Minimizing Complications: Sedation and Monitoring

Gastrointest Endoscopy Clin N Am 17 (2007) 11–28

Minimizing Complications: Sedation and Monitoring John J. Vargo, MD, MPH Section of Therapeutic and Hepatobiliary Endoscopy, Department of Gastroenterology and Hepatology, Desk A-30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA

How do we define risk for procedural sedation during gastrointestinal endoscopic procedures? This question is much more ponderous than it may appear. We should consider taking the high road, as suggested by Pierce [1], and state that there is no acceptable adverse event rate for elective patient sedation during nonsurgical procedures. Certainly the use of guidelines, the evolution of practice, and the implementation of technology have decreased the mortality during general anesthesia from 1 in 5500 to 1 in 20,000 [2–4]. Accreditation bodies and professional societies have acknowledged that moderate sedation is safe, but potentially serious cardiopulmonary events such as hypoxemia, apnea, hypotension, airway obstruction, and cardiopulmonary arrest may occur [5–7]. Critical event analyses have identified prolonged hypoxemia secondary to respiratory depression as the precipitating event in cases of pediatric sedation [8,9]. The exact incidence of cardiopulmonary complications (CPC) associated with gastrointestinal endoscopy is low; surprisingly, most of the data still reside in the form of survey studies and abstracts stemming from large databases [10–12]. A large survey of more than 200,000 upper endoscopies, performed in 1976, found an overall complication rate of 0.13%, of which nearly half were CPCs [10]. A survey study by Arrowsmith and colleagues [11] using a total of 21,011 procedures found the risks for serious CPC and death to be 5.4 and 0.3 per 1000 procedures, respectively. Again, CPCs were found to be the most common type of complication (40%). Many criticisms can be launched at these early studies. By the very nature of their survey design, issues of ascertainment bias and minimized reporting, due to the case-finding method employed, may work in concert to underestimate the incidence of CPCs. The practice of sedation and monitoring has E-mail address: [email protected] 1052-5157/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2006.10.004 giendo.theclinics.com

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changed along with the development of guidelines and policies by regulatory bodies. In a prospective survey of 14,149 upper endoscopies, the rate of immediate cardiopulmonary complications was 0.2%. The 30-day mortality rate, which included myocardial infarction, pulmonary embolism, and aspiration pneumonia, was 1 per 2000 cases [13]. The incidence of CPC was found to be 0.9% in a study that used the clinical outcomes research initiative database with 335,238 patients [12]. Ascending American Society of Anesthesiologists (ASA) physiologic classification, age greater than 60, inpatient status, the use of supplemental oxygen, and the involvement of a trainee in the procedure were found to be independent risk factors for CPC. Gangi and colleagues [14] evaluated the risk factors for cardiovascular complications in a large hospital system. In this case-control study, CPCs were defined as arrhythmia, chest pain or anginal equivalent, hypotension, or myocardial infarction occurring within 24 hours of endoscopy. Patients considered at risk for cardiovascular complications were selected based on intensive care unit admission on the day of or after endoscopy, cardiac enzyme determinations, and charges for cardiovascular medicines. The extrapolated rate of CPCs was 308 per 100,000 procedures. Independent CPC risk factors included the modified Goldman score, male gender, and the use of propofol. Fisher and colleagues [15] prospectively evaluated 130 consecutive endoscopic retrograde cholangiopancreatographies (ERCPs) performed on 100 patients for the occurrence of cardiopulmonary complications; the patients were dichotomized by age (group 1: R65 years; group 2: !65 years). Outcome measures included cardiac troponin 1 (cTn1) levels, the incidence of new electrocardiographic changes, and the incidence of abnormal respiratory and hemodynamic responses, including oxygen desaturation (!90%), sinus tachycardia, hypertension, hypotension, and changes in the rate-pressure product. New electrocardiographic changes occurred in 24% of older patients and in 9.3% of younger patients; they did not reach statistical significance. No differences were found between the groups in terms of hypoxemia, changes in blood pressure, rate-pressure product, or pressure-rate quotient. New post-ERCP rises in cTn1 were seen in six older patients and in none in the younger group. Of note, ST segment changes were present in only two of the six patients who had elevation of the cTn1. Risk factors for elevated cTn1 levels included a history of congestive failure (RR 2.6; 95% CI, 1.1, 6.1) and longer duration of the ERCP (37.7 28.9 minutes versus 24.2 12.3 minutes; P ¼ .007). The post-ERCP pancreatitis rate was similar for both groups (two procedures [2.7%] in the younger group and five procedures [8.9%] in older patients). Risk factors for pancreatitis, regardless of age, included desaturation (RR 5.9; 95% CI, 1.2, 32) and myocardial ischemia or injury (RR 4.4; 95% CI, 1.4, 7.8). This provocative study again emphasized the importance

