Use of Dexmedetomidine for Primary Sedation in a General Intensive Care Unit

Dexmedetomidine can help reduce duration of mechanical ventilation and number of days in the intensive care unit.Promotion of rest and sleep in critically ill patients facilitates healing. Multisystem adverse effects of sleep deprivation have been reported.1 Physical activity also plays a pivotal role in recovery and long-term outcomes.2 Use of sedation is important to help achieve the right balance between sleep and wakefulness; the correct balance is essential for incorporating physical activity and patients’ cooperation in the plan of care. Other goals of adequate sedation include optimizing safety for patients and caregivers, facilitating mechanical ventilation, reducing anxiety and delirium, inducing sleep, and, ultimately, providing comfort and safety.3Continuous chemical sedation in the intensive care unit (ICU) is commonly used to control respiratory rate and anxiety and thus promote sleep and ultimately optimize care. The sedatives used most often include propofol, midazolam, and lorazepam.4 All 3 of these medications provide adequate sedation but also can cause oversedation. Oversedation can lead to prolonged duration of mechanical ventilation, longer ICU and hospital stays, increased incidence of ventilator-associated pneumonia, and inability of patients to communicate with health care providers or family members.5 Undersedation is also harmful and can lead to anxiety, ventilator dysynchrony, dislodged equipment, delirium, increased oxygen consumption, and hyperactivity.6 Making the distinction between too much sedation and not enough sedation can sometimes be difficult when propofol, midazolam, or lorazepam is used.Achieving adequate sedation can also be a financial burden. Costs associated with undersedation include increased nursing and respiratory care staffing, discomfort and dissatisfaction of patients and their families, decreased staff satisfaction, adverse physiological consequences, and potential to progress to oversedation. Costs associated with oversedation include inadequate examinations of patients, increased costs of diagnostic imaging and other tests, possible delay in the diagnosis of treatable problems, prolonged duration of mechanical ventilation, prolonged stay in the acute care setting, and prolonged hospital stay.The purpose of this article is to increase nurses’ awareness of the pros and cons of chemical sedation in the ICU and of newer, alternative options. Dexmedetomidine has been available for more than 10 years, but information on its use and effectiveness is just now being published. In this article, I compare the profile of dexmedetomidine with the profiles of other common sedative agents used in the ICU. As more studies on dexmedetomidine are being performed, and positive results are being reported, the drug is becoming more popular. I describe the results of one hospital’s experience with dexmedetomidine and the usefulness and benefit of this sedative in the ICU.Dexmedetomidine was approved for use in the United States in 1999. It is a short-acting α2-agonist with anxiolytic, anesthetic, hypnotic, and analgesic properties.7 α-Agonists promote sedation by stimulating the locus caeruleus, a part of the brain stem involved in the sleep-wake cycle. Sedation is caused by inhibition of the sympathetic vasomotor center of the brain. Table 1 lists presynaptic and postsynaptic activation of α2-adrenoceptors.8,9 Unlike propofol and midazolam, which act on the γ-aminobutyric acid system and produce a clouding of consciousness, dexmedetomidine produces sedation by reducing sympathetic activity and the level of arousal.7The popularity of dexmedetomidine is due to its ability to promote cooperative sedation.8 Patients given this drug remain awake, but calm, and are able to communicate with health care providers. Because the patients remain awake, they may experience insomnia and require medication to facilitate sleep. The MENDS trial10 showed that patients given various doses of dexmedetomidine were completely arousable from sedation with a mild stimulus, such as a gentle touch or verbal stimuli. Dexmedetomidine does not affect the respiratory drive and therefore does not interfere with weaning from mechanical ventilation. Because of this characteristic, infusions of dexmedetomidine can be continued after extubation without the risk of respiratory failure, a complication that can occur with propofol, lorazepam, and midazolam.6,11 Control of anxiety after extubation is important to prevent reintubation. Studies10,12 have indicated that the need for rescue morphine postoperatively is reduced in patients given dexmedetomidine.The relatively short distribution half-life of about 6 minutes of dexmedetomidine results in rapid onset of sedation, and an elimination half-life of approximately 2 hours facilitates clearance of the drug.10 Dexmedetomidine is highly bound to protein and albumin. The drug is extensively metabolized in the liver, and its metabolites are excreted by the kidneys.10 Patients with severe liver disease may require a lower dose of dexmedetomidine than do other patients because the disease can increase the elimination half-life of the drug and decrease clearance.10Delirium is a common psychiatric problem in ICU patients. Up to 85% of ICU patients may experience some degree of delirium,4 leading to increased morbidity and mortality, prolonged hospital stays, prolonged duration of mechanical ventilation, patient injury or self-extubation, and respiratory complications.10 Table 2 lists the most commonly documented side effects associated with infusion of dexmedetomidine. Delirium has not been identified as a potential side effect of dexmedetomidine. In the MENDS randomized controlled trial10 in patients receiving