Journal of Bronchology:
An Update on Sedation and Analgesia During Flexible Bronchoscopy
Vincent, Brad D. MD; Silvestri, Gerard A. MD, FCCP
Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC
There is no conflict of interest.
Reprints: Gerard A. Silvestri, MD, FCCP, Medical University of South Carolina, Charleston, SC (e-mail: firstname.lastname@example.org).
Received for publication April 11, 2007; accepted May 7, 2007
Sedation during bronchoscopy is commonly used to facilitate patient comfort such that the procedure provides diagnostic or therapeutic results without interruption. An ideal sedative agent should have analgesic and amnestic properties and a favorable pharmacokinetic profile (eg, rapid onset, short duration of action, quick recovery) and minimal hemodynamic effects. The currently available agents (benzodiazepines, opioids, propofol) have some, but not all, of these properties. Midazolam, the most frequently used sedative, is highly lipid soluble, rapidly distributes across the central nervous system, and provides rapid onset of action and recovery. Opioids (eg, fentanyl, meperidine) are potent analgesic and sedative agents and have the added benefit of an antitussive effect. Propofol is also an effective sedative agent with amnestic and analgesic properties and a favorable pharmacokinetic profile but there is less experience with this drug in the outpatient setting. Sedative combinations are often used to produce synergistic effects. Although sedation is generally safe during bronchoscopy, all sedative regimens produce some cardiopulmonary depressant effects. This is particularly true for combination regimens. Careful monitoring of all patients is important to ensure a safe outcome. Here, we review pharmacologic sedation in the bronchoscopy laboratory and explore new agents which may become available in the future.
Flexible bronchoscopy is a commonly performed procedure in the United States with approximately 152,830 procedures performed in 2004 alone (http://hcup.ahrq.gov/HCUPnet.jsp). Some form of sedation is almost always used during bronchoscopy because of patient fear or anxiety, pain, oropharyngeal irritation, cough, dyspnea, and chest discomfort.1 Numerous studies demonstrate that sedation increases comfort and patient willingness to undergo future procedures and also2–5 improving the ability to obtain diagnostic results without interruption.4
Studies indicate that practice patterns vary regarding the type and usage of sedation during bronchoscopy6–9 (Table 1). There is variability in both the method and level of sedation delivered (eg, titration vs. fixed doses).6,8 The choice of sedative agent and dose generally depends on age, underlying medical comorbidities, and concomitant medications of the patient and also the preference of the bronchoscopist.21 Benzodiazepines (particularly midazolam) are by far the most commonly used sedative agent. A 1991 survey of members of the American College of Chest Physicians found that midazolam (48%) and diazepam (24.5%) were the most frequently used sedatives.7 More recently, a 2003 survey of consultants of the British Thoracic Society reported that 85% of bronchoscopists use midazolam.8 Regimens designed to combine the advantages of different sedative drug classes are frequently employed. Some clinicians have advocated that sedation is not required22–26 during bronchoscopy. Others advocate that complementary approaches (eg, distraction therapy) are also adequate alternatives to sedative agents,27 but this is the exception in the United States. In fact, the American Thoracic Society guidelines recognize the importance of21,28,29 sedation and topical anesthesia during flexible bronchoscopy.21 Similarly, the British Thoracic Society recommends that sedation should be offered to all patients when there is no contraindication.28
This article will review the pharmacodynamic and pharmacokinetic properties of the most frequently used sedative agents and summarize the results of studies evaluating sedative regimens in patients undergoing bronchoscopy. Additionally, investigational agents will be briefly discussed to provide a glimpse into future developments in the field of sedation during bronchoscopy.
GENERAL PRINCIPLES OF SEDATION PHARMACOLOGY
Familiarity with the pharmacokinetic and pharmacodynamic properties and variability of sedative agents is critical to tailoring dosing regimens to individual patients. Pharmacokinetic variability is defined as differences in plasma drug concentrations produced by a given dosage, and pharmacodynamic variability is the wide range of drug effects that can be produced in patients with identical plasma drug concentrations.30,31 Pharmacokinetic variability typically results from differences in age, weight, renal and hepatic function, whereas differences in receptor sensitivity may explain pharmacodynamic variability. For example, one study demonstrated a 5-fold range in the fentanyl plasma concentration required to produce analgesia.31 Thus, gradual titration of doses is generally superior to fixed dosage regimens.
