THE intravenous (IV) sedative/hypnotics have become first-line agents for the administration of purposeful, goal-directed sedation such as in ventilated critically ill patients. These agents are also increasingly used for procedural pain management. Benzodiazepines have been first-line drugs for procedural sedation for many years, and ketamine has been used extensively for pediatric sedation and is increasingly used in adults for procedural sedation. Following is a discussion of selected drugs used for these purposes. See Table V-1, pp. 748-756, for dosing and other general information about some of these agents.
Propofol (Diprivan) is a gamma aminobutyric acid (GABA) type A agonist with sedative and hypnotic effects. It is the most frequently used IV anesthesia induction agent (Reves, Glass, Lubarsky, et al., 2005) and a primary sedative for goal-directed sedation in the critically ill (Barr, Egan, Sandoval, et al., 2001; Devlin, Roberts, 2009); it has been associated with shorter ventilator time than when benzodiazepines are used for this purpose (Carson, Kress, Rodgers, et al., 2006) (see also discussion on dexmedetomidine later in this chapter). It is also increasingly administered for procedural sedation (Odom-Forren, 2008; Zed, Abu-Laban, Chan, et al., 2007) primarily because it has a significantly faster onset and shorter duration than the commonly used benzodiazepines and has amnestic properties at low doses (Devlin, Roberts, 2009). Advantages of propofol over traditional sedation with benzodiazpines include less nausea and faster recovery and discharge (Odom-Forren, 2008). Other uses are as an adjunct in the treatment of refractory metastatic cancer-related abdominal and hip pain (Graves, Moran, Porter, et al., 1996) and to relieve nausea (Kim, Han, Kil, et al., 2000; Odom-Forren, Watson, 2005) and intrathecal morphine-induced pruritus (Charuluxananan, Kyokong, Somboonviboon, et al., 2001). The drug can reduce intracranial pressure after traumatic brain injury and decreases cerebral blood flow and metabolism (Devlin, Roberts, 2009). A single IV propofol infusion (2.4 mg/kg) did not reduce pain or analgesic use and produced statistically significant, but not clinically meaningful, reduction in disability associated with chronic daily headache, which led the researchers in one study to recommend against its use for this type of pain (Simmonds, Rashiq, Sobolev, et al., 2009). The reader is referred to a comprehensive practical guide on the administration of moderate sedation/analgesia, which includes pharmacology, management of adverse effects and complications, and administration protocols (Odom-Forren, Watson, 2005). Following is an overview of the drug.
Propofol has an extremely rapid onset of sedation (30 to 45 seconds) and peak sedative effect (90 to 100 seconds) (Odom-Forren, Watson, 2005; Reves, Glass, Lubarsky, et al., 2005). The drug undergoes rapid hepatic metabolism, has no known active metabolites, and is excreted renally (Reves, Glass, Lubarsky, et al., 2005). Clearance of the drug is very high, exceeding hepatic blood flow, suggesting extrahepatic metabolism of the drug, probably via the lungs. Studies using a 3-compartment distribution model show initial and slower distribution half-lives of 1 to 8 minutes and 30 to 70 minutes, respectively (Reves, Glass, Lubarksy, et al., 2005). Its terminal half-life varies from 3 to 9 hours (Odom-Forren, Watson, 2005; Reves, Glass, Lubarksy, et al., 2005).
The drug is given intravenously only and can be administered by intermittent dosing or infusion. Because intermittent doses must be administered frequently, infusion is preferred when used for an extended period (Reves, Glass, Lubarksy, et al., 2005). Bolus doses also can cause severe hypotension, and if administered, caution is recommended (see the following material on adverse effects). Propofol infusion should be administered via an infusion device that does not allow free-flow delivery; to help ensure accurate dose delivery, programming should be verified by the independent double-check process (see Chapter 17). Propofol has been administered by patient-controlled sedation technique; however, one group of researchers concluded that although this approach was effective, the risk of oversedation is too high for such unsupervised use (Thorpe, Balakrishnan, Cook, 1999).
Some anesthesiologists administer a small dose to test for allergic reactions; however, a loading dose of propofol usually is not administered prior to goal-directed sedation in the intensive care unit (ICU). Dosing of propofol varies, but 5 mcg/kg/min for at least 5 minutes (0.3 mg/kg/h) via IV infusion with subsequent increases of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) every 5 to 10 min is used to achieve desired level of sedation in the intubated and ventilated critically ill (Clinical Pharmacology, 2010). The usual maintenance dose with this regimen is 5 to 50 mcg/kg/min (mean 27 mcg/kg/min) depending on the clinical situation and coadministration of other sedating agents. An infusion of 50 to 150 mg titrated by 50 mg increments as needed to a maximum of 300 mg/h in a 70 kg adult is a common propofol regimen for light to moderate sedation in the ICU (Odom-Forren, Watson, 2005).
