PROCEDURAL SEDATION is the technique of sedative or dissociative agent administration with or without analgesics that increases patients' tolerance of unpleasant or painful procedures (Jalili et al., 2016; Lameijer et al., 2017; "Procedural Sedation in the Emergency Department," 2017). In the emergency department (ED), some of these procedures may include joint dislocation reduction, fracture reduction, abscess incision and drainage, and direct cardioversion (Black, Campbell, Magee, & Zed, 2013; Lameijer et al., 2017). Procedural sedation is an important technique performed in the ED setting because it decreases the length of procedure time and increases the likelihood of success, while reducing injury risk to both the patient and health care providers from uncontrolled movements (Aminiahidashti et al., 2018; "Procedural Sedation in the Emergency Department," 2017).
Several agents may be utilized for this purpose, but they should be tailored to the patient's anticipated analgesic and sedation needs, as well as weighing the potential risks and benefits. As such, there is no universally recommended agent, or a combination of agents, for every procedural sedation; however, propofol is a commonly used agent in this setting (Lamperti, 2015; "Practice Guidelines for Moderate Procedural Sedation and Analgesia," 2018). Propofol is a sedative hypnotic agent with a rapid onset and short duration of action, making it an ideal drug for procedural sedation in the ED (Lameijer et al., 2017; Patanwala et al., 2013). Although it is commonly used in EDs for procedural sedation, factors affecting dosing requirements among patients are not well understood and it is theorized that dosing requirements may differ on the basis of patient-specific factors. Some authors have concluded that elderly patients may require lower induction and maintenance doses for procedural sedation in the ED than their younger counterparts when divided into various age cohorts (Patanwala et al., 2013). Other patient-specific factors that may affect both induction and total propofol dosing for procedural sedation in the ED have not been studied in detail.
Although propofol is a preferred procedural sedation agent and has been shown to be safe, it does not come without risks (Godwin et al., 2014). Patients who receive propofol alone rather than in combination with other sedative agents may be more likely to develop hypotension and apnea (Aminiahidashti et al., 2018; Bellolio et al., 2016; Ferguson et al., 2016; Krauss, Andolfatto, Krauss, Mieloszyk, & Monuteaux, 2016). There is an unclear association between patient-specific factors, propofol doses, and the incidence of adverse effects in the literature. The primary objective of this analysis was to determine the effect that age has on the total propofol dose required during procedural sedation in the ED.
METHODS
Study Design
This was a retrospective, single-center cohort study of adult (18 years or older) patients who received propofol for procedural sedation in the ED between January 1, 2015, and August 31, 2017. This study was approved by the study site's institutional review board. Patients were grouped on the basis of age 18-64 years and 65 years or older. The total and weight-based propofol dose requirements for procedural sedation, opioid requirements, and adverse events were compared between groups.
Study Setting and Population
The study site was a 700-bed academic teaching hospital ED with approximately 70,000 visits per year. The electronic medical record was utilized to identify patients who received propofol for procedural sedation in the ED. There was no standard dosing protocol for propofol, leaving dosing to the discretion of the provider. Patients were excluded if they were incarcerated, pregnant, or received any sedatives other than propofol either before or during the procedural sedation.
Study Protocol and Measurements
Data were extracted from the medical record by study authors to identify and review patients for study enrollment. Data abstraction was conducted following a collaborative review of an initial sample. Monthly meetings and random patient sample reviews were conducted to ensure adequate abstractor monitoring. Study data were collected and managed using REDCap (Research Electronic Data Capture). REDCap access was supported by the South Carolina Clinical & Translational Research Institute, with an academic home at the Medical University of South Carolina, through NIH-NCATS Grant No. UL1 TR001450 (Harris et al., 2009). Data collected included demographic information, illicit drug use disorders, alcohol use disorder, history of renal or hepatic dysfunction, baseline Aldrete score, procedure type and duration, propofol induction dose, number of propofol doses, total procedural propofol dose, opioid dose up to 4 hr prior to procedural sedation (in intravenous morphine equivalents), opioid dose used during procedure (in intravenous morphine equivalents), and pain score immediately prior to the procedure. The Aldrete score is a score ranging from 0 to 10 based on activity, respiration, circulation, level of consciousness, and color. A score of 0 reflects a patient who is unable to move and is cyanotic, and a score of 10 reflects a patient who is fully awake and able to move all extremities. Serum creatinine, liver function tests, and blood ethanol concentration at presentation to the ED were also collected. Intubation requirements, vomiting, and vitals at baseline and throughout the procedure were recorded to determine the incidence of adverse events. A systolic blood pressure of less than 90 mmHg or a 25% or more decrease from baseline indicated hypotension. Bradycardia was defined as a heart rate of less than 60 beats per minute. A respiratory rate of less than 12 breaths per minute, end-tidal carbon dioxide (ETCO2) of less than 30 mmHg, or ETCO2 of more than 50 mmHg indicated hypoventilation, whereas more than 20 breaths per minute suggested hyperventilation. Hypoxia was defined by an oxygen saturation of less than 90%. The primary outcome of this study was to evaluate differences between propofol doses required for procedural sedation in the ED for patients 18-64 years of age and those 65 years or older. Secondary outcomes included an evaluation of adverse events between the two groups, as well as the potential influence of additional patient-specific factors such as a history of substance use disorder (i.e., alcohol or illicit drugs) and a total body weight of 100 kg or more.
