Propofol-based Procedural Sedation and Analgesia: Beyond Current Controversies
September 1, 2009
Propofol-based Procedural Sedation and Analgesia: Beyond Current Controversies
Authors: Benjamin James Lawner, DO, EMT-P, Attending Physician and Clinical Instructor, Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore; Alfred Jump, MD, MS, Senior Emergency Medicine Resident, Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore.
Peer Reviewer: Michael L. Coates, MD, MS, Professor and Chair, Family and Community Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Introduction
Despite a growing body of supporting evidence, the use of propofol for procedural sedation and anesthesia (PSA) is still not routine practice in some emergency departments (EDs). The debate that revolves around the use of propofol mirrors other challenges that the discipline of emergency medicine has previously weathered and overcome. Many years ago, the use of paralytics outside of the operating room was highly controversial; rapid sequence intubation is now considered an obligatory part of the acute care clinician's skill set. The skill of endotracheal intubation also transcends the discipline of anesthesiology. Due to its rapid onset and safety profile, propofol has emerged as an attractive agent for sedation in the ED, but the safe implementation of procedural sedation requires expertise and input from several specialties and a careful and thorough understanding of current scientific evidence.
Although critical care, emergency medicine, and acute care organizations have articulated a uniform consensus statement supporting the use of propofol, barriers to its widespread use still exist.1 Recent Maryland Board of Nursing (MBON) regulations, for example, stipulate that registered nurses "may not administer" propofol because the drug is classified as an anesthetic. The board further cautions that an RN "must report when he or she has refused to administer or monitor the patient" undergoing procedural sedation with medications such as propofol.2 Declaratory rulings from agencies like the MBON do not prevent physicians from administering and monitoring procedural sedation. However, it has several implications for patient safety. Objections to the administration of propofol are not always evidence-based, and it is important for acute care clinicians to remain aware of the controversy and advocate for appropriate utilization. This article examines the current arguments in favor of continued integration of propofol into current PSA protocols. A MEDLINE literature search from 2000 to present returned more than 50 articles relevant to the use of propofol in the ED. Articles with the potential to positively impact ED practice were included for review.
Obstacle Course: Objections to Propofol Use
Source: Green SM, et al. Barriers to propofol use in emergency medicine. Ann Emerg Med 2008;52:392-398.
Propofol is emerging as one of the most frequently utilized medications for ED-based procedural sedation. Green et al review the controversies and criticisms surrounding this agent's use and safety profile. Several facilities have adopted policies that prohibit the use of propofol in the ED and the terminology surrounding recommendations by anesthesiologists and some hospital sedation committees have complicated the general acceptance and utilization of propofol in the ED.
The article offers evidence and information regarding some commonly cited objections regarding the use of propofol in the ED. Causes for concern often include the degree of respiratory depression induced by this sedative, the risk of aspiration, the ease at which oversedation can occur, and the fact that propofol does not have a reversal agent.
The first concern-the threat of ineffective ventilation or apnea-is real with the use of propofol. Some experts contend that its use by specialists other than anesthesiologists will lead to hypoxic injuries. Green and colleagues affirm that no cases of hypoxic brain injury have been reported in the emergency medicine literature to date despite the widespread use of this drug. They further argue that the liberal use of cardiac monitoring and continuous pulse oximetry functions to minimize threats to patient safety by continuous monitoring for this complication. In addition, the authors assert that emergency physicians possess the knowledge and skill set necessary to intervene in the event of respiratory depression or arrest.
Oversedation is a complication associated with the use of propofol for procedural sedation. The Joint Commission has recognized that oversedation may at times arise during deep sedation. The commission requires that practitioners be qualified to recognize complications, monitor the patient appropriately during the procedure and be capable of managing any complications. Not only are emergency physicians well versed in rescue techniques, but propofol's ultra-short duration of action renders resuscitative efforts extremely brief and unlikely. The brief effect of this sedative makes the fact that there is no reversal agent a non-issue. In the time that it would take to procure and circulate a reversal agent, the effects of propofol would have worn off.