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of maintaining a normal oxygen saturation. Silent myocardial damage may also occur and affect morbidity and mortality. Cardiovascular compromise also appears to play a role in the development of post-ERCP pancreatitis. Does age-related risk exist with propofol-mediated sedation? One hundred and fifty consecutive patients older than 80 years who had an ASA physiologic classification of III or IV were randomized to meperidine/ midazolam or bolus propofol that was administered by an independent physician who was not involved in the endoscopic procedure and was trained in airway management [16]. The primary outcome was the occurrence of hypoxemia. Even though the average decline in oxygen saturation was greater in the propofol group (6% versus 3%; P!.01), oxygen saturation less than 90% did not differ between the groups. The mean decreases in systolic and diastolic blood pressures were significantly lower in the propofol group; no subject in either sedation arm exhibited a systolic pressure decrease below 90 mm Hg. Three important aspects of CPCs in gastrointestinal endoscopy should be kept in mind: (1) ‘‘Minor’’ CPCs, such as transient hypoxemia, may not be clinically significant. (2) Because of the low incidence of serious CPCs, such as an oxygen saturation level less than 85%, large randomized, controlled trials will be needed to detect differences in the safety and effectiveness of sedation regimens and monitoring devices. (3) Because significant adverse events are fortunately rare, no data are available that show a decreased risk for such events’ occurrence due to physiologic monitoring or a particular sedation regimen. Given that critical event analyses have identified prolonged hypoxemia secondary to respiratory depression as the precipitating event in cases of pediatric sedation [8,9], we use the occurrence of CPCs as a surrogate marker of the risk for occurrence of a significant adverse event. Practice guidelines put forth by the American Society of Anesthesiologists Committee for Sedation and Analgesia by Non-Anesthesiologists have classified both moderate and deep sedation and analgesia in a continuum of sedation (Table 1) [6]. It is important to emphasize that candidacy for sedation and analgesia must still take into account a thorough preprocedure assessment, including a history of present illness, past medical history, and a physical examination [5,6]. In most endoscopic cases, moderate sedation is the goal, which is defined as a purposeful response after verbal or tactile (not painful) sensation, and no compromise of the patient’s airway, ventilation, or cardiovascular function. In comparison, deep sedation or analgesia may require the use of painful stimuli to elicit responsiveness. Additionally, the patient’s airway and spontaneous ventilation may become compromised; hence personnel must be designated for the complete and uninterrupted observation of the patient’s respiratory and cardiovascular status. An important component of these guidelines is that the endoscopy team must have the ability to rescue the patient from deeper than expected levels of sedation or analgesia.

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Table 1 Continuum of the depth of sedation

Minimal sedation (anxiolysis)

Moderate sedation/ analgesia (conscious sedation)

Responsiveness

Normal response to verbal stimulation

Airway

Unaffected

Purposeful response to verbal or tactile stimulation Unaffected

Spontaneous respiration Cardiovascular function

Unaffected

Unaffected

Unaffected

Usually maintained

Deep sedation/ analgesia Purposeful response after repeated/ painful stimulation Intervention may be required May be inadequate Usually maintained

General anesthesia No response, even with painful stimulation Intervention often required Intervention often required May require intervention

Adapted from Gross JB, Bailey PL, Caplan RA, et al. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1005.