Data Analysis
Descriptive statistics were used to describe demographic data. Nominal and continuous data were analyzed using the chi-square or Fisher's exact test and Student's t test, respectively. Significance was defined as an [alpha] = 0.05 and a [beta] = 0.2. All data analysis was conducted using GraphPad Prism Version 8.0.0 for Windows (GraphPad Software, San Diego, CA).
RESULTS
A total of 152 procedural sedations were screened for study inclusion. Of these, 51 were excluded, with the primary reason being the administration of another sedative (see Figure 1). The remaining 101 procedural sedations were included in the final analysis. Patients were categorized on the basis of age of 18-64 years (n = 82) or 65 years or older (n =19). Baseline characteristics were similar between the two groups, with statistically significant differences noted with regard to age and baseline Aldrete score (see Table 1). The most common procedure type among all groups was joint reduction, accounting for a total of 86.1% of procedures overall.
No significant difference was found with regard to opioid requirements prior to, or during, the procedure between the two groups, although pain scores were significantly higher in the younger patient group (see Table 2). Patients 65 years or older were noted to receive significantly fewer propofol doses (2 vs. 4; p = 0.043) and require a significantly lower total weight-based propofol dose (0.9 vs. 1.6 mg/kg; p = 0.024) than younger patients.
No significant differences were found in the occurrence of adverse effects between the two age groups (see Table 3). Two patients experienced hypotension and 12 (11.9%) were documented to have bradycardia. A total of 21 (20.7%) patients experienced a respiratory rate less than 12 breaths per minute, and there were 45 patients (44.6%) who had a recorded ETCO2 of less than 30 mmHg; however, only one patient was intubated.
In the secondary analysis to assess for the influence of other suggested patient-specific factors that may influence propofol requirements, patients with a documented history of substance abuse disorder were compared with those who did not have a history of substance abuse disorder and no significant difference was found with regard to the total weight-based propofol dose required (1.8 vs. 1.4 mg/kg, respectively; p = 0.913). Furthermore, patients with a total body weight of less than 100 kg were compared with those weighing 100 kg or more, and no significant difference was found in the total weight-based propofol dose required (1.5 vs. 1.1 mg/kg, respectively; p = 0.929).
DISCUSSION
In this analysis of 101 procedural sedations utilizing propofol alone, patients who were 65 years or older were found to require a significantly lower total dose of propofol and require fewer repeat doses of propofol during the procedure than patients 18-64 years of age. There was no significant difference in opioid requirements before or during the procedure, the duration of the procedure, or the induction propofol dose among the groups. There was also no significant difference found in the incidence of adverse effects between the two groups. Further analysis was done to assess if there was a significant impact on weight-based propofol requirements for a patient with a history of substance abuse disorder or a total body weight of 100 kg or more; neither was found to be significant.
