Introduction
Propofol is a sedative–hypnotic that was commercially introduced into U.S. anesthetic practice in 1989. Released under the trade name of Diprivan, it rapidly gained acceptance in the anesthesia community as an induction agent because of its rapid onset of action and other favorable pharmacokinetic properties. Because propofol undergoes a two-phase distribution, with the first phase lasting only 4 to 6 minutes, the sedative effects of a single bolus dissipate rapidly. Thus it was soon recognized that the “rapid-on, rapid-off ” profile of propofol also made it an ideal agent for sedation either as a continuous infusion or in small boluses.
Options
Even before its commercial release in the United States, specialties outside anesthesiology began to report on the use of propofol for procedures requiring sedation. Standard agents for procedures occurring in radiology and endoscopy suites, dental offices, and emergency departments were opioids and long-acting sedatives such as benzodiazepines. However, recovery from the prolonged effects of these medications was troublesome, and clinically significant side effects such as respiratory depression limited the amounts administered. The rapid redistribution properties of propofol and its minimal effects on most patients’ hemodynamic variables made it appear to be a much safer alternative.
The pharmacokinetic properties of propofol allow patients to emerge more quickly after administration, and they appear less sedated compared with other barbiturate or benzodiazepine combinations, even though complete elimination from the body can take hours or even days. It also may produce amnesia and has a dose-dependent, mood-altering effect that can be euphorogenic. Studies have shown that mood and psychomotor function return to baseline within an hour or less after brief infusions of the medication are stopped in healthy volunteers, which is similar to other modern general anesthetics. Propofol also has an antiemetic effect that further supports its selection for procedures in an outpatient setting.
Unfortunately, the ideal anesthetic agent does not exist, and propofol has its share of undesirable side effects. Most notable is the dose-dependent respiratory depression that can abruptly result in apnea or airway obstruction. This effect ends quickly when administration is stopped, which gives a false sense of safety to those providing or directing the sedation. Another commonly encountered effect is the decrease in mean arterial pressure that is similar or somewhat more pronounced when compared with other sedative–hypnotics. Again, these observed effects end quickly when dosing stops.
Evidence
Investigators in three medical specialties and dentistry have compared propofol with other traditional options and currently recommend propofol as a safe addition to everyday practice, supporting its administration by practitioners who are not anesthesia professionals. In nearly every instance, studies conclude that propofol is associated with minimal postprocedural sedation, which results in a faster recovery, provides amnesia and comfort to the patient, delivers better procedural conditions, and has a better safety profile than traditional choices.
Evaluation of the data on propofol use by nonanesthesia providers is complex because of several factors, the foremost of which is the lack of adequately powered studies that statistically support the conclusions made. In addition, a direct comparison among the different specialties cannot be made. Procedural needs, patient presentation, and defined endpoints are quite different for each specialty. Gastroenterology has evolved from simple procedures such as colonoscopy and diagnostic esophagogastroduodenoscopy (EGD) that require only moderate sedation, to more invasive and stimulating ones such as endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography (EUS). The diagnostic and therapeutic value of these newer endoscopic methods has led to a substantial increase in annual procedural numbers, but by their very nature, they require deeper sedation for patient acceptance and optimal conditions. The traditional approach has been to combine a benzodiazepine with or without an opioid, and this is the combination against which propofol-based sedation protocols with or without adjuvants are compared. Similarly, physicians in the specialty of emergency medicine are often faced with the need for deep sedation and analgesia to perform short, painful procedures such as the reduction of a dislocated joint or closed fracture. The specialty of radiology has supported the development of pediatric sedation units (PSUs) primarily for radiologic procedures. The sedation teams are supervised at times at a distance by pediatric intensivists or emergency department physicians. Because these cases can require hours of sedation, propofol is one of several options used. Finally, dentistry has long been associated with painful procedures. Although local infiltration or nerve blocks remain the techniques of choice, patients may receive supplemental sedation to accompany the procedure, especially at the time of the nerve block or local infiltration. Current studies report sedation being maintained throughout the entire procedure, albeit at a more responsive level.
The American Society of Anesthesiologists (ASA) House of Delegates approved a document in 1999 describing the continuum of depth of sedation. However, the aforementioned specialties had already begun to report on sedation with propofol against other traditional medications and, in so doing, used the definitions for sedation depth to which they were accustomed. This makes comparisons between fields difficult ( Table 47-1 ). Studies often report the use of basic monitors such as a pulse oximeter and automated blood pressure cuff (except in dentistry), but supplemental oxygen and capnography are not standard. Even though propofol is commonly used for sedation in the critical care unit, there is often input from the available anesthesiology service and patients receive ventilation under heightened monitoring conditions; therefore the critical care unit setting will not be considered in this chapter.
| Ramsay Sedation Scale | ASA Continuum of Depth of Sedation (Responsiveness) | Observer’s Assessment of Alertness/Sedation (OAA/S) | ||
|---|---|---|---|---|
| 6 | No response | General anesthesia | 0 | No response to pain |
| 5 | Sluggish to light glabellar tap/noise | Deep sedation/analgesia | 1 | No response to mild prodding/shaking |
| 4 | Response to light glabellar tap/noise | Moderate sedation/analgesia | 2 | Responds to mild prodding/shaking |
| 3 | Responds to loud noise or repeated name | |||
| 3 | Responds to commands only | 4 | Lethargic response to name called | |
| 2 | Cooperative, oriented, calm | Minimal sedation to awake | 5 | Responds to name, alert |
| 1 | Anxious, agitated, restless | Not defined | 6 * | Anxious, agitated, restless |
* The Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) includes level 6.