How facile are we at achieving moderate sedation with the traditional combination of an opioid and benzodiazepine? A balanced cohort of 80 ASA class I and II patients undergoing upper endoscopy, colonoscopy, ERCP, and endoscopic ultrasound (EUS) received meperidine and midazolam according to a standardized protocol [17]. Hemodynamic parameters and levels of sedation were determined at 3-minute intervals using the Modified Observer’s Assessment of Alertness and Sedation. Deep sedation occurred in 68% of patients. The procedures with the highest percentage of deep sedation assessments were EUS (29%) and ERCP (35%). Multivariate analysis showed that only ERCP and EUS were independent risk factors for deep sedation; body mass index, sedation dose, and procedure duration were not. The practice of endoscopic sedation and monitoring remains surprisingly variable. An observational study evaluating sedation and monitoring practice was performed at 21 endoscopy centers in 11 countries involving 6004 patients undergoing colonoscopy [18]. Pulse oximetry was used in only 77% of patients, blood pressure monitoring in 34%, and electrocardiography in 24%. Fifty-three percent received moderate sedation, 30% received deep sedation, and 17% received no sedation. Oxygen saturation of less than 85% occurred in 5% of patients. In contrast, a survey of endoscopic sedation in the United States found that the vast majority of patients (O98%) received sedation, and 98.6% routinely used pulse oximetry [19].

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Pulse oximetry and supplemental oxygen Transient oxygen desaturation has been found during both sedated and unsedated procedures [20,21]. Prospective outcomes studies linking the use of pulse oximetry with a reduction in the risk for CPC for both endoscopic and anesthesia-requiring procedures have not been performed. In a systematic review of four randomized trials using perioperative pulse oximetry, no differences were found with regard to postoperative complications, duration of hospital stay, and mortality [22]. Supplemental oxygen has been found to decrease, or in some cases to abolish, hypoxemic episodes during endoscopy in which sedation was employed [20,21]. This effect may have a benefit, particularly in patients who have ischemic heart disease in which a reduction in the incidence of ST segment abnormalities has been shown [22]. Risk factors for hypoxemia include a baseline oxygen level of less than 95%, the presence of significant comorbid illness, emergent indication for endoscopic procedure, a lengthy procedure, and difficulty with esophageal intubation [12,20,21]. Despite the lack of data linking pulse oximetry to a reduction in complications, both the ASA and American Society for Gastrointestinal Endoscopy recommend that pulse oximetry be used during all endoscopic procedures and that supplemental oxygen be available for all cases [5,6]. This recommendation is the result of critical event analyses in the anesthesia literature that have identified prolonged hypoxemia secondary to respiratory depression as the precipitating event in cases of adult and pediatric sedation [8,9,23,24] and the risk for myocardial ischemia [25]. It is also important to emphasize that the use of supplemental oxygen can delay the detection of alveolar hypoventilation [26–28]. The administration of additional sedation to a patient who exhibits hypoxemia while receiving supplemental oxygen should be approached carefully: the patient is at risk for alveolar hypoventilation and may manifest with prolonged apnea or respiratory arrest. Are all pulse oximeters the same? Signal averaging times can affect the degree of hypoxemia measured in sleep laboratories; this has not been evaluated in the endoscopy laboratories, but the same phenomenon may occur [29]. Additionally, use of an ear sensor leads to decreased incidence of motion-induced failures when compared with finger placement. The recent development of noninvasive cerebral oximetry provides a measurement of cerebral arterial oxygen tension and may prove to be useful during procedural sedation, particularly in patients who are receiving deep sedation or in whom supplemental oxygen is being used [30–32].

Hemodynamics Although there is insufficient evidence to reach an evidence-based conclusion, guidelines put forth by the American Society for Gastrointestinal Endoscopy and the American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists recommend periodic

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hemodynamic assessment because (1) medications used for sedation and analgesia may have an untoward effect on hemodynamics and (2) early detection of hemodynamic changes can result in early intervention and, it is to be hoped, in the prevention of a significant adverse event. Continuous electrocardiogram monitoring should be considered in those patients who have a significant cardiac or pulmonary disease, in elderly patients, and in those in whom prolonged procedures or deep sedation are anticipated [5,6,15].