There is no consensus on propofol dosing regimens for procedural sedation either. One group of researchers administered an initial dose of 0.25 to 0.5 mg/kg administered over 60 seconds followed by 10 to 20 mg/min in subsequent doses (mean dose required was 1.6 mg/kg) to achieve procedural sedation in the emergency department (ED); this dosing resulted in adequate sedation in 90% of the patients and was well tolerated (Zed, Abu-Laben, Chan, et al., 2007) (see following material on adverse effects).
The propofol dose should be lowered for older adults because they are more sensitive to the hypnotic and cardiovascular (CV) effects of propofol than younger adults (Odom-Forren, Watson, 2005; Olmos, Ballester, Vidarte, et al., 2000; Reves, Glass, Lubarksy, et al., 2005; Schnider, Minto, Shafer, et al., 1999). The dose should also be lowered when propofol is combined with other agents, such as opioids and benzodiazepines, because these drugs (particularly benzodiazepines) produce additive sedative and hemodynamic (e.g., hypotensive) effects (Odom-Forren, Watson, 2005; Olmos, Ballester, Vidarte, et al., 2000). Reves, et al. (2005) noted that marked reductions in propofol dose are possible when patients are premedicated with an opioid or benzodiazepine prior to surgery (see the following material on propofol analgesia). Abrupt discontinuation of propofol can result in rapid awakening with anxiety and agitation, so the dose should be tapered prior to the end of therapy.
Common adverse effects associated with propofol administration are nausea, vomiting, abdominal cramping, headache, dizziness, twitching and myoclonic movement, hypertension and hypotension, bradycardia, respiratory depression, and apnea. Patients and families should be warned that the drug causes some patients to experience vivid sexual dreams (Odom-Forren, Watson, 2005). Reports of tolerance to the drug have not been supported by research; the need for individualized titration is stressed (Reves, Glass, Lubarksy, et al., 2005).
Propofol is formulated in a 10% lipid solution, which has been associated with elevated triglyceride and glucose levels in some patients (Odom-Forren, Watson, 2005). This formulation also heightens the risk of bacteremia, one of the most serious complications of propofol. Strict aseptic technique when handling the medication, infusion tubing changes every 12 hours, and regular assessment for signs of local and systemic infection are essential for safe administration of the drug (Odom-Forren, Watson, 2005).
Propofol injection may cause pain at the injection site, which occurs in as many as 70% of those who receive the drug (Schaub, Kern, Landau, 2004). Very slow injection is recommended to reduce this. Various other approaches to reduce injection pain have been successful and include pretreatment with injected lidocaine (Schaub, Kern, Landau, 2004; Zed, Abu-Laben, Chan, et al., 2007) or ondansetron (Ambesh, Dubey, Sinha, 1999). The 10% emulsion lipid formulation of propofol is reported to be less painful on injection than other formulations; however, this solution was associated with a higher incidence of propofol injection pain than pretreatment with 40 mg of IV lidocaine prior to administration of propofol 1% for Bier’s block (Schaub, Kern, Landau, 2004). The addition of lidocaine to propofol infusion solutions was reported to produce antibacterial activity (Gajraj, Hodson, Gillespie, et al., 1998); however, this practice has been associated with a higher incidence of CV reactions and is discouraged (Wild, Shinde, Newton, 1999).
Deaths have occurred with the use of propofol for purposeful sedation in critically ill patients. A systematic review of reported deaths in the United States with “long-term” nonprocedural propofol use concluded that higher doses and concentrations and longer durations of therapy increase the risk of what is referred to as “propofol syndrome” (mean duration of use was 7.3 days; peak propofol dose was 7.2 mg/kg/h) (Wysowski, Pollock, 2006). Propofol syndrome is described as a CV and metabolic derangement characterized by progressive cardiac dysfunction, bradycardia, hypotension, cardiac failure, rhabdomyolysis, and metabolic acidosis. Risk factors associated with propofol syndrome include a dose higher than 83 mcg/kg/min, duration of therapy longer than 48 hours, concomitant use of catecholamine vasopressors or glucocorticoids, and patient age older than 18 years (Devlin, Roberts, 2009). It is important to note that there is no antidote for propofol.