Gastroenterology
There are two meta-analyses and a Cochrane Database review on the administration of propofol by nonanesthesia personnel for moderate sedation in endoscopic procedures. Of these, the Cochrane review discusses the use of propofol for colonoscopy only; one meta-analysis reviews the use of propofol for diagnostic EGD and colonoscopy but not for those procedures requiring deep sedation such as ERCP, enteroscopy, or EUS ; and the other analysis reviews studies that included colonoscopy, EGD, and ERCP.
The Cochrane Review analyzed 22 studies published since 1989, of which most were small, randomized controlled trials (RCTs) of limited power. The review’s primary objective was to appraise studies that evaluated the safety and efficacy of propofol, either alone or in combination with adjuvants, in comparison with the traditional medications of benzodiazepines, opioids, or both. A secondary objective was to assess studies that compared the administration of propofol by nonanesthesia personnel to that by anesthesia professionals, but only one study reported that comparison. Although several of these studies show similar outcomes between providers, they do not have sufficient power to detect a statistical difference in the outcomes of interest. The Cochrane review authors noted that the studies were generally of poor quality and concluded that studies of better design, sufficient power, and standardized outcome reporting are needed, as well as comparative data about propofol administration by nonanesthesia personnel versus anesthesia professionals.
The meta-analysis by Qadeer et al evaluated 12 studies that specifically compared the incidences of hypoxia (defined as a pulse oximetry reading of less than 90), hypotension (defined as a systolic pressure less than 90 mm Hg), arrhythmias, and apnea from sedation with the use of propofol against traditional techniques for colonoscopy, EGD, and ERCP. Anesthesiologists administered the sedation in two of the studies; in one of these, the propofol arm was a patient-controlled design that was compared with traditional sedation by the anesthesiologist. Two other studies did not specify the sedation administrator, one used a nurse directed by the endoscopist, and the remaining seven used an endoscopist dedicated to the sedation. Hypoxia and hypotension occurred frequently with both sedation techniques, and arrhythmias and apnea were rare but of equal frequency when reported, which makes a statistical comparison of frequency not possible. One study of the 12 markedly favored propofol, and when the authors removed that study in a sensitivity analysis, they acknowledged an implied influence. Nonetheless, they reported that the pooled analysis demonstrated a 26% lower incidence of the defined complications when propofol was used, which led them to conclude that propofol had a lower risk profile than traditional methods for colonoscopy but not for EGD or ERCP. Of note, they added that better studies are needed to prove its superiority.
The meta-analysis by McQuaid et al compared sedation techniques used for diagnostic EGD and colonoscopy. Inclusion criteria were studies in which protocols included both traditional and propofol-based practices used in healthy, adult, outpatient populations with the goal of moderate sedation. Thirty-six RCTs, systematic reviews, and the Qadeer et al meta-analysis were included for assessment, in which the primary goal was to evaluate patient satisfaction, physician satisfaction, and efficiency metrics. In this analysis, who administered the sedation was not specifically reported other than to state it was a health care professional. It also rated the methodologic quality of each study using a tool called the Jadad scale. This scale assigns a score of 0 to 5, and a score of 3 or less means the study is of relatively poor quality. Of the studies meeting inclusion criteria, 23 of the 36 rated a 3 or less on the Jadad quality scale. The authors concluded that traditional sedation protocols and those that use propofol have similar outcome profiles when the goal is moderate sedation; the only exception is that recovery times for propofol-based methods are significantly shorter. Moreover, they acknowledged that higher quality RCTs are needed to better assess the role of propofol either alone or with adjuvants for moderate sedation.
Aside from the studies included in the meta-analyses and Cochrane review, the number of RCTs published within the past decade that compared propofol with or without other medications against traditional protocols and that used nonanesthesia professionals to administer the sedation is difficult to determine. Many do not report who gave the sedation in the newer publications. More concerning, one survey from 2006 noted 25% of endoscopy units in the United States use propofol for routine procedures, and of those not yet doing so, 68% plan to move to it in the future with proper staff training. This same survey reported that 82% of propofol-based sedation was provided by an anesthesia professional at that time but that, in some European countries, such as Switzerland, the incidence of nonanesthesia personnel administering propofol was 34%. The recent literature suggests this shift may be happening.