Extended monitoring Transcutaneous carbon dioxide monitoring Transcutaneous carbon dioxide monitoring (PtCO2) is a noninvasive method for measuring arterial CO2. An electrode is placed on the skin, which is heated to ‘‘arterialize’’ the microcirculation. CO2 then diffuses through the skin and into an electrolyte solution between the skin–electrode interface, which produces carbonic acid. A pH reading is then rendered, and the CO2 value is obtained by means of the Henderson-Hasselbach equation. More recently, an earlobe sensor similar in design to a pulse oximetry device has been developed that makes this type of monitoring more convenient. Nelson and colleagues [26] randomized 395 patients undergoing ERCP to standard monitoring coupled with PtCO2 guiding sedation and analgesia (group 1) or to standard monitoring alone in which the endoscopist was blinded to the PtCO2 data (group 2). Significantly, more group 2 patients experienced carbon dioxide retention of greater than 40 mm Hg above baseline values. Predictors for peak PtCO2 included baseline PtCO2 value, the use of naloxone, the maximum fall in oxygen saturation by pulse oximetry, the maximum supplemental oxygen rate, and the combination of a benzodiazepine and an opioid for sedation and analgesia. An important finding of this study and the studies that used capnography was that there was a poor correlation between clinical observation and objective measures of ventilation.

Capnography Capnography is based on the principle that carbon dioxide absorbs light in the infrared region of the electromagnetic spectrum. Quantification of the absorption leads to the generation of a curve, which represents a real-time display of the patient’s respiratory activity [33]. In a case series of 49 patients undergoing prolonged upper endoscopic procedures, capnography was found to be more sensitive than pulse oximetry or visual assessment in the detection of apneic episodes [27]. In a series of 80 colonoscopy patients who were randomized to undergo the procedure with and without supplemental oxygen, extended monitoring with capnography was employed [34]. The endoscopist and nursing personnel were blinded to the capnography data. Though the number

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of apneic events was similar between the two groups, significantly more episodes of apnea were missed in the group receiving oxygen (7% versus 42%, P!.001). Moreover, significantly more patients receiving supplemental oxygen received sedation following an apneic episode. Capnography has also been used to allow the safe titration of propofol by a qualified gastroenterologist during ERCP and EUS. The first randomized controlled trial of capnography in a group of pediatric patients undergoing upper endoscopy, colonoscopy, or the combination of both was recently published [35]. The primary aim of this study was to determine whether intervention based on capnographic evidence of alveolar hypoventilation reduces the incidence of hypoxemia in children who are undergoing moderate sedation with fentanyl and midazolam for elective upper endoscopy, colonoscopy, or a combination thereof. In this study, hypoventilation was defined as a pulse oxiometry value of less than 95% for more than 5 seconds. All procedural personnel were blinded to the capnographic data. Trained observers were used to alert the staff of alveolar hypoventilation. In the intervention arm, personnel were alerted if the capnographs indicated alveolar hypoventilation for more than 15 seconds. In the control arm, the personnel were alerted if alveolar hypoventilation was noted for more than 60 seconds. In both arms, once the personnel were alerted to the occurrence of alveolar hypoventilation, the subjects were stimulated. A total of 163 patients were randomized. Patients in the intervention arm were significantly less likely to experience hypoxemia when compared with controls (11% versus 24%; P!.03). The majority of hypoxemic episodes were preceded by alveolar hypoventilation by a median interval of 3.4 minutes. Alveolar hypoventilation occurred in 58% of patients and in 56% of the procedures. Bispectral index monitoring Bispectral index (BIS) monitoring represents a complex mathematical evaluation of electroencephalographic parameters of frontal cortex activity, corresponding to various levels of sedation. The BIS scale varies from 0 to 100 (0, no cortical activity or coma; 40–60, unconscious; 70–90, various levels of conscious sedation; 100, fully awake). Theoretically this index should reflect the same level of sedation regardless of the medications used, except for ketamine. In a preliminary observational study involving 50 patients undergoing ERCP, colonoscopy, and upper endoscopy, BIS levels were found to correlate with a commonly used score for the degree of sedation [36]. A BIS range of 75 to 85 demonstrated a probability of 96% or greater that the patient would exhibit an acceptable sedation score. However, there was increasing variability of the BIS score with deeper levels of sedation. Additionally, there was no correlation between the BIS score and standard physiologic parameters such as pulse oximetry, blood pressure, and heart rate.

