Adjuvant Agents for Goal-Directed Sedation in the Critically Ill and for Procedural Sedation

Chapter 27


Adjuvant Agents for Goal-Directed Sedation in the Critically Ill and for Procedural Sedation



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


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.



Adverse Effects


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.



Analgesia During Propofol Sedation


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 Outside of the ICU


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).

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Related posts:

  1. Perioperative Nonopioid Use
  2. Other Challenges in Pain Assessment
  3. Intravenous Patient-Controlled Analgesia
  4. Switching to Another Opioid or Route of Administration

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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Adjuvant Agents for Goal-Directed Sedation in the Critically Ill and for Procedural Sedation

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