Subanesthetic doses of propofol produce only negligible analgesia (Frolich, Price, Robinson, et al., 2005; Odom-Forren, Watson, 2005; Zacny, Coalson, Young, et al., 1996). It is, therefore, essential to address the analgesic needs of patients receiving propofol sedation. Research supports the co-administration of analgesics (e.g., opioids, nonopioids) with drugs such as propofol because the conditions under which the propofol is administered are painful. For example, mechanical ventilation is required in patients receiving propofol for goal-directed sedation, and mechanical ventilation and endotracheal suctioning in addition to multiple other procedures ICU patients undergo while receiving propofol sedation have been shown to be painful (Konstantatos, Silvers, Myers, 2008; Puntillo, White, Morris, et al., 2001; Stanik-Hutt, Soeken, Belcher, et al., 2001). As mentioned, propofol is also used in lower doses for procedural sedation in nonventilated patients. These procedures are clearly painful (see following discussion), justifying the need for analgesia. Further, as mentioned, the addition of an opioid may allow lower propofol doses and thus fewer adverse effects. (See Section II for pain assessment in the nonverbal critically ill.)
Propofol is being used with increasing frequency for procedures performed outside of the ICU setting. A prospective, observational study (N = 113) evaluated the use of a propofol protocol for painful procedures in the ED and found the drug to be safe and effective in this setting (Zed, Abu-Laban, Chan, et al., 2007). The study protocol required an attending physician to be responsible for the procedure; a registered nurse (RN) to initiate the IV, administer the drug, and monitor patient response; and a respiratory therapist to monitor ventilation and oxygenation throughout the procedure. Administration involved the administration of a low initial propofol dose of 0.25 to 0.5 mg/kg followed by 10 to 20 mg/min until adequate sedation was achieved. Lidocaine to prevent injection pain and fentanyl for procedural pain control were administered at the discretion of the treating physician. Sedation was reached and procedures were completed in 90% of the patients. Reasons were not given for failure to complete 10% of the procedures. Nine patients experienced hypotension, but there were no major complications. Interestingly, while lidocaine was administered to 78% of patients to prevent injection pain, fentanyl was administered to only 17% despite treatment of known painful procedures, such as orthopedic manipulation, cardioversion, and abscess incision and drainage. Reluctance to use opioids may have been for fear of additive respiratory depressant effects as the authors mentioned this opioid characteristic. Further, they noted that only 6.2% of the patients had procedural recall, confirming amnesia in the majority and implying that most patients experienced no pain. However, patients were not asked specifically about pain; when they returned to baseline mental status postprocedure, they were asked if they remembered the procedure and to rate overall satisfaction but were not asked about whether or not they experienced pain during the procedure, and no follow-up information (e.g., next day pain recall) was provided. Most patients (92%) and physicians (85%) reported that they were very satisfied with the use of propofol; however, the process for obtaining patient satisfaction was not clear.
Another prospective, observational 6-month study (N = 82) administered propofol by a less well-defined protocol and also found it to be safe and effective for sedation during painful procedures in the ED (Weaver, Hauter, Brizendine, et al., 2007). The most common procedures were incision and drainage, joint reduction, and fracture care. Adverse sedation events occurred in 21% of the patients. Clinical hypoventilation and transient, brief hypoxemia were the most common. Simple corrective measures, such as increased physical stimulation and head repositioning, were implemented to treat hypoventilation; no patients required assisted ventilation or intubation. More fentanyl analgesia was administered in this study (61%) than in the previous study, but those who received fentanyl were more likely to experience an adverse event. However, it is unknown if the adverse events in those who received fentanyl might have been less common if the dose of propofol had been reduced. The addition of opioid analgesia is known to allow lower and potentially safer doses of sedative agents (Olmos, Ballester, Vidarte, et al., 2000; Reves, Glass, Lubarsky, et al., 2005), but no adjustments in propofol dose were made for those who received fentanyl (i.e., there were no significant differences in the mean initial and cumulative amounts of propofol administered to those who had an adverse event and those who did not). ASA classification is another important consideration when evaluating the incidence of adverse events in this study. Of those who experienced an adverse event, 24% were classified ASA III, and only 5% of those who did not experience an adverse event were classified ASA III. The ASA classification of those who received fentanyl is unknown, so that relationship cannot be fully evaluated either. The researchers appropriately concluded that an association between opioid use and hypoxia should not be interpreted as proving a cause-effect relationship.
Of concern is the apparent general lack of attention to analgesia during propofol sedation for very painful procedures. Some of the studies suggest that providing analgesia increases adverse events, but not enough information is provided to adequately evaluate this or to determine whether the noted adverse events have a detrimental effect on patient outcomes. That is, further research is needed to determine if transient hypoventilation and brief hypoxemia that are as easily corrected as they appear to have been in the previously discussed studies are harmful.
In summary, it is important for those who provide procedural sedation to remember that low doses of propofol do not provide sufficient analgesia (Frolich, Price, Robinson, et al., 2005; Odom-Forren, Watson, 2005; Zacny, Coalson, Young, et al., 1996). Protocols for propofol administration for procedures thought to be painful should include the administration of analgesia regardless of the amnestic qualities of the sedative agent used. At all times, the goals of procedural sedation are to provide both pain control and sedation (Peck, Down, 2009).