Knowledge of the time course of drug effect is especially important to optimize sedation regimens. In particular, it is important to know the latency to peak effect after bolus injection to ensure that previous doses have reached peak effect before additional doses are administered. The time to peak effect varies considerably within drug classes. For example, although midazolam has a shorter half-life than diazepam, it is associated with a longer time to peak effect (9 to 12 min vs. 2 to 5 min, respectively).32,33 Similarly, fentanyl has a very short time to peak effect (∼5 min)34; whereas morphine has a much later peak (20 to 30 min).
CURRENT SEDATION AGENTS
A rapid onset of action, a short duration of action, a quick recovery with rapid return of cognitive function, ease of use, and a predictable pharmacokinetic/pharmacodynamic profile are important properties for a sedative agent. Analgesic and amnestic properties, cardiovascular stability, and a lack of respiratory depressant effects are also desirable.10 The most commonly used agents include benzodiazepines, opioids, and propofol. Each of these agents has some of the properties of an ideal sedative but all have limitations. Other agents such as ketamine and chloral hydrate have also been evaluated but are infrequently used. The pharmacokinetic properties of the most frequently used sedative agents are summarized in Table 2. Table 3 summarizes randomized, controlled trials evaluating sedative agents in patients undergoing bronchoscopy.
All benzodiazepines produce similar pharmacologic activity (eg, amnestic, anxiolytic, sedative-hypnotic) with their effects mediated by the same receptor (γ-aminobutyric acid), but there are some differences in pharmacokinetic properties (Table 2).35 The 2 most frequently used benzodiazepines are midazolam and lorazepam. Midazolam is highly lipophilic and has a rapid distribution into the central nervous system (CNS) and adipose tissue, resulting in rapid onset of action (<2.5 min).35 The rapid redistribution of the drug from the brain to peripheral tissues and a short half-life produce a rapid recovery.36 However, in patients with decreased clearance and/or when drug accumulates in adipose tissue prolonged sedation may result.35,36 Because of its lower lipophilicity and longer half-life, lorazepam has a slower onset of action (15 to 20 min) and a longer duration.35
Benzodiazepines have been evaluated in patients undergoing bronchoscopy.2,11–14,43,44,53–60 Generally, these studies have found that benzodiazepines are associated with high patient and investigator satisfaction and are well tolerated. As a single agent, midazolam demonstrated better postprocedure comfort compared with opioids alone in some,13,59 but not all, studies.14
The anterograde amnestic effect of benzodiazepines was demonstrated in a placebo-controlled trial of oral lorazepam as a premedication for bronchoscopy.2 In the immediate postprocedure period, there was no significant difference in patient perception between those receiving lorazepam and placebo-treated patients. However, 24 hours later, those in the lorazepam group were more likely to rate the procedure as “easy” and to be willing to undergo a second bronchoscopy.
