Synopsis  

This chapter will review the definitions encompassing the spectrum of sedation as outlined by the American Society of Anesthesiologists. Particular emphasis will be given to the reversal of deeper than intended states of sedation. Extended monitoring of respiration with transcutaneous carbon dioxide measurement and capnography will then be reviewed. The application of bispectral index (BIS) monitoring, which represents a complex mathematical evaluation of electroencephalographic parameters of frontal cortex activity will then be reviewed. Trials utilizing topical anesthetics, the bolus administration of meperidine and midazolam via dosing nomograms as well as the use of droperidol will then be addressed. The emerging use of the anesthetic agent propofol by non-anesthesiologists for endoscopy will then be critically reviewed.

 Introduction   

'Sedation and analgesia' represents a continuum ranging from minimal sedation or anxiolysis through general anesthesia. In this era of open access endoscopy, candidacy for sedation and analgesia still must take into account a thorough preprocedure assessment including a history of present illness, past medical history, and a physical examination [1]. New 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 to the continuum of sedation (Fig. 1) [2].

Moderate sedation   

In most endoscopic cases, moderate sedation is the goal. This is defined by the patient giving a purposeful response after verbal or tactile (not painful) sensation, and no compromise of the patient's airway, ventilation, or cardiovascular function.

Deep sedation/analgesia   

In this state, patients may respond only to painful stimuli. Additionally, the patient's airway and spontaneous ventilation may become compromised, and 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/analgesia.

 Advances in monitoring during sedation   

Cardiorespiratory complications are a leading cause of morbidity and mortality associated with gastrointestinal endoscopy. Both ventilatory depression and oxygen desaturation stemming from the medications used to achieve sedation and analgesia are thought to be important risk factors for these complications.

Standard pulse oximetry   

Pulse oximetry has become a defining standard of care during sedation and analgesia for endoscopy, owing to the evidence that clinical observation alone is inaccurate in the detection of hypoxemia and that supplemental oxygen can minimize the degree of desaturation and hopefully its deleterious effects. To date, neither pulse oximetry nor supplemental oxygen administration has yet been shown to decrease the severity or incidence of cardiopulmonary complications.

CO₂ monitoring   

It is important to point out that pulse oximetry does not measure alveolar hypoventilation, which is measured by hypercapnea or a rise in arterial carbon dioxide pressure.[3–6] Although oxygen administration may prevent hypoxemia and its deleterious effects, it will not detect the development of hypercapnea. Deleterious consequences of alveolar hypoventilation include myocardial depression, acidosis, intracranial hypertension, narcosis, and arterial hypertension or hypotension.

Transcutaneous CO₂ monitoring   

Transcutaneous CO₂ monitoring (PtCO₂) is a non-invasive 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 at the skin/electrode interface, and so produces carbonic acid. A pH reading is then taken and the CO₂ value is obtained via the Henderson-Hasselbach equation.

Nelson et al. randomized 395 patients undergoing ERCP to standard monitoring coupled with transcutaneous CO₂ monitoring guiding sedation and analgesia (group 1) or to standard monitoring alone in which the endoscopist was blinded to the PtCO₂ data (group 2) [3]. Significantly more group 2 patients experienced carbon dioxide retention > 40 mmHg above baseline values. Predictors for peak PtCO₂ included baseline PtCO₂ value, the use of naloxone, the maximum fall in oxygen saturation via pulse oximetry, maximum supplemental oxygen rate, and the combination of a benzodiazepine and an opioid for sedation and analgesia. 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. 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 [5]. 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 [6]. The endoscopist and nursing personnel were blinded to the capnography data. Though the number of apneic events was similar between the two groups, significantly more episodes of apnea were missed in the group receiving oxygen (7% vs. 42%, p < 0.001). Moreover, significantly more patients receiving supplemental oxygen received sedation following an apneic episode. Capnography has also been utilized to allow the safe titration of propofol by a qualified gastroenterologist during ERCP and Endoscopic Ultrasonography (EUS).