The studies described above demonstrate that propofol is increasingly being administered for procedural sedation outside of the operating room and monitored settings; however, its administration by professionals who are not trained anesthesia providers is controversial (Institute for Safe Medication Practices, 2006; Odom-Forren, 2006; Sullivan, 2006). Concerns over the safety of this practice are based on the unique pharmacokinetics and pharmacodynamics of the drug as well as reports of near-fatal and fatal respiratory events (Institute for Safe Medication Practices, 2006). Anesthesia provider groups, such as the American Association of Nurse Anesthetists (AANA) and the American Society of Anesthesiologists (ASA) oppose propofol administration by non-anesthetists because of the rapid and profound changes in depth of sedation that can occur with the drug and a lack of antagonistic agents to reverse its effects (AANA, ASA, 2004). A survey conducted of monitoring practices during sedation by non-anesthetists revealed alarming findings including a failure to follow guidelines and protocols in 30%, inadequate monitoring (e.g., 47% failure to use ECG monitoring, 0% use of capnography), Advanced Cardiac Life Support (ACLS) certification in only 29% of providers, and a 22% incidence of adverse effects during procedures (Fanning, 2008). Nevertheless, the American College of Gastroenterology (ACG) and others have petitioned the United States Food and Drug Administration to change propofol labeling to allow non-anesthetists to administer the drug (United States Food and Drug Administration, (U.S. FDA), 2005c). In an effort to better control the quality of non-anesthetist administration of propofol during endoscopy, the American Association for the Study of Liver Diseases, ACG, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy issued a joint position statement that discusses the safety of this practice and provides recommendations for non-anesthetists’ training prior to administration (Vargo, Cohen, Rex, et al., 2009).
Research has shown no major complications with nurse-administered propofol sedation (NAPS) in 11,000 patients in the GI setting (Odom-Forren, 2008). However, the studies that have been conducted so far on non-anesthetist propofol administration for procedural sedation make it difficult to adequately evaluate its safety. The authors of the joint position statement described in the preceding paragraph concluded that sedation administered by non-anesthetists appears to be as safe as that of standard sedation, but that the worldwide experience with this practice is insufficient to draw definitive conclusions about its safety (Vargo, Cohen, Rex, et al., 2009). Randomized, placebo-controlled trials are lacking, and there are no well-defined and agreed-upon criteria of what signifies an adverse sedation event. Further, the clinical significance of transient hypoxemia that can occur during propofol administration is unknown (Weaver, Hauter, Brizendine, et al., 2007). Safe dosing guidelines are also lacking. As discussed, the administration of sedation without analgesia for painful procedures is a serious error, yet this practice appears to be widely accepted in part because the impact of analgesic administration on propofol dosing and adverse effects has not been fully evaluated. The ability of non-anesthetists to adequately address analgesia during propofol sedation is a concern and requires further examination.
Boards of nursing have confirmed that the administration of moderate sedation by competent RNs is within the scope of RN practice; however, Odom-Forren (2006) emphasizes that propofol sedation is often deep (not moderate) sedation and borders on anesthesia. Regardless of the outcome of this controversy and the FDA decision regarding labeling, RN scope of practice is determined ultimately by the nurse’s individual state board of nursing. Nurses should be aware of their scope of practice, state board of nursing’s opinions, and institutional policies and procedures regarding the administration and monitoring of agents such as propofol.
Fospropofol (Lucedra) is a relatively new GABA agonist approved for use in adults undergoing diagnostic or therapeutic procedures in a monitored care setting. It is a prodrug of propofol with very similar pharmacokinetic and pharmacodynamic characteristics. The same concerns about safety apply to fospropofol as apply to propofol, and like propofol, it is approved for administration only by trained anesthesia providers, such as nurse anesthetists and anesthesiologists. Research and clinical experience with this drug were lacking at the time of publication.
Dexmedetomidine (Precedex) is an alpha2-adrenergic agonist that was initially approved in the United States for IV sedation in intubated patients and later approved for IV sedation before and during surgery and other procedures in nonintubated patients. It is used perioperatively as an adjunct to general and IV regional anesthesia (Kamibayashi, Maze, 2000; Reves, Glass, Lubarsky, et al., 2005) and has been shown to produce a significant opioid dose-sparing effect (Akin, Aribogan, Arslan, 2008; Arain, Ruehlow, Uhrich, et al., 2004; Buvandendran, Kroin, 2007; Golembiewski, 2005; Takrouri, Seraj, Channa, et al., 2002; Panzer, Moitra, Sladen, 2009). It has been added to morphine for administration via IV patient-controlled analgesia (PCA) (no basal rate) to produce superior analgesia, less nausea, and no sedation and adverse hemodynamic effects compared with morphine-only IV PCA (no basal rate) in 100 women following hysterectomy (Lin, Yeh, Lin, et al., 2009). Reports of remarkable reductions in high opioid doses without loss of pain control have implications for the treatment of opioid-induced hyperalgesia (OIH) (Kamibayashi, Maze, 2000) (see Chapter 11 for more on OIH).