One would expect that because of its shorter half-life, midazolam would be associated with a shorter recovery time compared with other benzodiazepines, such as diazepam. However, direct comparative trials between midazolam and diazepam in patients undergoing bronchoscopy have produced conflicting results.43,44 In 1 study, patients receiving midazolam performed significantly better than those receiving diazepam on a psychomotor test performed 4 hours postprocedure.43 However, another study found that high-dose midazolam was associated with a longer time to recovery as assessed by the ability to walk a straight line. However, the same study found no difference in psychomotor assessments.44
One advantage of benzodiazepines is the availability of a competitive benzodiazepine receptor antagonist (flumazenil) to reverse the CNS depressant effects of these drugs and aid in recovery. In controlled trials, flumazenil successfully reversed benzodiazepine-induced sedation in patients undergoing bronchoscopy, and it may be effective for reversing benzodiazepine-induced hypoxia.11,58 However, because flumazenil has a shorter duration of action than benzodiazepines, there is the potential for relapse necessitating a second dose of the drug.11
Benzodiazepines are often used in combination with opioids because of the synergistic activity between these drug classes.35 These regimens can reduce the requirement for local anesthesia and provide a better antitussive effect.14,26,27,49,61 In randomized studies, the addition of an opioid to intravenous midazolam was associated with a significant reduction in cough and increased patient tolerance when compared with midazolam alone.14,49 In 1 study, there was a nonstatistically significant trend toward a decrease in the requirement for supplemental lidocaine with combination therapy.49
Safety and Limitations
Like other sedative agents, benzodiazepines can produce cardiopulmonary depression. In a comparative trial with propofol, midazolam was associated with significantly higher heart rate and systolic blood pressure during the bronchoscopy when at the level of the vocal cords.15 Although low to moderate doses of midazolam (ie, <5 mg) do not seem to increase the risk of hypoxemia during flexible bronchoscopy, hypoxemia can occur with or without sedation.62 Another potential disadvantage of benzodiazepines is a prolonged effect with repeat dosing owing to drug accumulation in adipose tissue.35
Opioids have both sedative and analgesic effects. The most frequently used opioids are fentanyl and meperidine. Morphine sulfate is the least commonly used opioid.7 Because of synergistic activity, these agents are often used in combination with a benzodiazepine for moderate sedation.35 As with benzodiazepines, the availability of an opiate antagonist (ie, naloxone) is important to reverse the untoward side effects of opioids.16
Fentanyl is a potent (∼80-fold more potent than morphine) and highly lipid-soluble opioid.37 After intravenous administration, the drug is rapidly distributed to the CNS, producing a rapid onset of action (1 to 2 min).35 Because of its rapid redistribution and relatively short half-life, the drug has a short duration of action (1 to 2 h). Drug accumulation and a prolonged duration of action can occur with repeat administration.35,37 Compared with fentanyl, meperidine is less potent, has a slower onset (5 min) and a longer duration of action (2 to 4 h) after intravenous administration. Thus, meperidine is generally associated with a longer recovery time than other opioids. Meperidine is metabolized primarily via hepatic metabolism to inactive and active metabolites.35,37 Morphine sulfate has an onset of action similar to fentanyl (2 to 3 min) but a longer half-life (2 to 4 h).35 Drug and metabolite accumulation can occur in hepatic and renal dysfunction. Morphine is also a potent releaser of histamine and may produce more itching and hypotension than other opioids.63
Studies comparing opioids with benzodiazepines have generally found both of the sedation regimens effective. Fentanyl and its derivatives and also meperidine have been studied prospectively while morphine has not. A randomized trial among patients undergoing outpatient bronchoscopy found no difference between alfentanyl and midazolam regarding patient or bronchoscopist-rated levels of discomfort or recovery time. However, alfentanyl-treated patients experienced fewer coughs and required less lidocaine.14 In another randomized, double-blind trial of 69 patients undergoing flexible bronchoscopy, there was no difference between midazolam and alfentanyl in postprocedure patient tolerance or discomfort, ease of procedure, or oxygen saturation.13 Alfentanyl was associated with less cough, while patient discomfort scores at 24 hours favored midazolam.13
A nonrandomized study comparing midazolam alone with combination fentanyl plus droperidol in patients undergoing bronchoscopy showed no difference in bronchoscopist scores of patient discomfort, but patient-rated scores significantly favored midazolam.59 Patients receiving fentanyl had “vague” recollections of the procedure, whereas those receiving midazolam had virtually no memory of the procedure.