In a review of 13 randomized controlled trials and 20 observational studies evaluating propofol use in adults undergoing procedural sedation in the ED, total doses of propofol ranged from 0.75 to 1.86 mg/kg, with the most common dosing regimen being a 1-mg/kg bolus, followed by 0.5 mg/kg as needed for additional sedation (Black et al., 2013). The authors also noted that most of the studies were conducted in a young, healthy population and excluded patients who were intoxicated. The 2018 update of the Clinical Practice Guideline for Emergency Department Procedural Sedation with Propofol provides a wealth of guidance on the use of this agent for this indication (Miller, Andolfatto, Miner, Burton, & Krauss, 2019). For adults, the authors suggest an initial bolus dose of 0.5-1 mg/kg, with additional boluses of 0.25-0.5 mg/kg every 1-3 min as necessary. Regarding special populations, the authors suggest that obese patients require a lower total body weight dosing and that dosing should be based on lean body mass; however, what constitutes "obesity" is not defined. The authors also suggest that lower starting doses, defined as 0.5 mg/kg, should be utilized in elderly patients. However, the actual age of what constitutes an "elderly" patient is not provided. Furthermore, there is no guidance provided regarding dosing adjustments that may be needed in patients who have a history of substance use disorder, or long-term use, of medications that may affect the efficacy of concomitant analgesics and sedatives, such as propofol.
Procedural sedation in the ED does not come without associated risks. Fortunately, serious adverse events appear to be rare, with the most common adverse event being hypoxia occurring with an incidence of 40.2 per 1,000 sedations and hypotension occurring 15.2 times per 1,000 sedations (Bellolio et al., 2016). Although the noted incidence of these risks may not be uniformly distributed across all patient populations. Homfray, Palmer, Grimsmo-Powney, Appelboam, and Lloyd (2018) analyzed prospectively collected data on 740 elderly patients (older than 75 years) undergoing procedural sedation, 571 of whom received propofol. They identified a 2.6% sentinel adverse event rate and concluded that elderly patients are more susceptible to the adverse effects of all sedative drugs. They also recommended the use of 0.5 mg/kg initial propofol boluses, followed by subsequent 0.25-mg/kg boluses. One study prospectively reviewed 312 patients undergoing procedural sedation to identify predictors for apnea and the need for clinical intervention (Krauss et al., 2016). That study found that increasing age predicted both apnea and clinical intervention. Another study looked at 1,008 consecutive procedural sedations in the ED using propofol and found a sentinel adverse event rate of 1% and concluded that a 0.5-mg/kg dose should be utilized in elderly patients to minimize these adverse effects (Newstead et al., 2013). Unfortunately, none of these investigations actually compared the dosing between age groups; they only noted the adverse event profile and then made a recommendation to use the lower end of the dosing range to minimize side effects.
There are multiple physiological alterations that occur with age that have the potential to influence the pharmacokinetics and pharmacodynamics of anesthetic agents such as propofol (Ekstein, Gavish, Ezri, & Weinbroum, 2008). These can include a reduced ability to compensate for hypovolemia, hypoxia, and hypercarbia, in addition to decreased peripheral vascular resistance and altered mental status. One analysis in 24 healthy volunteers did suggest that those older than 65 years may be more sensitive to the hypnotic effects of propofol following a bolus dose, with a loss of consciousness at a serum concentration approximately half that of their younger colleagues (Schnider et al., 1999). The pharmacokinetic alterations of propofol metabolism with age have also been shown in 12 healthy volunteers to result in a significantly lower rate of propofol clearance and a lower volume in the central compartment in those aged 65-80 years when than in those aged 18-35 years (Kirkpatrick, Cockshott, Douglas, & Nimmo, 1988). However, once propofol reached equilibrium in these patients, there was no difference noted in the volume of distribution, half-life, or elimination. These pharmacokinetic changes in propofol clearance may explain our study results regarding the significant difference in the median total dose of propofol and the median number of propofol doses administered between the two groups.
One other investigation has explored the effect of age on the clinical use of propofol for procedural sedation. Patanwala et al. (2013) looked at three different age groups receiving propofol for procedural sedation to ascertain whether there was an effect of patient age on the propofol dose required. They found that patients 65 years or older required significantly less propofol (mg/kg) for induction and the entire procedure than their younger comparators. They concluded that elderly patients may require lower induction and total doses of propofol. To our knowledge, this is the only other investigation that has objectively compared propofol requirements in procedural sedation across different age groups. Although our results are consistent with their findings regarding the total dose of propofol required, they do differ in that we did not identify a significant difference in the induction dose utilized.