The drug has demonstrated a median onset of IV analgesia of 7.8 minutes (Gomez-Vasquez, Hernandez-Salazar, Hernandez-Jimenez, et al., 2007). By the intranasal route, dexmedetomidine had a 45-minute onset of sedation with a peak at 90 to 150 minutes and no effect on pain pressure threshold in 18 healthy volunteers (Yuen, Irwin, Hui, et al., 2007). It is metabolized in the liver by the cytochrome P450 enzyme system and excreted in the urine and feces. It has a very rapid distribution phase (half-life of 6 minutes) and a terminal half-life of 2 hours. Its pharmacokinetic properties are unchanged by age, weight, or renal or hepatic failure (Reves, Glass, Lubarsky, et al., 2005), which indicates that dose adjustment may not be necessary for these factors.
Benzodiazepines, such as lorazepam (Ativan) and midazolam (Versed) (see pp. 724-725), and the IV sedative/hypnotic propofol (Diprivan) (see pp. 718-722) have been the most commonly used sedation agents in critically ill patients in the ICU for many years; however, dexmedetomidine may be a better choice for this purpose (Riker, Shehabi, Bokesch, et al., 2009). The drug does not produce respiratory depression, and it has both analgesic and anxiolytic properties (Golembiewski, 2005; Takrouri, Seraj, Channa, et al., 2002; Wunsch, Kress, 2009). It has also been found to provide hemodynamic stability, cause minimal postsedation cognitive impairment, and allow easy arousal of the patient such that coherent communication between caregiver and patient is possible (Venn, Grounds, 2001). It is reported to be the only drug to both reduce the development of delirium and improve the resolution of delirium in the ICU (Riker, Shehabi, Bokesch, et al., 2009).
Recommended dexmedetomidine dosing for goal-directed sedation in the critically ill is an initial IV bolus dose of 1 mcg/kg over 10 minutes followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/h for 24 hours (Pandharipande, Ely, Maze, 2006; Clinical Pharmacology, 2010). The drug is administered by an infusion device that does not allow free-flow delivery, and to help ensure accurate dose delivery, programming should be verified by the independent double-check process (see Chapter 17).
A barrier to more common use of dexmedetomidine in the United States is the U.S. FDA–imposed maximum dose of 0.7 mcg/kg/h and use of the drug for up to 24 hours only. Research suggests that these restrictions should be reconsidered (Brush, Kress, 2009; Panzer, Moitra, Sladen, 2009). A study conducted in two tertiary ICUs obtained approval to administer dexmedetomidine for longer than 24 hours and randomized 106 mechanically ventilated adults to receive either dexmedetomidine or lorazepam sedation for up to 120 days (Pandharipande, Pun, Herr, et al., 2007). Patients who received dexmedetomidine experienced more days alive without delirium or coma, a lower prevalence of coma, more time at their sedation goal, and a better 28-day mortality rate. The 12-month time to death was 363 days in the dexmedetomidine group compared with 188 days in the lorazepam group. A large multicenter, 2-year, randomized controlled trial compared midazolam and dexmedetomidine in ventilated ICU patients (Riker, Shehabi, Bokesch, et al., 2009). The researchers received approval to administer dexmedetomidine in up to twice the approved dose for up to 30 days (Wunsch, Kress, 2009). While time at targeted sedation level did not differ, those who received dexmedetomidine experienced less time on the ventilator and less delirium, tachycardia, and hypertension than those who received midazolam. There was a greater incidence of bradycardia in the dexmedetomidine group, and 4.9% of the bradycardic patients required treatment that included titration or interruption of the study drug and use of atropine.
Dexmedetomidine is also used for monitored anesthesia care. A prospective, double-blind, multicenter trial randomized 326 patients prior to elective surgery or procedure to receive dexmedetomidine 0.5 mcg/kg, or dexmedetomidine 1 mcg/kg, or placebo for an initial loading dose administered over 10 minutes followed by a maintenance (titrated) infusion of 0.2 to 1 mcg/kg/h of dexmedetomidine in all of the patients (Candiotti, Bergese, Bokesch, et al., 2010). All patients were given a local anesthetic block for their surgery or procedure. Those who received dexmedetomidine (in either dose) required lower midazolam and fentanyl doses compared with placebo. The anesthesiologists reported greater ease of achieving and maintaining targeted sedation and higher satisfaction with dexmedetomidine. Patient satisfaction was also higher with dexmedetomidine. The most common dexmedetomidine-induced adverse effects were bradycardia and hypotension, which were described as mild to moderate, and there were fewer episodes of bradypnea and oxygen desaturation in those treated with dexmedetomidine.