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A recent refinement in the BIS algorithm has spawned new interest in this technology. Bell and colleagues [37] used BIS in a group of patients undergoing interventional gastrointestinal (radiologic) procedures. Thirty were titrated with fentanyl and midazolam using the Ramsay sedation score while being blinded to BIS (group A). Based on this information, an additional 70 patients were titrated to an optimal BIS value (group B). Group B patients exhibited less time in deep sedation/general anesthesia (0% versus 5.5%), and there was a tendency toward fewer ‘‘unplanned events’’ (17% versus 27%), such as hypoxia, apnea, hypotension, agitation, and cardiac arrest. No difference was found in the recovery parameters between the groups. Chen and Rex [38] recently employed an updated BIS algorithm that is designed to be more sensitive to variations in lighter levels of procedural sedation for colonoscopy. They found a substantial lag time between the depth of sedation with nurseadministered propofol that was evident clinically using the Modified Observer’s Assessment of Alertness Sedation Scale score and the BIS score, for both the induction and recovery phases of the procedure. Moreover, a substantial amount of variability in the BIS score (22–88) was seen during the maintenance phase of sedation.

Propofol Propofol (2-6 diisopropylphenol) is classified as an ultra-short-acting sedative hypnotic agent that provides amnesia but minimal levels of analgesia. The cumulative experience with non–anesthetist-administered propofol exceeds 150,000 patients. Currently, there are no reported cases of endotracheal intubation or death (Tables 2 and 3) [39–43]. The issues of propofol safety are quickly becoming a thing of the past: this medication is now the most studied of all agents for sedation during gastrointestinal endoscopy. A series of 36,743 endoscopic procedures in which patients received nurse-administered propofol sedation from three high-volume centers has recently been published [44]. Each site established a training program with the assistance of anesthesiologists. The primary outcome was the occurrence of apnea or other airway compromise (ie, laryngospasm) that required assisted ventilation. No cases of endotracheal intubation, death, neurologic sequelae, or other permanent injury occurred. A total of 49 patients required assisted ventilation, which in all cases was temporary bag mask ventilation. The center-specific event rate ranged from 9 per 10,000 to 19 per 10,000. Multivariate analysis did not identify age, gender, or ASA class as risk factors for assisted ventilation at two of the sites. Higher event rates were seen for upper endoscopy at two of the sites. The non–weight-based dose of propofol was not a risk factor for assisted ventilation. The combination of bolus administration followed by infusion was used in a series of 500 ASA I and II patients who underwent elective upper gastrointestinal EUS [45]. In this scenario, the propofol was administered by the