Greene and colleagues also address the terminology surrounding the use of propofol and with whom the authority to restrict the use of the drug resides. The American Society for Anesthesiologists (ASA) has issued guidelines about the administration of sedation by non-anesthesiology trained professionals. The guidelines distinguish between anesthesiologists and "nonanesthesiologists." Greene et al argue that the distinction is an oversimplification and incorrectly implies that anesthesiologists are the only group of physicians who possess adequate sedation skills. Furthermore, ASA guidelines fail to address the unique sedation and procedural skills of an ED physician that has been subspecialty trained. ED physicians are trained in selection of agents, monitoring during sedation and highly skilled to manage adverse events that may occur.
While The Joint Commission is specific about provider qualifications, patient monitoring, and the ability to effectively address complications, The Joint Commission nevertheless introduces a fair amount of flexibility into their guidelines. Hospital-appointed committees typically make policies about sedation procedures and are usually composed of intensivists, emergency physicians, anesthesiologists, and other professionals involved in administering sedation. Ultimately, the decision of who can administer deep sedation lies with these committees and hospital administrations. Hospitals are therefore encouraged to craft policies that incorporate the specifics of local needs, resources, safety, and specialist availability.
Commentary
This article by Green and colleagues delves into the core issues regarding the use of propofol in the ED. The authors explore and discuss through an evidence based approach the drug's side effects and effective strategies to minimize risks associated with utilization in the ED. The authors refute the indiscriminate delineation of "nonanesthesiologists" as providers unable to successfully and safely use propofol in the ED, and emphasize the unique skills and knowledge which qualify emergency physicians to provide this service in the ED. The controversy regarding deep sedation is explored including what are appropriate skill requirements for providers, the appropriate monitoring and environment for utilization of this procedure. A 2006 ASA position statement recommended that deep sedation only be administered by those who are qualified to administer general anesthesia. It is important to understand the reasoning behind these policy statements and to find ways to dissolve these barriers.
Fortunately, many anesthesiologists actively collaborate with emergency physicians to produce appropriate protocols that have patient safety at their core. The policies focus on medication selection, potential adverse events, the safety profile of the patient and agent selected, monitoring during the procedure and the ability of the provider to manage any complications or adverse events. Any time a procedure or technique that has been utilized within one specialty is expanded to a larger role within the field of medicine, controversy will result (such as the use of bedside ultrasound). Issues include lost revenue, which was discussed at the ASA Practice Management Conference in January 2007. At this conference, the ASA president stated that one of the largest problems facing the anesthesiology field was other practitioners using sedation techniques. In describing his concern, he used the phrase "poachers and dabblers" to imply that other physicians were performing aspects of anesthesiology and therefore competing for the financial benefits. "ER MDs" were amongst the groups that were listed as other physicians intruding on their field.3
ED physicians need to educate other specialties regarding the ED's unique practice environment and specific specialty training. Airway management, resuscitation, and procedural sedation have long been core competencies within emergency medicine. Patients that present to the ED require and deserve effective pain management even when the procedure must be done immediately to preserve life or limb. ED patients may be critically ill and present to the ED with a full stomach. Anesthesia requirements for elective procedures may not be achieved in the ED population, and therefore, ED physicians must conduct research within the ED environment to identify what agents are optimal to utilize. Other conditions such as cutaneous abscesses and orthopedic procedures present with regularity throughout the shift and require a short-acting agent to facilitate performance of a painful procedure. ED physicians must be skilled at providing this service because it is simply unreasonable to assume that an anesthesiology specialist would be readily available in a timely enough fashion.
So what must emergency physicians do to ensure the ability to use effective drugs such as propofol? They must take a proactive stance by becoming members of their hospital's sedation committees and continuing to express interest in the articulation of cutting edge, evidence-based sedation protocols, emphasizing trials conducted within the realm of emergency medicine. A sizeable body of evidence suggests that the use of propofol in the ED is safe and highly effective. Sharing scientific evidence with hospital committees and other subspecialists allows the opportunity to discuss the role of a variety of agents and the provision of safe and effective sedation and pain control in the ED.
Is Propofol Really Safe for Use in ED Procedural Sedation?
Source: Burton JH, et al. Propofol for emergency department procedural sedation and analgesia: A tale of three centers. Acad Emergy Med 2006;13:24-30.