Dexmedetomidine has also been compared with propofol. One study randomized critically ill postoperative patients to receive either propofol or dexmedetomidine and found no differences between the groups in time of ideal sedation and time to extubation, and there were no clinically significant adverse effects in either group (Venn, Grounds, 2001). However, those who received propofol required three times more opioid than those who received dexmedetomidine. Patients who received dexmedetomidine also had lower heart rates during infusion, which the researchers proposed may help to protect against myocardial infarction (MI). An early meta-analysis called for more randomized trials but concluded that alpha2-adrenergic agonists reduce mortality and MI following vascular surgery (Wijeysundera, Naik, Beattie, 2003); however, a later meta-analysis of dexmedetomidine’s effect on CV outcomes after noncardiac surgery showed a trend but no statistically significant improvement in cardiac outcomes (Biccard, Goga, de Beurs, 2008). Further research is needed to draw conclusions (Panzer, Moitra, Sladen, 2009).
The lack of a respiratory depressant effect with dexmedetomidine has implications for its use during weaning from mechanical ventilation and extubation as administration can be continued throughout these processes (Panzer, Moitra, Sladen, 2009). A study of patients who had failed previous attempts at ventilator weaning secondary to agitation unresponsive to traditional sedatives described successful extubation of 14 of the 20 patients who were given dexmedetomidine (Arpino, Klafatas, Thompson, 2008). Dexmedetomidine has also been reported to facilitate terminal weaning and withdrawal of ventilatory support at end of life in palliative care (Kent, Kaufman, Lowy, 2005).
In addition to the previously discussed studies, numerous others have reported that dexmedetomidine allows a reduction in concomitant sedative and analgesic use and produces minimal adverse effects (Arpino, Klaftas, Thompson, 2008; Bulow, Barbosa, Rocha, 2007; Gurbet, Basagan-Mogol, Turker, et al., 2006; Siobal, Kallet, Kivett, et al., 2006; Unlugenc, Gunduz, Guler et al., 2005). These findings have implications in particular for patients at high risk for respiratory depression, such as older surgical patients (Akin, Aribogan, Arslan, 2008) and obese patients undergoing bariatric surgery (Ramsay, 2006).
Dexmedetomidine has analgesic properties but is not appropriate as a sole analgesic for painful conditions or procedures, and it should not be used alone in patients receiving a neuromuscular blocking agent (Venn, Grounds, 2001). A study comparing dexmedetomidine (0.3 mcg/kg for 50 minutes) to propacetamol (IV acetaminophen, 2 g for 10 minutes) following knee surgery found dexmedetomidine produced comparable analgesia but higher total morphine requirements at 8 hours postoperatively (Gomez-Vasquez, Hernandez-Salazar, Hernandez-Jimenez, et al., 2007). A cross-over study randomized six healthy volunteers to receive infusions of the opioid remifentanil or dexmedetomidine during painful heat stimuli (Cortinez, Hsu, Sum-Ping, et al., 2004). Withdrawal from painful stimuli was recorded for any subject who was unarousable and unable to report pain using the VAS. The magnitude of the analgesic effect of dexmedetomidine was smaller than that of remifentanil, confirming that alpha2-agonists are not as effective analgesics as opioids. This research supports the observation that dexmedetomidine has an analgesic ceiling (Kent, Kaufman, Lowy, 2005).
An exception to this was described in an interesting letter to the editor that reported profound analgesia with a dexmedetomidine loading dose (1 mcg/kg) and infusion (0.5 mcg/kg/h) in two adults with severe pain associated with sickle cell vaso-occlusive crisis (VOC) that was refractory to opioid analgesia (Phillips, Gadiraju, Dickey, et al., 2007). Complete pain relief was achieved with dexmedetomidine without opioid analgesia. The infusion was gradually reduced by 0.1 mcg/kg/h and discontinued after 4 hours. There were no adverse effects, and both patients were discharged reporting no pain. An observational study reported that patients’ memories of their ICU experiences were better in patients who received dexmedetomidine than in those who received propofol, and patients in both groups recalled “discomfort” but no pain during mechanical ventilation (Venn, Grounds, 2001). Nevertheless, until research and more clinical experience with the drug demonstrate otherwise, opioid analgesia should always be provided when dexmedetomidine is administered to patients with painful pathology and those undergoing painful procedures.
