of patients like encephalopathy, diabetic gastropa-resis sleep apnea syndrome, severe chronic obstructive pul-monary disease, or coronary heart disease and in the setting of emergency treatment of upper gastrointestinal hemor-rhage, and during long-lasting procedures. Satisfactory oral suction and airway control are mandatory issues [59]. TPA should be avoided [15]. In order to prevent aspiration, pa-tients should be fasted far enough time before sedation (2 hours for clear liquids and 6 hours for light meals) [2].

Conclusion

Today standard procedure for diagnostic EGDE usually con-sists of topical pharyngeal anesthesia (TPA), minimal seda-tion or anxiolysis, which may be complemented with analge-sia when needed. When a prolonged, complex, or particularly troublesome or painful examination is foreseen, deeper se-dation with multiple drugs may be required.It is of paramount importance to use standart monitoring and recussitation equipment during procedure. Start with a low dose, assessing the response of the patient’s sedation level, ventilatory and cardiovascular status; and proceeding gradually with titration along with topical pharyngeal anes-thesia is the most common technique used for EDGE. Pa-tients may require different levels of sedation for the same procedure and may attain varying levels of sedation during a single procedure due to interindividual variability of re-sponse to drugs used for sedation.

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Tayfun Aydin, Sacit Gulec. Sedation for Esophagogastroduodenal Endoscopy. J Clin Anal Med. 2011;2(2):61-67

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