Until recently, the majority of studies aimed at proving the efficacy and safety of propofol for sedation purposes in EDs have involved small sample sizes. The lack of larger studies created an atmosphere of persistent doubt and concern surrounding propofol's use. This is one of the reasons that Burton and colleagues performed a large study that pooled patients from three busy trauma centers. The study quantified the frequency of adverse events during the administration of propofol for PSA. Burton et al focused on the incidence of respiratory depression and failure.
This study was a prospective, descriptive series that involved the consecutive sampling of ED patients who received propofol for PSA. In total, 792 patients were included in the series. Patients underwent either dislocation and fracture reductions, abscess incision and drainage, cardioversion, CT imaging, or tube thoracostomy. While the individual practices of monitoring and sedation were not standardized among the three facilities, each individual hospital followed consistent monitoring protocols in accordance with existing institutional policy. Dosing guidelines included a 1 mg/kg initial bolus of propofol, followed by 0.5 mg/kg boluses as needed. These doses were open to adjustment as determined by the administering physician. Use of intravenous (IV) analgesia was also encouraged, especially for painful procedures, but was not regulated. During PSA, patients were continuously monitored for blood pressure, heart rate, and oxygen saturation changes.
Sixty-one patients (7.7%) had respiratory events in which oxygen saturation levels dropped below 90%. Of these patients, 3.9% required brief intervention with bag-mask ventilation. Twenty-eight patients (3.5%) had episodes of hypotension described as a systolic blood pressure less than 100 mmHg or requiring administration of IV fluids. Bradycardia, defined as a decrease in heart rate from baseline to less than 60 beats per minute or a decrease in heart rate leading to clinical intervention, was witnessed in three patients. All of these events resolved with supportive measures only. No patients required endotracheal intubation, observation out of the expected period of time, or hospital admission.
Respiratory incidents, for which brief supportive measures were curative, were the most common PSA related events associated with the use of propofol. This was consistent across all three research sites. The majority of other propofol related PSA events resolved with minimal supportive measures and without sequelae.
Commentary
This study filled a persistent void regarding the safety of propofol use in the ED. Prior to this study, several publications described positive results with ED-administered propofol. However, concern persisted due to small sample sizes. This series involved approximately 800 patients, reproduced positive results, and gave further credibility to the drug's safety profile.
Particularly important results from this study were that of the 7.7% of patients with respiratory events, all resolved with either stimulation, repositioning of the airway, increased oxygen delivery, or bag mask assisted ventilation. Each of these actions is part of standard training for the emergency physician. The few patients with episodes of hypotension improved after simple observation or administration of IV fluids. The bradycardic patients required no interventions or changes in their management. It was also noted that there was no statistically significant association between the amount of propofol given and the occurrence of respiratory events. Although the events did seem to happen more frequently to patients of increased age (mean age of 51 vs 40 years) and to those with increased weight (81 kg vs 74 kg).
It is important to mention that there was no standardized method for performing PSA or documenting the data for the PSA across the three sites. However, each individual site did have its own standardized protocols. While not ideal for study design, the lack of standardization emulates clinical practice in allowing for variation to meet particular patient. hospital, and community needs.
Propofol Versus Etomidate: Can Propofol Compete?
Source: Miner JR, et al. Randomized Clinical Trial of etomidate versus propofol for procedural sedation in the emergency department. Ann Emerg Med 2007;49:15-22.
Both etomidate and propofol are commonly implemented in procedural sedation protocols. The ultra short onset of action and quick recovery time makes these drugs popular in today's practice environment of ever-increasing patient volume. This study was the first conducted to compare the efficacy, adverse events, and recovery times of these two sedatives.
This prospective, randomized, nonblinded, clinical trial studied a total of 214 patients receiving procedural sedation over a 15-month period at an urban county medical center. One-hundred-five (105) patients were included in the etomidate arm of the study and 109 patients received propofol. Patients receiving etomidate were bolused at 0.1 mg/kg followed by subsequent boluses of 0.05 mg/kg every 3-5 minutes as needed. The patients receiving propofol received 1 mg/kg initial boluses followed by 0.5 mg/kg boluses every three minutes as required.