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gastroenterologist. No instances of hypotension, bradycardia, or tachycardia occurred. Minor hypoxemia, defined as a pulse oximetry value of less than 95% but greater than 90%, occurred in 12 patients (2.4%). Moderate hypoxemia (defined as !90% but O85%) occurred in four patients (0.8%). In these 12 patients, nine responded to an increase in the supplemental oxygen flow rate. One patient required a jaw lift in addition to increased oxygen flow rate. The remaining six patients also required a temporary interruption of the propofol infusion. Walker and colleagues [46] have published a large case series encompassing 9152 procedures in which propofol was administered by specially trained registered nurses in the setting of an ambulatory surgical center. Seven instances of respiratory compromise were noted (0.7%), which included prolonged apnea, laryngospasm, and aspiration. Temporary support with mask ventilation for 30 seconds was employed, and no patient required endotracheal intubation. All respiratory complications occurred in patients undergoing upper endoscopy. In a subset of 440 patients who had received the combination of a narcotic and benzodiazepine in previous endoscopic procedures, 79% preferred sedation with propofol. Table 2 summarizes selected randomized, controlled trials in which propofol was used for sedation and analgesia for a variety of endoscopic procedures [16,28,47–51]. These studies primarily involved ASA class I to III patients who underwent elective procedures, and they are not suitably powered to detect significant differences in adverse events. Again, the important concepts of these studies are that propofol exhibits a more rapid attainment of an appropriate level of sedation and a more rapid recovery to baseline. Interestingly, the patient satisfaction outcomes were mixed. Theoretically, the use of a target-controlled infusion of propofol would result in a rapid induction to the desired level of sedation and maintenance of the sedation level by achievement of a steady-state plasma concentration. The bulk of the propofol data rely on intermittent boluses, which can be labor intensive and lead to ‘‘peaks and valleys’’ in the patient’s level of sedation. Fanti and colleagues [52] used anesthesiologist-administered target-controlled infusion with a target plasma range of 2 to 5 mg/mL in 205 adult inpatients undergoing ERCP. Each patient received premedication with midazolam, and a rescue dose of 50 to 100 mg of fentanyl was frequently required to provide analgesia. Severe hypoxemia (SAO2 ! 85%) occurred in four patients (1.9%), all of whom had ASA physical status III or higher. In three of the cases, hypoxemia resolved with turning the patient to the supine position and ‘‘improving airway patency.’’ The fourth required manual ventilation for a few minutes. A disadvantage of propofol-mediated sedation is the tendency to achieve deep sedation or, in some cases, general anesthesia. Though deep sedation is not uncommon during standard sedation and analgesia with an opioid and benzodiazepine, there is a concern that with propofol the probability of losing protective airway reflexes and maintaining cardiovascular stability is

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Table 2 Propofol case series Propofol administration

Procedure type

N

Sedation regimen

Rex, et al [44]

EGD, colonoscopy, ERCP

36,743

Registered nurse

Clarke, et al [39]

d

28,472

P bolus for EGD/ colon P infusion/ fentanyl for ERCP EGD, colonoscopy

General practitioner

Tohda, et al [40]

EGD, colonoscopy

27,500

P bolus

Registered nurse

Walker, et al [46]

EGD, colonoscopy, liver biopsy

9152

P bolus

Registered nurse

Patient satisfaction

Cost-effectiveness

Bag-mask ventilation (0.13%); no deaths

Not addressed

Not addressed

3.8:1000 airway problems; 2.7:1000 hypotension; no intubation or deaths Hypoxemia (6.7%); hypotension (3.5%) Apnea (0.3%), laryngospasm (0.3%), aspiration (0.1%)

Not addressed

Not addressed

85% preference over standard sedaton

Not addressed

79% preference rate for P over M/Md

Not addressed

Complications

VARGO

Author

EGD, colonoscopy, ERCP, EUS

2574

P bolus: EGD/ colonoscopy; infusion: ERCP/EUS

Registered nurse

Rex, et al [42]

EGD, colonoscopy, sigmoidoscopy, enteroscopy, ileoscopy EGD, colonoscopy

2000

P bolus

Registered nurse

819

M/Md/P bolus

Physician

Cohen, et al [53]

Yusoff, et al [45]

EUS

500

P bolus

Physician endoscopist

Koshy, et al [43]

EGD, colonoscopy

274

P bolus/F versus M/Md

Nurse anesthetist

Airway supporta (0.2%); hypotension (14.6%); bradycardia (3.7%) Airway supporta (0.2%); bradycardia (0.05%)

Not addressed

Not addressed

Not addressed

Not addressed

Hypotension (27%); hypoxemia (9%) Hypoxemia (SaO2 !90%) (1%) NS

Not addressed

26 min

Patients preferred propofol

Not addressed

P/F superior comfort

NS

Abbreviations: F, fentanyl; M, meperidine; Md, midazolam; NS, not statistically significant; P, propofol. a Temporary airway support, not intubation.