BIS monitoring   

Bispectral index (BIS) monitoring represents a complex mathematical evaluation of electroencephalographic parameters of frontal cortex activity, corresponding to varying levels of sedation. The BIS scale varies from 0 to 100 (0, no cortical activity or coma; 40–60, unconscious; 70–90, varying 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 [7]. A BIS range of 75–85 demonstrated a probability of >= 96% 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, or heart rate.

 Topical anesthetics: are they worth the effort?   

Prospective, randomized controlled trials addressing the use of topical anesthetics during upper endoscopy for improved patient tolerance have been mixed (Fig. 2) mixed [8–13]. Existing study designs differ in the presence of double-blinding, the type of topical anesthetic employed, endoscope diameter, and the use of conscious sedation. Soma et al. recently conducted a study of 201 Japanese patients who were randomized to receive either 2% lidocaine or placebo [8]. No conscious sedation was employed. Multivariate analysis found that the use of topical anesthesia reduced the relative risk of discomfort by 44% (95% CI: 0.31–1.01). Patient age less than 40 was associated with a higher relative risk of discomfort (RR 2.22, 95% CI: 1.04–4.74). Subgroup analysis found that patients less than 40 years of age who were pretreated or those undergoing endoscopy for the first time benefited most from topical anesthesia.

 Titration vs. bolus administration of sedation and analgesia   

Practice guidelines call for the call for the careful titration of sedative medications using small, incremental doses and allowing sufficient time between doses to assess effect [1]. Morrow et al.,utilizing a dosing nomogram based on the age and weight, performed a prospective, randomized, double-blind trial comparing bolus vs. titration dosing of meperidine and midazolam for outpatient colonoscopy [14]. Exclusion criteria included age < 18 years or > 65 years, active use of narcotics or benzodiazepines, pulmonary disease requiring home oxygen, end-stage liver or kidney disease, and a New York State Heart Association class III or IV congestive heart failure. The groups were well matched in terms of demographics. Patient tolerance scores were equivalent between both groups. Physician time was significantly shorter in the bolus group (20.1 vs. 32.2 min, p < 0.001). Episodes of oxygen desaturation occurred significantly more often in the titration group. Further evaluation of bolus administration is needed for patients undergoing upper endoscopy and prolonged therapeutic procedures such as ERCP and endoscopic ultrasonography.

 Propofol   

Propofol is classified as an ultrashort acting sedative hypnotic agent that provides amnesia, but minimal levels of analgesia. Propofol rapidly crosses the blood–brain barrier, and causes a depression in consciousness that is thought to be related to a potentiation of the γ-aminobutyric acid activity in the brain. Typically, the time from injection to the onset of hypnosis is 30–60 s, which is essentially the time for one arm–brain circulatory pass [15]. The plasma half-life ranges from 1.3 to 4.13 min. Dose reduction is required in patients with cardiac dysfunction and in the elderly due to decreased clearance of the drug. Propofol potentiates the effects of narcotic analgesics and sedatives such as benzodiazepines, barbiturates, and droperidol and therefore the dose requirements may be reduced.

Problems with propofol   

Pain at the injection site is the most frequent local complication, occurring in up to 5% of patients.

Episodes of severe respiratory depression necessitating temporary ventilatory support have occurred in large series utilizing propofol for endoscopic procedures [16–18]. Capnography has been successfully used to graphically assess the respiratory activity in patients receiving gastroenterologist-administered propofol for therapeutic upper endoscopy [19,20]. Monitoring with graphic assessment of respiratory activity detected early phases of respiratory depression, resulting in a timely decrease in the propofol infusion without significant hypoxemia, hypercapnea, hypotension, or arrhythmias.

Specific training for use of propofol   

Propofol has a narrow therapeutic window—its administration, even in the hands of an anesthesiologist, does not prevent the occurrence of severe respiratory compromise [2]. It cannot be overemphasized enough that personnel specifically trained in the administration of propofol with expertise in emergency airway management need to be present during the procedure, constantly monitoring the patient's physiologic parameters. In this author's opinion, the use of propofol usually results in a state of deep sedation and analgesia. It is our practice to utilize nasopharyngeal capnography to detect early signs of respiratory depression such as apnea, which would otherwise, go undetected by standard pulse oximetry [19,20]. The presence of a person who is dedicated to the administration of propofol and the uninterrupted monitoring of the patient's physiologic parameters is another important requirement [19,20].