Safety and Limitations
The primary safety concern with opioids is respiratory depression, although most comparisons of single-agent regimens have not demonstrated a significant difference in hypoxemia between opioids and benzodiazepines.13,14,45,59 Risk of hypoxemia is enhanced when opioids are combined with other sedatives. In 1 randomized trial, oxygen saturation fell significantly more in patients receiving alfentanyl plus midazolam compared with those receiving alfentanyl alone.14
Opioids effectively blunt cardiovascular responses (eg, hypertension, tachycardia) that occur during mechanical stimulation of laryngeal and tracheal tissues. However, there is a risk of inducing hypotension with these agents.50 One small study suggested that remifentanil was more effective than fentanyl for preventing intraoperative hypertension and tachycardia and lowered the requirement for propofol for maintenance of anesthesia in patients undergoing rigid bronchoscopy.51
Propofol and Related Compounds
Propofol is a phenolic derivative structurally unrelated to other sedatives. It is formulated in an oil-in-water emulsion containing soybean oil, glycerol, and egg lecithin. The sedative, amnestic, and analgesic properties of propofol make it an attractive agent for sedation during short procedures.35 The pharmacokinetic properties of propofol are characterized by a high lipophilicity with rapid penetration into the CNS, producing a rapid onset of action (within 2 min). This is followed by a rapid redistribution and metabolic clearance from the plasma thus giving it the rapid recovery (10 to 15 min) characteristic of the drug.64
Propofol is an effective sedative in patients undergoing bronchoscopy.46–48,65 In 2 randomized trials, propofol was associated with a faster recovery compared with midazolam.47,48 One of these studies evaluated 41 asthmatic patients undergoing outpatient fiberoptic bronchoscopy in which intravenous propofol and midazolam were titrated to achieve adequate sedation.47 Time to induction of sedation was significantly shorter in the propofol group (125 vs. 179 s; P<0.001), but requirements for local anesthesia and investigator-rated patient tolerance were similar between groups.47 Recovery was faster in propofol-treated patients compared with those receiving midazolam as assessed by time to recall name and date of birth and by Digital-Symbol Substitution Test (DSST) scores.47 In another study, computer-controlled infusion of propofol was compared with incremental doses of intravenous midazolam in 42 patients undergoing bronchoscopy.48 Time to sedation and procedure duration were not significantly different, and both regimens produced similar patient and investigator satisfaction.48 However, time to recovery was significantly shorter in patients receiving propofol compared with those in the midazolam group (5 vs. 10 min; P<0.01), as assessed by psychomotor tests.48
The value of adding an opioid to propofol sedation has not been established. In patients undergoing colonoscopy, combination therapy with remifentanil plus propofol was associated with lower patient satisfaction, longer recovery, and more respiratory and blood pressure depression compared with propofol alone.66 In bronchoscopy studies, propofol/alfentanyl combinations were not associated with benefits in recovery time or satisfaction ratings compared with propofol alone50 or propofol plus ketamine.52
Safety and Limitations
Safety issues with propofol include cardiopulmonary depression, injection site pain, and the risk of microbial contamination of the emulsion formulation.38,64 The cardiopulmonary effects of propofol (respiratory depression, hypoxemia, hypotension, decreased cardiac output) are generally dose dependent and are enhanced when the drug is combined with opioids.50,64,66
Comparative studies between propofol and midazolam in patients undergoing bronchoscopy have found that there were no significant differences between the 2 agents in oxyhemoglobin desaturation and hemodynamic parameters.47,48 Propofol was associated with significantly less respiratory depression compared with a combination of fentanyl and diazepam in patients undergoing fiberoptic bronchoscopy in 1 study; however, there were no instances of apnea and there was no significant difference between groups for oxyhemoglobin desaturation.46
NEWER SEDATIVE AGENTS
Fospropofol disodium (Aquavan Injection, MGI Pharma, Inc, Bloomington, MN) is a novel sedative/hypnotic, water-soluble prodrug of propofol with pharmacokinetic and pharmacodynamic properties that differ from those of propofol emulsion.17,18,39,67 After intravenous administration, propofol is released from the prodrug by enzymatic action, resulting in a predictable and controlled release of propofol.18,39 Compared with the conventional formulation of propofol, the plasma concentration profile of fospropofol is characterized by lower peak concentrations and a more gradual decline in propofol concentrations.18
In patients undergoing colonoscopy, fospropofol has demonstrated satisfactory depth and duration of sedation.68 A phase 3, randomized, double-blind, dose-controlled study in 252 patients to evaluate the efficacy and safety of fospropofol after pretreatment with fentanyl in patients undergoing flexible bronchoscopy has recently concluded with final analysis underway. Primary end points of sedation success and also secondary end points were met during the study.