Respiratory events were measured both subclinically and clinically. Subclinical respiratory depression was defined as oxygen saturation levels less than 92%, an end-tidal CO2 (ETCO2) change from baseline of greater than 10 mmHg, or airway obstruction as evidenced by an absent ETCO2 waveform. Clinical respiratory events were considered to be those requiring adjustment of supplemental oxygen, use of a bag mask ventilation system, airway repositioning, or patient stimulation to encourage breathing. Special attention was also paid to presence of hypotension, cardiac rhythm abnormalities, and myoclonus.
Subclinical respiratory events occurred in 36 (34%) of the etomidate patients compared with 46 (42%) of the propofol patients. Clinical respiratory events led to 6.7% of the etomidate group requiring an increase in supplemental oxygen vs 5.5% of the propofol group, while subclinical events led to 3.8% of the etomidate patients needing bag-mask assistance vs 4.6% of the propofol patients. Other clinical respiratory events as described above were similar between the two groups.
Systolic blood pressures dropped below 100 mmHg for four patients who had received propofol and one patient who had received etomidate. None had negative sequelae as a result. There were no documented cardiac arrhythmias in either group. Myoclonus was noticed to be more present in the etomidate group (20% vs 1.8%). Finally, successful completion of the procedure being performed was more common in the propofol group (97% vs 89%).
The authors concluded that both drugs were equally safe for procedural sedation in an ED setting, but that etomidate had a lower success rate and induced more myoclonus than propofol.
Commentary
Studies across different medical specialties have compared the efficacy and safety of propofol with other sedatives commonly used for procedural sedation. Propofol use has been tested against midazolam and meperidine in the setting of nurse administration for endoscopic ultrasound. Evidence from these studies reveals similar adverse event rates and quicker induction and recovery rates for propofol. Furthermore, propofol's use has been associated with improved patient comfort and satisfaction.4 That being said, this study by Miner and colleagues is unique in that it was the first to compare the two short-acting sedatives etomidate and propofol. The results not only revealed similar rates of adverse events without negative sequelae, but reported more favorable procedural success rates with propofol. While the rate of myoclonus was higher among all patients with unsuccessful procedures, there was a higher incidence of myoclonus seen with the administration of etomidate.
Though the occurrence of respiratory depression and hypotension did not lead to clinically significant adverse events, it is important to recognize that proper patient selection prior to the administration of propofol is critical. More profound decreases in blood pressure have been documented in older patients and in the critically ill.5,6
One particular strength of this study was the inclusion of ETCO2 monitoring. Traditionally, respiratory monitoring has been performed with oxygen saturation monitors and clinical observation for signs of bradypnea and decreased respiratory drive. However, with the addition of capnography the physician is able to follow changes over time of the breath-to-breath variation in ventilatory status. This is accomplished by the display of the CO2 measured at the airway in number format and by the changes in the gas during the respiratory cycle via waveform.7 Use of this tool may assist in earlier detection of respiratory depression and airway compromise.
ETCO2 Monitoring: A New Safety Paradigm?
Source: Burton JH, et al. Does end-tidal carbon dioxide monitoring detect respiratory events prior to current sedation monitoring practices? Acad Emerg Med 2006;13:500-504.
Practice guidelines for ed procedural sedation currently recommend that patients be assessed with continuous oxygenation and cardiac monitoring. While this has long been accepted as adequate, the use of capnography as an adjunct to alert the physician to respiratory decompensation or compromise earlier than the more traditional methods of pulse oximetry and clinical observation has been considered. If this is true, then it would stand to reason that capnography would be a beneficial addition to current practices. ETCO2 has been used by anesthesiologists for more than 35 years for the monitoring of their patients in the operating room.7 The authors of this study delved into this topic and attempted to determine if ETCO2 monitoring during PSA would detect respiratory events prior to pulse oximetry.
Burton and colleagues organized this prospective observational case series of ED patients undergoing PSA at an institution that typically performed 250 PSA interventions per year. Analgesic and sedative medications were chosen at the physician's discretion. Monitoring parameters included continuous heart rate, cardiac rhythm, respiratory rate, blood pressure, and oxygen saturation. This study also implemented a coordinator dedicated to assuring the quality of the pulse oximetry and ETCO2 monitor. The clinical physicians were blinded to the findings reported via ETCO2 throughout the procedures. One requirement by the study center's institutional review board (IRB) was for an interim safety analysis to occur after each 30-patient enrollment period.