Research on dexmedetomidine for sedation during painful procedures has contributed to a better understanding of the limitations of the drug’s analgesic effectiveness and its adverse effect profile in this setting. One study randomized 64 patients to receive an initial IV dose (1 mcg/kg) followed by IV infusion (0.2 mcg/kg) of dexmedetomidine, or an initial IV dose of meperidine (1 mg/kg) plus midazolam (0.05 mg/kg), or an initial IV dose of fentanyl (0.1 to 0.2 mg) for outpatient colonoscopy (Jalowiecki, Rudner, Gonciarz, et al., 2005). Supplemental fentanyl was required in 47%, 42.8%, and 79.2% of those who received dexmedetomidine, meperidine plus midazolam, and fentanyl, respectively. Adverse effects, such as nausea and vertigo, were greatest, and time to discharge readiness was longest in those who received dexmedetomidine. Dose-dependent adverse effects have been noted by others, reinforcing the importance of administering the lowest effective dexmedetomidine dose (Riker, Shehabi, Bokesch, et al., 2009; Venn, Grounds, 2001). This research suggests that lower loading doses and continuous infusion rates should be administered for patients undergoing procedures than for ventilated patients undergoing goal-directed sedation in the ICU.
A cross-over, placebo-controlled study found that intranasal dexmedetomidine provided effective, well-tolerated, and convenient sedation in 18 healthy volunteers (Yuen, Irwin, Hui, et al., 2007). More research and clinical experience with the use of dexmedetomidine by this noninvasive route of administration for procedural pain is needed.
Dexmedetomidine is generally well-tolerated. The most common adverse effects are bradycardia and hypotension (Gomez-Vasquez, Hernandez-Salazar, Hernandez-Jimenez, et al., 2007). It has been shown to blunt perioperative hypertensive responses without causing hypotension or bradycardia in patients undergoing craniotomy, a procedure frequently complicated by hypertensive episodes (Bekker, Sturaitis, Bloom, et al., 2008). As discussed, some researchers have proposed that lower heart rates during dexmedetomidine infusion may help to protect against MI (Venn, Grounds, 2001); however, further research is needed (Panzer, Moitra, Sladen, 2009).
The beneficial respiratory effect profile of dexmedetomidine was demonstrated in a study comparing it with the ultra-short–acting opioid analgesic remifentanil in 6 healthy volunteers (Hsu, Cortinez, Robertson, et al., 2004). Remifentanil decreased respiratory rate and minute ventilation and produced respiratory acidosis and apneic episodes resulting in desaturation. In contrast, dexmedetomidine did not produce any respiratory depression and, in fact, decreased the apnea/hypopnea index and exhibited similarities to natural sleep.
A case report described pyrexia of 39° C (102.2° F) in a 59-year-old man who was receiving dexmedetomidine and that resolved when the drug was discontinued (Okabe, Takeda, Akada, et al., 2009). All other potential causes of fever, such as infection, had been eliminated.
As mentioned, dexmedetomidine causes minimal postsedation cognitive impairment (Venn, Grounds, 2001) and reduces ICU delirium (Riker, Shehabi, Bokesch, et al., 2009). Research has shown excellent tolerability in older patients and a very high satisfaction rate with dexmedetomidine (Akin, Aribogan, Arslan, 2008).
Dexmedetomidine is indicated for purposeful, goal-directed sedation to control agitation and anxiety in the critically ill ventilated patient in the ICU setting (Brush, Kress 2009). It is also approved for sedation during procedures in nonintubated patients outside of the ICU. Dexmedetomidine is not adequate as a sole analgesic; therefore, an appropriate analgesic, such as an opioid, must be administered when the drug is used in patients who have painful underlying pathology and prior to and during any procedure thought to be painful.
Many hospitals restrict the administration of dexmedetomidine to specific clinical areas, such as the ICU and ED. Nurses should be aware of their scope of practice, state board of nursing’s opinions, and institutional policies and procedures regarding the administration and monitoring of agents such as dexmedetomidine.
Benzodiazepines, such as midazolam (Versed), lorazepam (Ativan), and diazepam (Valium), have been used for procedural sedation for many years. An extensive systematic review of the various agents used for moderate sedation during endoscopic procedures found marked variability in studies and problems in pooling data but established benzodiazepines as first-choice agents for these procedures (McQuaid, Laine, 2008). At the time of the review, 85% of endoscopists in the United States used midazolam, and 10% used diazepam. Physicians cited their preference for midazolam based on its faster onset, shorter duration, and a belief that the drug has sufficient amnestic properties. There was high physician satisfaction with the level of sedation achieved and a high patient satisfaction rate with the use of midazolam. However, the researchers concluded that midazolam-based regimens have longer sedation and recovery times than propofol-based regimens (see earlier in the chapter for propofol).
Of interest, 3 patients experienced transient apnea in a study that administered a combination of ketamine and midazolam for procedural sedation (Chudnofsky, Weber, Stoyanoff, et al., 2000) (see discussion in following paragraphs on ketamine). All 3 of these patients weighed in excess of 97 kg and received large doses of midazolam, which led the researchers to recommend midazolam dosing based on ideal rather than actual weight.