SEDATION AND MONITORING

Heuss, et al [41]

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Author

Procedure type N

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Table 3 Propofol randomized controlled trials Sedation regimen

Propofol administration Complications

Patient satisfaction Recovery time

ERCP

150 M/Md versus P bolus

‘‘Assisting physician’’

Ulmer, et al [48] Vargo, et al [28]

Colonoscopy

100 P bolus versus F/Md 75 P bolus versus M/Md

Registered nurse Gastroenterologist

P ¼ M/Md

Registered nurse

P: hypotension (1.25%); M/Md: hypotension (3.75%), arrhythmia (2.5%) P þEEG ¼ P EEG Not addressed

P þEEG ! P EEG

P ¼ M/Md

P!M/Md

Sipe, et al [49]

ERCP, EUS

Colonoscopy

Wehrmann, et al ERCP [50] Weston, et al EGD [51]

198 P bolus versus Md/Pz

Not stated

80 P bolus versus M/Md

80 P bolus ‘‘Assisting physician’’ EEG titration 20 M/Md versus Registered nurse P bolus

Not addressed

P!Md/Pz

P ¼ M/Md

P!M/Md

P ¼ F/Md

P!F/Md

P ¼ M/Md satisfaction, discomfort POM/Md satisfaction

P!M/Md

POM/Md

Abbreviations: EEG, electroencephalogram; F, fentanyl; M, meperidine; Md, midazolam; P, propofol; Pz, pentazocine. a Temporary airway support, not intubation.

P!M/Md

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Riphaus, et al [16]

P ¼ Md/Pz; SaO2 ! 85% P: airway supporta (1%) No hypotension, hypoxemia, or respiratory support P ¼ Md/F

Wehrmann, et al ERCP [47]

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higher. The use of triple-agent or ‘‘mixed’’ sedation with propofol, an opioid, and benzodiazepine would intuitively be dismissed because of the theoretic risk of pharmacologic synergy and an amplification of sedationinduced untoward events. Cohen and colleagues [53,54] have used a mixed sedation protocol for ambulatory upper endoscopy and colonoscopy. The opioid and midazolam were administered in bolus fashion at the beginning of the procedure, and propofol was then administered in intravenous boluses as determined by patient comfort level and physiologic parameters. The level of sedation was assessed every 2 minutes. A total of 100 subjects undergoing either EGD or colonoscopy received the mixed sedation regimen [54]. Of the 729 assessments of the level of sedation, 77% were minimal sedation, 21% were moderate sedation, and only 2% were in the deep sedation range. Patient satisfaction with sedation was nearly universal (98%), and 71% returned to usual activities within 2 hours of discharge. Even though propofol exhibits a superior recovery profile and impressive safety profile, at least in case series, the current data in randomized controlled trials are insufficient adequately to answer the question of its safety compared with standard sedation and analgesia. A recent meta-analysis identified 12 randomized controlled trials comparing propofol with traditional sedation. Of the 1162 patients included in the meta-analysis, 634 received propofol and 527 received midazolam, meperidine, and/or fentanyl [55]. Hypoxemia and hypotension were used as endpoints. For colonoscopy, the pooled odds ratio with the use of propofol for developing hypoxemia or hypotension during colonoscopy was 0.4 (95% CI, 0.2, 0.79). For upper endoscopy, the pooled odds ratio was 0.74 (95% CI, 0.44, 1.44), and for ERCP/EUS it was 1.07 (95% CI, 0.38, 3.01). This evidence indicates that, for the parameters analyzed, propofol-mediated sedation is as safe as traditional sedation for EGD, ERCP, and EUS and appears to be safer for colonoscopy. Recently, a water-soluble prodrug of propofol (fospropofol sodium) has been studied in humans [56]. The prodrug is activated to propofol after removal of the water-soluble moiety by endothelial alkaline phosphatase. If successful, this would make possible a weight-based bolus frequency similar to that of traditional agents used for procedural sedation. A potential drawback is that the increased plasma half-life may translate into prolonged recovery. We await the results of current studies to determine the safety and efficacy of this agent. In summary, the use of propofol for procedural sedation is burgeoning, particularly in the private practice setting. Such a potential shift in the sedation paradigm has occasioned the scrutiny of regulatory agencies and thirdparty payers and the jostling of professional societies [57]. Will proprofol or a similar agent become the standard of care for procedural sedation? The next few years should give us the answer.