Results of the study were so impressive that the initial trial was halted to permit the use of ETCO2 monitoring in a nonblinded fashion for all patients. Abnormal ETCO2 results were found in 36 (60%) of the encounters. Twenty of these events developed into what the authors described as acute respiratory events in which there was a change in ETCO2 level of at least 10 mmHg from the patient's presedation baseline and an intrasedation ETCO2 level less than 30 mmHg or greater than 50 mmHg. The majority of these patients (17) had ETCO2 levels that indicated periods of hypoventilation or apnea during the procedures. Fourteen of the patients who had acute respiratory events demonstrated abnormal ETCO2 levels before changes were noted in pulse oximetry or before there was clinical evidence of hypoventilation. Finally, none of these patients required intubation. All events were corrected with either an increase in oxygen delivered, airway repositioning, stimulation, bag mask ventilation, or a combination of these.
Commentary
ETCO2 monitoring has long been believed to be the earliest mode of detecting airway compromise. However, its use has not been fully incorporated into ED PSA, as there has been a lack of evidence demonstrating its ability to increase detection of acute respiratory events. A temporal relationship between change in oxygen saturation levels and the ETCO2 was demonstrated in this study. In fact, during the acute respiratory events of this study, the blinded abnormal ETCO2 levels were present up to four minutes before recognition of the event. The IRB at this institution was so impressed with these results that it ended the study prematurely and recommended the unblinded use of ETCO2 monitoring.
It is important to recognize that there were several other patients involved in this study that had transient changes in their end-tidal values that were not associated with clinical events. Also, the authors comment on the fact that the rate of acute respiratory events was substantially higher than they had anticipated. It is possible that a sampling bias occurred and that a large number of patients enrolled in this study required deeper sedation or were at higher risk for an acute respiratory event at baseline.
While the information gained from this study does suggest a benefit to this modality, several important questions remain. First, it would be valuable to know if ETCO2 monitoring would reduce the number of respiratory events in PSA, and therefore lead to a reduction in the number of airway interventions. If continuous monitoring revealed an early change in ETCO2, then it would hopefully signal the physician to act sooner to avoid airway compromise. Another potential area of interest is assessing the significance of ETCO2 increases that are not associated with hypoxemia. Finally, it is not known what range of ETCO2 values is reliably associated with airway compromise during PSA.7 Introducing ETCO2 monitoring to ED PSA protocol may increase patient safety through the early detection of hypoventilation. However, more research is needed to answer questions about the clinical significance of hypercapnia documented during routine ED procedural sedation.
Ketofol: The Best of Both Worlds
Source: Willman EV, et al. A prospective evaluation of "Ketofol" (Ketamine/Propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;49:23-30.
Although few emergency physicians would argue with propofol's safety profile, concerns associated with the drug's use nevertheless remain. Events such as hypotension and respiratory depression have been associated with propofol administration at doses utilized for procedural sedation. Furthermore, propofol lacks analgesic properties. Ketamine, a dissociative sedative, provides both amnestic and analgesic qualities, while causing little to no cardiovascular or respiratory effects. This agent has not been popular for adult PSA given its potential for emergence phenomena and concerns about laryngospasm. The authors of this study recognized that these drugs had been used in combination in multiple settings with good results, likely because of the opposing cardiovascular and respiratory effects. Their goal was to combine the two agents into a single agent ("Ketofol") and evaluate its effectiveness and safety for PSA. This was the first such published study of this drug combination for that purpose.
Willman and colleagues organized this prospective case series in a community hospital ED that saw trauma patients over an eight-month period and enrolled 114 patients of all ages. The majority of procedures were orthopedic in nature. The ketofol was prepared as a 1:1 mixture of ketamine and propofol, both in 10 mg/ml doses. The dosing and depth of sedation were intentionally not standardized to emulate real life situations in the ED. The drug was administered in 1-3 mL aliquots to the desired effect. The median dose administered was 0.75 mg/kg of both components.
All but four of the procedures in this series were completed without additional doses of propofol. One procedure was not successful secondary to muscular rigidity despite additional doses of both medications. None of the patients became hypotensive during the sedation event. Three patients (2.6%) required simple airway adjustments. Three patients became hypoxic (as low as 86%) and one of these (0.9%) required bag mask ventilation for two minutes. One patient developed an emergence reaction consisting of agitation. The patient was treated with midazolam and had complete resolution of symptoms. No patients required endotracheal intubation, and all were discharged from the ED with a median recovery time of 15 minutes. The authors concluded that the ketofol combination was easy to use and effective in PSA.