Contraindications of propofol   

Specific contraindications to propofol administration include allergies to propofol or any of the emulsion components, pregnant or lactating females, and patients with an American Society of Anesthesiologists IV or V physical status classification [15].

Clinical trials of propofol   

Propofol or midazolam?   

Upper endoscopy   

In a randomized study, 90 patients received a bolus administration of propofol or midazolam both before and during upper endoscopy [21]. The propofol treatment arm was superior in terms of patient tolerance, maximum level of sedation achieved, and shorter recovery room times. In contrast, a smaller series of 40 patients randomized to receive the same medications before upper endoscopy found that propofol provided a more rapid recovery room time, but was also associated with pain at the injection site, reduced patient acceptance, and a shorter amnesia span [22].

ERCP   

Two randomized, controlled trials have compared propofol alone to midazolam specifically for ERCP [16,23]. In one study, an anesthesiologist administered propofol; in the second study, an assisting physician who was not involved in the endoscopic procedure administered propofol. In both studies, patients receiving propofol exhibited significantly improved quality of sedation and shorter recovery times. Untoward effects such as hypotension and hypoxemia occurred equally in both treatment groups. However, it is important to point out that in both series, one patient in the propofol group developed prolonged apnea that necessitated discontinuation of the procedure and temporary ventilatory support.

Upper endoscopy and colonoscopy   

Koshy et al. compared the combination of propofol and fentanyl to midazolam and meperidine in a non-randomized group of 274 patients undergoing upper endoscopy and colonoscopy [24]. Propofol and fentanyl led to better patient comfort and deeper sedation without an increase in untoward side-effects. There was not, however, a significant difference in the recovery times between the two groups.

Propofol with or without midazolam   

A prospective, randomized trial compared the efficacy of propofol alone to the combination of midazolam and propofol in 239 patients undergoing therapeutic upper endoscopy or ERCP [25]. While sedation efficacy and the incidence of hypotension and hypoxemia were comparable in both groups, patients receiving midazolam and propofol exhibited a significantly longer mean recovery time.

Patient-controlled administration of propofol   

Patient-controlled sedation and analgesia (PCS) with propofol has recently gained in popularity. Kulling et al. randomized 150 patients to three sedation arms: PCS with propofol/alfentanil (group I), continuous propofol/alfentanil infusion (Group II), and nurse-administered midazolam/meperidine (Group III) [26]. Group I exhibited a higher degree of patient satisfaction and more of a complete recovery at 45 min when compared to conventional sedation and analgesia. In a similar study, Ng and colleagues randomized 88 patients undergoing colonoscopy to PCS with propofol alone or midazolam [27]. Patients receiving propofol PCS exhibited significantly shorter recovery times (43.3 min vs. 61.0 min) and improved satisfaction with overall level of comfort. PCS for ERCP however, has not been as successful. In a pilot study utilizing a software system designed to deliver a 'ceiling' for the plasma propofol concentration, only 80% of patients received a safe and fully effective sedation [28].

Nurse-administered propofol   

The safety and experience with propofol administered by registered nurses has been addressed in a case series including 2000 patients undergoing elective EsophagoGastroDuodenoscopy (EGD) and/or colonoscopy [17]. All patients were ASA class I or II. No extended monitoring was used and all patients received 3 L of nasal cannula oxygenation. The propofol dosage was an initial bolus of 20–40 mg, followed by 10–20 mg to maintain sedation. Five episodes of oxygen desaturation to < 85%, four of which required temporary mask ventilation, occurred. Four of these episodes occurred during upper endoscopy. Propofol has been compared in a prospective, randomized trial to midazolam and meperidine in 80 ASA Class I or II outpatients undergoing elective colonoscopy [18]. Propofol was superior in terms of the rapidity and depth of sedation, recovery times, and overall satisfaction. Additionally, patients receiving propofol exhibited improved recovery of psychometric function