As mentioned throughout this chapter, pain control should be a primary goal during painful procedures. Benzodiazepines can diminish pain associated with musculoskeletal spasm, reduce anxiety, and at high doses produce amnesia; however, they lack analgesic properties for acute tissue injury (American Pain Society, 2003; Pasero, McCaffery, 1999). The benzodiazepine dose required to produce amnesia varies widely among patients. Many individuals recall pain and other unpleasant procedural experiences when benzodiazepines are used as a sole agent during painful procedures. It is encouraging to note that most endoscopists believe a combination of a benzodiazepine and opioid is superior to either drug alone; however, it is concerning that 25% of procedures were performed with just a benzodiazepine (McQuaid, Laine, 2008). This is likely due to a fear of opioid-induced respiratory depression. Research is lacking regarding the effectiveness of combining the two types of drugs for procedural sedation; however, several studies have established efficacy and opioid dose-sparing effects with the use of multimodal strategies (e.g., adding ketorolac or celecoxib to opioids) for acute pain, and the same principles of providing the lowest effective opioid dose can be applied during procedures (see Chapter 12). The importance of providing adequate analgesia cannot be overemphasized. This is especially important for patients who must endure repetitive procedures (Pasero, McCaffery, 1999).
Ketamine has been discussed elsewhere in this section for its use in treating various types of intractable persistent pain (see Chapter 23) and postoperative and other types of acute pain (see Chapter 26). See Chapter 23 for mechanisms and adverse effects and Box 23-1 on pp. 675-677 for administration guidelines. Following is a brief discussion of its use for sedation and analgesia during painful procedures.
Low doses of ketamine have been administered for many years to provide procedural sedation, particularly in children (Mistry, Nahata, 2005). For procedural sedation, ketamine is usually combined with other agents, such as opioids or benzodiazepines. A drawback of opioids and benzodiazepines is that they can produce dose-dependent respiratory depression. In contrast, ketamine produces dose-sparing effects and is rarely associated with respiratory depression. Its addition allows lower doses of these other agents and reduces the likelihood of respiratory depression.
Midazolam is one of the most common benzodiazepines combined with ketamine for sedation. The drug can both enhance sedation and minimize psychotomimetic and other adverse effects (Deng, Xiao, Luo, et al., 2001). Patients (N = 77) undergoing painful procedures in the ED setting were given 0.07 mg/kg of IV midazolam followed by IV ketamine 2 mg/kg over a 2-minute period (Chudnofsky, Weber, Stoyanoff, et al., 2000). Procedures were begun immediately after ketamine administration. The mean dose of midazolam administered was 5.6 mg, and the mean dose of ketamine was 159.1 mg. Adverse effects were considered minimal; 5 patients reported unpleasant dreaming, 3 experienced transient apnea, and 2 experienced emergence anxiety. As mentioned earlier, all 3 of the patients who experienced apnea weighed in excess of 97 kg and received large doses of midazolam. The mean time to discharge alertness was 63.4 minutes. All patients in this study, including those who experienced an adverse effect, stated that they would choose the same drugs to sedate them for future painful procedures.
A midazolam-ketamine combination has also been administered via IV PCA. A PCA dose of 10 mg of ketamine and 0.5 mg of midazolam per mL was self administered by 44 adult patients during painful burn dressing changes (MacPherson, Woods, Penfold, 2008). The incidence of adverse effects was low; hallucinations were the most common adverse effect, occurring in 11 of the 44 patients. Both patients and staff rated the method as highly effective.
The undesirable effects of ketamine have led some experts to recommend its prescription and management only by those skilled in pain management and anesthesiology (Bell, 2009; Cvrcek, 2008). Palliative care specialists are also among those knowledgeable in the safe administration of the drug. Some hospitals restrict the administration of ketamine to specific clinical areas, such as the ICU, palliative care, and the ED. Nurses should be aware of their scope of practice, state board of nursing’s opinions, and institutional policies and procedures regarding the administration and monitoring of agents such as ketamine.
Benzodiazepines have a long history as first-line drugs for procedural sedation, and ketamine has been used extensively for pediatric sedation and is increasingly used in adults for procedural sedation. Propofol and dexmedetomidine have become first-line agents for the administration of purposeful, goal-directed sedation such as in ventilated critically ill patients. They are also used with increasing frequency for procedural pain management. A major objective of goal-directed sedation and procedural sedation is to provide both analgesia and sedation. This underscores the importance of carefully considering the analgesic properties of the agents to be administered and providing appropriate analgesia such as opioids whenever indicated by the presence of a painful pathology, condition, or procedure.