Earlier RCTs focused on the safety of propofol as an alternate sedation strategy in endoscopy units and whether nonanesthesia personnel could safely administer it either under endoscopist direction, by protocol, or via patient-control. These studies tended to use healthy patients undergoing routine procedures requiring moderate sedation. Table 47-2 summarizes these earlier studies, of which two were designed to demonstrate the safety of using registered nurses to administer the sedation while under the direction of the endoscopist, one compared patient-controlled sedation (PCS) against nurse-administered sedation (arguing that nurse administration was preferred), and one other argued that the use of another endoscopist to administer the propofol was not cost-effective. Trained nurses were identified as the most cost-effective providers of propofol. Hypoxia was the most common complication, yet supplemental oxygen was not given in one study and only 2 L/min was delivered in four. The incidence of hypoxia and other defined complications were similar with either sedation technique, but valid statistical evaluations could not be made. Recovery was faster in the groups that received combination therapy and were kept to a moderate level of sedation. These early reported findings in the endoscopy literature laid the foundation for two more recent RCTs that studied propofol use for more invasive procedures in sicker patients. Although these studies were underpowered, they concluded that nurse-administered propofol sedation in this sicker population was not associated with a higher incidence of complications and thus was safe ; patients given propofol had faster recovery times and propofol was more efficient ; and propofol was better tolerated in an elderly population with liver disease.
| Author (Date) | Study | Responsible for Administration of Medications | Medications | Population (N) | Mean Dose (mg/kg) | Hypoxia <90% (%) | Hypotension <25% (%) | Heart Rate Changes (%) | Study Conclusions |
|---|---|---|---|---|---|---|---|---|---|
| Lee (2002) | Colonoscopy in >65-yr-olds | Patient-controlled | Pfl and A | 50 | 0.79 NR | 0 | 4 | NR | Total Pfl dose was low and allowed a faster recovery. Patient satisfaction was high in both. |
| Endoscopist-directed RN | D and Mep | 50 | 5.8 30.1 | 8 | 28 | NR | |||
| Vargo (2002) | ERCP/EUS | Endoscopist | Pfl | 38 | 4.67 | 37 | 16 | 0 | Cost analysis study. End-expired CO 2 measured. No differences in cardiopulmonary parameters. Pfl allowed a shorter recovery. Author argued for RN delivery because of expense of second physician. |
| Endoscopist | Mid and Mep | 37 | 0.12 1.54 | 57 | 19 | 8 | |||
| Sipe (2002) | Colonoscopy | RN | Pfl | 40 | 2.61 | 0 | 0 | 0 | Pfl had faster onset, greater sedation (unresponsive to pain versus response to verbal), and faster recovery. Author claimed within the past decade safety in RN administration. |
| RN | Mid and Mep | 40 | 0.06 1.09 | 0 | 5 | 5 | |||
| Heuss (2004) | Colonoscopy | PCS | Pfl | 36 | 1.78 | 2 | 23 | NR | Similar cardiopulmonary changes regardless of technique, but 35% of patients refused PCS. Author concluded that patient preference makes NAPS the preferred method. |
| NAPS | Pfl | 40 | 1.53 | 2 | 25 | NR | |||
| Riphaus (2005) | ERCP in >80-yr-olds | Intensivists | Pfl | 75 | 322 mg mean total | 9 | 4 | 8 | ASA III and IV elderly patients. No statistical difference in clinical parameters except desaturation during recovery was less and recovery faster with Pfl. |
| Intensivists | Mid and Mep | 75 | 6.3 mg and 50 mg mean totals | 11 | 5 | 4 | |||
| Chen (2005) | ERCP | Intensivists | Pfl | 35 | NR | 6 | 20 | 6 | With Pfl, 43% had significant changes in blood pressure versus 60%. Heart rate and SpO 2 changes similar. Recovery time was faster with Pfl. |
| Intensivists | Mid and Mep | 35 | NR | 9 | 0 | 11 | |||
| VanNatta (2006) | Colonoscopy | Endoscopist-directed RN | Pfl | 50 | 215 mg median dose | 0 | Cannot interpret | Occurred but cannot interpret data as presented | The mean sedation score (MOAA/S) with Pfl was 0.9 but was >3.0 for the three combinations. The Pfl + F group had the lightest mean sedation score and never reached deep sedation. None had O 2 desaturation below 90%. Shorter recovery times occurred with the mixtures versus Pfl alone. |
| Endoscopist-directed RN | Pfl + F | 50 | 140 mg Pfl median dose F: NR | 0 | |||||
| Endoscopist-directed RN | Pfl + Mid | 50 | 125 mg Pfl median dose Mid: NR | 0 | 0 | ||||
| Endoscopist-directed RN | Pfl + Mid + F | 50 | 82.5 mg Pfl median dose F and Mid: NR | 0 | Cannot interpret |
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