Interestingly, Patanwala et al. (2013) also found that increased presedation opioid use was a positive predictor of increased propofol requirements. Although this could be indicative of poor pain control, they found no difference in pain scores between the groups and these scores were not predictive of propofol requirements. The authors did not document an assessment of substance use disorders in their study population, but one alternative explanation for this finding may be that higher opioid use requirements presedation were reflective of those with opioid-induced hyperalgesia (OIH). Patients treated with long-term opioid therapy may experience worsening pain sensitivity with injury or have a lower threshold for pain than that at baseline, often referred to as OIH (Tompkins & Campbell, 2011). The pathophysiology and molecular mechanism for the development of OIH are not well understood; however, neural plasticity in the nervous system is theorized to cause changes in the opioid mu receptor, glutamate receptors, and other excitatory receptors in the inhibitory pathway (Tompkins & Campbell, 2011). Propofol does not have analgesic properties, but it does reduce responsiveness to external stimuli (Aminiahidashti et al., 2018; Chidambaran, Costandi, & D'Mello, 2015; Ferguson et al., 2016). Long-term opioid therapy may increase a patient's need for higher total propofol doses in order to blunt the sympathetic stimulatory effects of painful external stimuli due to their hyperalgesic state. In addition, both propofol and alcohol exert their sedative action by binding to and activating the central inhibitory [gamma]-aminobutyric acid A (GABA) receptor (Chidambaran et al., 2015). Long-term alcohol use results in an imbalance between GABA and glutamate, the primary excitatory neurotransmitter. Compensation occurs with an upregulation of GABA receptors in an attempt to restore equilibrium and homeostasis (Liang & Olsen, 2014). The potential for upregulation of GABA receptors in patients with a history of alcohol use disorder may necessitate higher propofol doses to provide adequate sedation for procedures. In our analysis, we found no significant difference in propofol requirements between those who had a history of substance abuse disorder and those who without a history of substance abuse disorder; however, this is an area that warrants further investigation.
Another patient-specific factor that may alter propofol requirements is obesity. As noted, the current guidelines note that obese individuals may have lower total propofol requirements than nonobese individuals (Miller et al., 2019). In one study looking at 1976 pediatric patients ranging in age from 2 to 21 years, they found that those patients who were overweight and those who were obese used significantly less propofol than those who were of a normal weight (Rogerson, Abulebda, & Hobson, 2017). Furthermore, those who were underweight had a significantly higher proportion of adverse events than those who were of a normal weight. The authors' protocol was to give an initial 1-2 mg/kg propofol bolus at the start of the procedure and a subsequent 0.5-1 mg/kg dose as needed. We compared patients with a total body weight of 100 kg or more with those who had a weight of less than 100 kg and found no significant difference in the total propofol requirements; however, this is also an area that needs to be explored further to minimize potential medication side effects.
Although the focus of our investigation was into the effect that age may have on propofol requirements in the setting of procedural sedation, this is but one factor among a constellation of patient-specific factors that may impact the use of propofol in this setting, many of which have yet to be elucidated. The very characteristics of propofol that makes it ideal in this setting such as a rapid onset and short duration of action have the potential to make it harmful when the initial dose is too large and the frequency of administration is too often. Many of the pharmacokinetic and pharmacodynamic alterations that occur with age discussed here are also not limited to propofol; they are also true of benzodiazepines as well, another common agent used in this setting (Ekstein et al., 2008). To ensure safe and effective sedation during procedures, it is important for practitioners to individualize the dose of each agent utilized to the extent possible, ensure adequate and real-time monitoring of the level of sedation and side effects, adjust subsequent dosing based on that monitoring, and be prepared to manage those side effects should they occur.
LIMITATIONS
The study was limited because of the reliance on accurate chart documentation. This study also relied on accurate documentation for the procedural sedation and for patient-specific characteristics, such as weight. There was also no standard dosing protocol for propofol, leaving dosing to the discretion of the provider. However, this is an accurate reflection of real-world practice and doses of propofol would have been tailored to the sedation needs of the individual patient, allowing for a more accurate reflection of their true propofol dose requirements.
CONCLUSION
Patients older than 65 years required significantly less propofol for procedural sedation in the ED than younger patients. They also required significantly fewer repeat doses of propofol for the duration of the procedure despite a nonsignificant difference in the duration of procedure or types of procedures between the two groups. No differences in adverse effects were noted between the two groups. Future studies should continue to explore patient-specific factors, in addition to age, that may contribute to increased or reduced propofol requirements to limit the incidence of sentinel events.
REFERENCES