Commentary
The use of propofol and ketamine together as a single agent for PSA is an interesting combination that theoretically should provide a safer procedure than either agent alone. The use of ketamine allows for lower doses of propofol, which should limit hypotension and respiratory effects. The use of propofol in the mixture allows for lower doses of ketamine, decreasing the occurrence of emergence phenomena and emesis. This study's results corroborated the theory of safety in combination. No episodes of hypotension, bradycardia, laryngospasm, or vomiting occurred. There were also no negative sequlae from the adverse events that did occur. A second objective of the study was to determine staff and patient satisfaction regarding the procedure. Results of this aspect of the study were also favorable, with the median satisfaction scores for physicians, nurses, and patients being equivalent to a rating of completely satisfied.
Despite the positive results, the study's sample size was quite small. Conclusive data about ketofol's safety and side effect profile is therefore lacking. Also, the fact that ketofol was not directly compared to other sedative drugs in a blinded manner precludes commentary about its superiority over other agents. Physicians in this study used their own discretion in deciding which patients received the study drug. This practice, though reflecting current standards of care, may have introduced an element of selection bias into the study's results.
However, this study's strengths were difficult to ignore. A particularly strong aspect was the fact that patients of all ages from 1 month to older than 80 years were included in the study. There were 25 patients younger than 16 years of age, and 23 older than age 60. Also, patients with comorbid conditions were not excluded. In fact, the only people excluded were those with documented allergies to the agents or their components.
While ketofol appears to be a favorable sedation choice, more studies should be conducted.
To establish the safety and efficacy of ketofol, larger sample sizes are needed. Furthermore, it is imperative to directly compare ketofol with other agents more commonly used for ED PSA.
Conclusion
In spite of mounting evidence testifying to the safety and efficacy of propofol, challenges to its widespread use remain. A thorough understanding of these difficulties promotes debate that is at once informed and focused on patient interest. Emergency physicians may choose to include propofol in their procedural sedation armamentarium because it has the advantage of being an ultra-short-acting sedation agent with an excellent safety profile. Early recognition and identification of respiratory events allows early intervention and enhances the safety of propofol use. Advances in technology improve our ability to monitor patients undergoing procedural sedation. Cardiac monitoring, pulse oximetry, and ETCO2 monitoring improve the ED safety. Rigorous patient surveillance coupled with the ability to provide patients with rapid and definitive airway management solidify the ED's place as an ideal location for the administration of procedural sedation. The use of a rapid-acting, safe, and effective sedation agent like propofol enhances the ability of the ED physician to successfully and safely complete procedures and enhance patient outcomes.
References
1. AAEM Policy Statement: Procedural Consensus Consensus Statement 2008. Accessed online at: http://www.aaem.org/positionstatements/procedural_sedation.pdf on 02/05/09.
2. Maryland Board of Nursing: Declaratory Ruling 2002-2: Re: Registered nurse administration of procedural sedation for operative, invasive, and diagnostic procedures for episodic treatments or therapies for the adult and pediatric patient, (e.g. intravenous, intramuscular, inhalation, oral, rectal, and intranasal. 2002. Accessed online at: http://www.mbon.org/main.php/disc/volunteer/main.php?v=norm&p=0&c=practice/advisory/2002-2.html on 02/05/09.
3. Flynn G. "Poachers and Dabblers?": ASA president's incautious comment riles emergency physicians. Ann Emerg Med 2007; 50:264-267.
4. DeWitt J, et al. Nurse-administered propofol sedation compared with midazolam and meperidine for EUS: a prospective, randomized trial. Gastrointest Endosc 2008;68:499-509.
5. Burton JH, et al. Propofol for emergency department procedural sedation and analgesia: A tale of three centers. Acad Emerg Med 2006;13:24-30.
6. Miner JR, et al. Procedural sedation of critically ill patients in the emergency department. Acad Emerg Med 2005;12:124-128.
7. Krauss B, et al. Capnography for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;50:172-181.