mechanical ventilation who were managed with individualized targeted sedation, a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than did a lorazepam infusion. The use of lorazepam and other agents that stimulate γ-aminobutyric acid receptors is a risk factor for delirium. Therefore, medications, such as dexmedetomidine, that do not stimulate these receptors may minimize the development of delirium.7On the basis of the results of 2 randomized, double-blind, placebo-controlled trials in which total duration of treatment could not exceed 24 hours, dexmedetomidine currently is approved by the Food and Drug Administration for use in the ICU for no more than 24 hours. Several investigators4,7,8 have reported that the drug can be used safely for longer periods. Many institutions that allow prolonged infusions of dexmedetomidine in the ICU have not had patients’ experiencing hemodynamically significant, unexpected side effects.4,12 Approval by the Food and Drug Administration for use of infusions for longer than 24 hours is currently being explored. A 16% reduction in mean systolic blood pressure and a 21% reduction in heart rate during the first 4 hours of infusion but stabilization for the duration of the infusion have been reported.8 Even after abrupt discontinuation of the infusion, no significant clinical side effects occurred.In the Safety and Efficacy of Dexmedetomidine Compared With Midazolam study,4 the efficacy, safety, and pharmacokinetics of prolonged sedation with dexmedetomidine and midazolam in ICU patients receiving mechanical ventilation were examined. Compared with patients treated with midazolam, patients treated with dexmedetomidine had a significantly lower cumulative incidence of delirium. Nurses thought that the patients treated with dexmedetomidine were more cooperative, better able to communicate, and easier to treat overall than were patients sedated with midazolam. Patients given dexmedetomidine required 44.6 fewer hours of mechanical ventilation and 1.8 fewer days in the ICU than did patients given midazolam.4 Tables 3 and 4 compare the clinical effects and pharmacokinetics of dexmedetomidine with those of other commonly used sedatives.In a study performed in 2000,14 a total of 356 patients receiving dexmedetomidine with midazolam and propofol had lower total hospital charges, despite higher pharmacy and anesthesia charges, than did 9996 patients receiving midazolam and propofol without dexmedetomidine. The difference in total cost was mainly due to shorter ICU stays. The wholesale price is $55 to $61 for 100 mL of propofol and approximately $57 for a 200-μg vial of dexmedetomidine. The estimated cost of therapy for a 70-kg patient for 24 hours of treatment is $110 to $305 for propofol and $114 to $342 for dexmedetomidine.8Research on the use of dexmedetomidine during pregnancy, labor, delivery, and lactation is limited. The Food and Drug Administration has classified dexmedetomidine as a category C pregnancy risk, so the drug should be used with extreme caution in women who are pregnant. Dexmedetomidine should not be used in patients with advanced heart block or severe ventricular dysfunction.7 Studies have indicated the safety of dexmedetomidine infusions in intubated children and its benefit in providing sedation for procedures, such as magnetic resonance imaging.8Salina Regional Health Center, Kansas, is a 200-bed regional medical center with a 12-bed general medical-surgical ICU. Dexmedetomidine was first used in the center in September 2007, with prompting and support from the pulmonary/critical care specialist. Previously, propofol was the primary drug for sedation. Midazolam was used occasionally if a patient had an allergy to propofol or another medical reason the drug could not be used. The types of patients who commonly received propofol included postoperative patients and patients who had respiratory failure or sepsis. The ICU had a routine order set for patients receiving propofol (Table 5). A nurse would start the infusion at 5 μg/kg per minute and titrate the dose by 5 to 10 μg/kg per minute every 5 to 10 minutes to reach the desired level of sedation. The patient’s level of sedation was assessed by using the Ramsay Sedation Scale (RSS; Table 6). Typically, the target score was 3 (responds to commands only). At 5 AM each day, the nurse would decrease the propofol infusion by 5 to 10 μg/kg per minute every 5 to 10 minutes until the patient reached light levels of sedation. Once the nurse was confident the patient would awaken and move all extremities, an evaluation was performed to determine if the patient was ready for weaning from mechanical ventilation. If the patient was ready for weaning, the propofol infusion would be left at a low level so the patient could participate in weaning. If the patient was not ready for weaning, the propofol dose would be increased to provide a level of adequate sedation (according to the RSS).The dissatisfaction associated with oversedation that commonly occurs with propofol and other sedative agents5 led to the consideration of experimenting with dexmedetomidine. Other problems encountered with the use of propofol included the daily wake-up not being performed, disorientation or delirium with prolonged use (>48 hours), and the excessive amount of calories associated with high rates of propofol administration.A daily assessment of neurological status must be performed on patients receiving sedative agents. Prolonged immobility paired with critical illness places patients at high risk for central nervous system events, such as strokes. A daily decrease in sedation and assessment of neurological status will alert health care providers to any changes in a patient’s function. Propofol is a lipid-soluble agent that provides 1.1 kcal/mL as fat.15 High doses of