A modified cyclodextrin-based formulation of propofol has also been developed in an effort to mitigate some of the formulation-dependent problems of propofol (eg, pain on injection, microbial growth).69 Preliminary data suggest that the cyclodextrin-based formulation produces sedative, hemodynamic, and respiratory effects similar to those produced by the lipid emulsion.70
Other short-acting sedative agents that have been evaluated for sedation during bronchoscopy include ketamine19,71,72 and chloral hydrate,73,74 but these agents are not frequently used. Ketamine is a structural analogue of phencyclidine with potent analgesic properties.64 The drug has a high lipophilicity with rapid distribution to the CNS, producing a rapid onset of action and a short duration of action.64 One disadvantage of ketamine is the production of emergence reactions (eg, disorientation, hallucination, delirium).64 Disadvantages to the uses of chloral hydrate include the lack of an intravenous formulation, a slow onset of effect, and a prolonged duration of action.
SEDATION IN SPECIAL POPULATIONS
Risks to the pregnant patient and the fetus during bronchoscopy include impairment of gas exchange, severe cough, and barotrauma (eg, pneumothorax, pneumomediastinum).75 Sedative medications may also pose a risk during pregnancy both directly (ie, teratogenic, hemodynamic) and indirectly (via hemodynamic effects of sedatives on the mother).75 Although no formal guidelines for bronchoscopy sedation in pregnant patients exist, agents with an FDA pregnancy category D or X (eg, midazolam, diazepam) should likely be avoided. The pregnant patient should receive continuous cardiac, pulse oximetry, and blood pressure monitoring during the procedure with fetal monitoring if possible.75
Patients With Asthma
Bronchoscopy-induced bronchospasm is a potential concern in patients with reactive airway disease.76 Studies demonstrate that bronchoscopy with midazolam sedation can be performed safely. Patients can experience a temporary decline in lung function and oxyhemoglobin saturation depending on asthma severity.76,77 Relative contributions from bronchospasm and sedation to these effects on lung function are not clear. Extreme caution and rigorous monitoring should be the rule in patients with severe asthma undergoing flexible bronchoscopy.76,77
Surveillance flexible bronchoscopy is commonly performed in lung transplant recipients for the detection of rejection or infection.78,79 Sedation regimens, including combinations of benzodiazepines and opioids (eg, midazolam or diazepam plus fentanyl or meperidine) have been used successfully in this patient population.78,79 Dransfield et al78 used standardized guidelines developed at their institution for surveillance bronchoscopy in lung transplant recipients. Recommendations for the stepwise administration of midazolam and meperidine were included in these guidelines.78 The authors credit implementation of these guidelines, which resulted in the judicious use of sedative agents, with a reduction in bronchoscopy complication rates.78
Elderly and Young Patients
Because of age-related decline in lung function, increased sensitivity to sedative drugs, and an increase in sedation-related adverse events, caution is warranted when administering sedation during bronchoscopy in the elderly.45,80 Elderly patients generally require smaller doses of sedative agents80 owing to prolonged time to recovery and increased amnestic effects of benzodiazepines in this patient population.53 In a study of patients over 75 years of age, temazepam plus nebulized lidocaine was associated with less coughing and better patient satisfaction with a trend toward less hypoxemia compared with alfentanyl alone.45 Doses of sedative agents should be titrated carefully and these patients should be closely monitored both during and after the procedure.
Sedatives used in children are generally similar to those used in adults, although the amnestic, analgesic, and dissociative properties of ketamine allow better control of the procedure.81 In addition, some advocate the use of inhalational anesthetics due to fear of needles by most children.82
Sedation during bronchoscopy is routinely provided to improve patient comfort and cooperation with the procedure, and also willingness to have repeat procedures. Although complications associated with bronchoscopy are low, patient monitoring is important to ensure a safe outcome. As bronchoscopy is often performed in patients with a diminished respiratory reserve, maintenance of adequate ventilation and oxygenation is critical for all patients.28 As bronchoscopy can produce cardiac arrhythmias or myocardial ischemia, electrocardiogram and blood pressure monitoring should also be performed.20,83 As all sedative agents produce respiratory depression, doses should be titrated to avoid respiratory compromise, particularly when drug combinations are used.84–86
A number of agents are available that provide effective sedation during bronchoscopy. There are advantages and disadvantages to each drug, with no single-agent possessing all attributes of an ideal agent. Newer drugs under investigation will hopefully increase the available sedative options and provide patients with a safe and pain-free bronchoscopic experience.
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sedation; bronchoscopy; analgesia; midazolam; fentanyl; propofol
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