Gastroenterologist-administered propofol   

Vargo et al. completed a randomized, controlled trial of gastroenterologist-administered propofol vs. meperidine and midazolam for elective ERCP and EUS [20]. In this study, a separate gastroenterologist, who was trained in propofol administration, was utilized. Additionally, capnography was used to detect apnea or hypercapnea, and thus adjust the propofol dosing accordingly. This study was also the first to address issues of cost effectiveness from an institutional standpoint. Visual analog scales (VAS) were used to address patient and endoscopist satisfaction. Patients randomized to propofol exhibited a faster mean recovery time (18.6 vs. 70.5 min), could perform independent transfer following the procedure and were able to achieve a baseline return to a baseline food intake and activity level (71% vs. 16%). Cost effectiveness data with a sensitivity analysis found that nurse-administered propofol to be the dominant strategy, when compared to standard sedation and analgesia.

 Droperidol   

Droperidol, a narcoleptic of the butyrophenone class, produces a dissociative state while enhancing the effects of other sedative medications. It is routinely used in some centres as a premedication for patients undergoing ERCP. Other indications include: a history of alcohol use or withdrawal, narcotic use, and a history of paradoxical agitation to conventional conscious sedation. In a retrospective study involving 1102 procedures, droperidol was found to be a safe adjunct to the combination of narcotics and benzodiazepines [29].

In a prospective, double-blind, placebo-controlled trial, in 140 patients undergoing elective upper endoscopy, droperidol led to a 10% reduction in procedure time and significantly reduced meperidine and midazolam requirements [30]. However, four patients in the droperidol group received naloxone for excessive drowsiness. Rizzo et al. addressed the use of different doses of droperidol in patients undergoing EUS [31]. When compared to placebo, 5 mg of droperidol led to significantly less medication costs, while at the same time, not affecting the mean recovery time.

Complications   

Complications attributable to droperidol occurred in 1.5% of procedures and was comprised mainly of hypotension, responsive to IV fluids. Reports of QT interval prolongation and torsades des pointes have occurred, at or below the recommended doses resulting in death. Some of these cases have occurred in patients without risk factors for QT interval prolongation. This prompted the Food and Drug Administration to issue a 'black box' warning which will severely curtail the use of this drug in the endoscopy suite [32].

 Outstanding issues and future trends   

The importance of preprocedural assessment and appropriate monitoring cannot be overemphasized. The endoscopist must have a thorough knowledge of the pharmacology of the agents used for sedation and the training necessary to recognize and manage oversedation. Numerous regulatory groups are carefully scrutinizing the practice of sedation and analgesia. It appears that ventilatory monitoring will be required for at least a subset of our patients. Although both hypercapnea and apnea can be reliably measured, the most important questions to be answered are: will such monitoring affect patient outcomes, and which patients are at risk for apnea and alveolar hypoventilation?

The use of propofol for gastrointestinal endoscopy has been shown to be safe in experienced hands. Its narrow therapeutic window demands that specially trained personnel who are not directly involved in the endoscopic procedure administer it. Controversy exists over nurse-administered propofol. Currently only a minority of states allow this practice. The use of anesthesia personnel to administer propofol while safe and increasing the throughput of the endoscopy suite is quite costly. It is doubtful that third-party payers will approve of this practice on a large scale. Extended monitoring with capnography appears to offer an advantage over conventional monitoring in that it can detect early phases of respiratory depression, which can allow for a timely adjustment in the propofol infusion and thus prevent significant respiratory depression. Emerging cost effectiveness data suggests that propofol is superior to conventional sedation and analgesia, even with the use of added personnel. In the future, 'smart machines' which utilize software-driven algorithms, based on the physiologic feedback from standard and extended monitoring devices may lead to the practical, safe, and universal acceptance of propofol in the endoscopy suite.

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32 FDA information on Droperidol http://www.fda.gov/medwatch/SAFETY/2001/safety01.htm#inapsi

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