propofol in addition to enteral or parenteral feeding can lead to a high caloric load. All of these issues can lead to prolonged duration of mechanical ventilation, prolonged stay in the ICU, and a prolonged hospital stay.15I worked with a pharmacist to develop a protocol for initiation of the dexmedetomidine infusion. Dexmedetomidine is supplied in a single 2-mL clear-glass vial at a concentration of 100 μg/mL. It must be diluted to a final concentration of 4 μg/mL.10 The infusion is prepared with 200 μg of dexmedetomidine in 50 mL of normal saline (concentration=4 μg/mL). The decision was made to omit the loading dose because patients in the ICU commonly experience hypotension, and the loading dose is associated with a high risk for hypotension. After obtaining a physician’s order, the nurse would start the infusion at 0.2 μg/kg per hour and titrate up to a maximum of 0.8 μg/kg per hour to the desired level of sedation, typically a score of 2 or 3 on the RSS. According to the protocol (Table 7), if a patient requires the maximum dose of dexmedetomidine and agitation persists, a fentanyl infusion could be started at 50 μg/h. The protocol also allows the nurse to administer midazolam 1 to 5 mg intravenously as needed for procedures. Zolpidem is available on the physician’s routine orders if it is needed for sleep at night.At times, agitation was severe enough that the maximum dose of dexmedetomidine plus fentanyl did not keep a patient calm. In this circumstance, a physician would be contacted, the dexmedetomidine and fentanyl would be discontinued, and treatment with propofol would be started. Patients given propofol typically required titration of the drug to an RSS score of 4, which is defined as a brisk response to light glabellar tap or loud auditory stimulus. This level of sedation is higher than that typically used at the center, but protecting the patient from harm (eg, self-extubation, pulling out catheters) is always the first priority. When these patients’ clinical status was stable and they were ready to be weaned from mechanical ventilation, the propofol dose would be titrated down and dexmedetomidine would be initiated to alleviate anxiety. This drug combination seemed to keep the patients calm enough to cooperate with weaning.During the study period (September 2006 through May 2007), a dexmedetomidine infusion was started in 42 patients. A data tool (Table 8) was developed to keep track of the patients receiving dexmedetomidine. This tool was used to track diagnosis, date of intubation, dose of dexmedetomidine, use of other sedatives, mean blood pressure, mean heart rate, score on the RSS, ventilator settings, and any weaning from mechanical ventilation that was started. Of the 42 patients, only 4 continued to be agitated when given the maximum dose (dexmedetomidine 0.8 μg/kg per hour plus fentanyl 50 μg/h) and had to be given propofol. Table 9 gives the study results. None of the 42 patients experienced hypotension or bradycardia sufficient to require discontinuation of the dexmedetomidine infusion.Table 10 gives the data on days of mechanical ventilation (ventilator days) before dexmedetomidine was used (September 2006 through May 2007) and during use of the drug (September 2007 through May 2008). Total ventilator days were 1003 for September 2006 through May 2007 and 928 for September 2007 through May 2008, an 8% decrease (75 fewer days) in total days of mechanical ventilation (P = .05). Table 11 gives data on ICU length of stay before dexmedetomidine was used (October 2006 through May 2007) and during use of the drug (October 2007 through May 2008). Total ICU days were 1686 for October 2006 through May 2007 and 1414 for October 2007 through May 2008, a 19% decrease (272 fewer days) in total ICU days (P = .05). Mean length of stay decreased from 2.34 days to 2.31 days (1.5% reduction; P = .05). All of these results are statistically significant.Decreasing the duration of mechanical ventilation and length of stay in the ICU can have a significant effect not only on the recovery period of a patient but also financially. Studies4–6 have confirmed that agitation can have a deleterious effect on patients by contributing to ventilator dysynchrony and an increase in oxygen consumption, situations that can lengthen the duration of mechanical ventilation.4–6 The use of sedatives is essential in the ICU.15 This study showed that dexmedetomidine can help reduce duration of mechanical ventilation and number of days in the ICU. Because dexmedetomidine facilitates a cooperative sedation, weaning from mechanical ventilation can be started sooner, and patients are able to cooperate with physical therapy while communicating their needs. Both of these factors are important in recovery, which can be hastened when a patient is alert. Dexmedetomidine is as effective as propofol and midazolam for sedation of critically ill patients.4,6,10 In this study, patients receiving dexmedetomidine were calm, in stable hemodynamic status, and able to participate in the weaning process more quicker than were patients given midazolam or propofol.An incidental discovery was that the rate of ventilator-associated pneumonia was 0% during the time dexmedetomidine was used. Previously the center had 5 cases February through May 2007 and 1 case June through September 2007. This finding supports the well- established fact that less time receiving mechanical ventilation helps prevent pneumonia.Because patients in the ICU account for nearly one-third of total inpatient costs, efforts to reduce duration of mechanical ventilation, time in the ICU, and complications associated with being in the ICU have a significant effect on hospital costs.16 In the experience at Salina Regional Medical Center, dexmedetomidine is a safe, effective sedative for use in the ICU.