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Droperidol Droperidol is a buyrophenone that is widely used as an antipsychotic. Numerous studies have shown its efficacy in the successful sedation of patients who are resistant to the combination of a narcotic and benzodiazepine [58,59]. In December 2001, the US Food and Drug Administration required a ‘‘black box warning’’ because of concern about possible Q–T interval prolongation leading to fatal arrhythmias [60]. Yimchareon and colleagues [61] performed a retrospective review of the use of droperidol in 3113 ERCPs and its effect on the Q–T interval. The mean dose of droperidol was 4.5 mg in men and 4.3 mg in women. A total of 233 patients (7.48%) developed Q–T interval prolongation. Of these, only 15 (0.48%) had marked prolongation of the Q–T interval, yet no serious arrhythmias occurred.

Topical anesthesia A recent review of the US Food and Drug Administration adverse events database from 1997 to 2002 identified two deaths and 107 serious adverse events associated with benzocaine-induced methohemoglobinemia [62]. Additionally, anaphylactoid reactions have been reported [63]. A systematic review was conducted to evaluate the effectiveness of topical anesthetic agents in improving patient tolerance and procedural ease during sedated upper endoscopy [64]. Five randomized controlled studies comparing topical anesthesia with placebo or with no treatment were identified, comprising 491 patients. Patients who rated their discomfort as ‘‘none’’ or ‘‘minimal’’ were more likely to have received topical anesthesia (OR 1.18; 95% CI, 1.13, 3.12). Additionally, endoscopists were more likely to rate the procedure as ‘‘not difficult’’ for patients who received pharyngeal anesthesia (OR 2.60; 95% CI, 1.63, 4.17). Drawbacks of the study included the lack of standardized outcomes and the heterogeneity of sedation regimens.

Summary In summary, we are left with an insurmountable fact: Serious adverse events are fortunately quite rare for procedural sedation. Current physiologic monitoring recommendations are therefore either based on ‘‘softer’’ outcomes, such as transient hypoxemia, or on expert opinion. Based on the available data and practice guidelines, a list of interventions designed to reduce the risk for sedation-related complications is presented: 1. Obtain an adequate preprocedural history and physical examination. 2. Training in basic and advanced cardiac life support is suggested. In the vast majority of cases of respiratory compromise, a temporary head-tilt or jaw-thrust maneuver and (occasionally) a nasopharyngeal tube may

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3. 4. 5. 6. 7. 8. 9. 10.

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be used to treat temporary intervals of respiratory compromise, along with the judicious use of reversal agents. Know the pharmacology of the sedation and reversal agents. Individualize sedation dosing in each patient to achieve the desired effect. Continuous intravenous access is paramount. The level of sedation, blood pressure, pulse, and oxygen saturation should be assessed periodically. Oxygen supplementation should be used in all patients. EKG monitoring should be employed in all patients who have known cardiovascular disease. Consider capnography in patients undergoing prolonged procedures who are at risk for deep sedation. Utilize standardized discharge criteria (ie, Aldrete score) to determine candidacy for discharge. Remember, the risk for deeper than intended levels of sedation may be more common in the recovery room, when the stimulation of the endoscopic procedure has been removed.

Pulse oximetry and supplemental oxygen are recommended for the reduction of hypoxemia. Outcomes-based data for extended monitoring are just starting to emerge, and one of these technologies may become a recommended component of patient monitoring. With data on more than 150,000 patients published in the literature, propofol is the most studied sedative agent for gastrointestinal endoscopy. In this author’s opinion, its safety and efficacy have been established. It is to be hoped that, when the policy and regulatory maelstrom settles, this agent will be globally accepted in the endoscopy suite.

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