Analgesia and sedation in mechanically ventilated patients

Although significant advancements have been made to help guide clinicians in the appropriate management of analgesia and sedation in patients requiring ventilator support, areas of controversy remain.  Further complicating the issue is that optimal management strategies may differ based on patient population (e.g., surgical versus medical patients), underlying disease states (e.g., patients with or without underlying pulmonary disease), and concomitant conditions that may affect drug pharmacokinetics (e.g., therapeutic hypothermia, hepatic or renal disease, heart failure).  The following is a collection of evidence-based strategies for managing analgesia and sedation in medical patients requiring ventilator support.

Optimizing the patient environment.  While most patients will require pharmacologic therapy for the management of agitation, several non-pharmacologic strategies have also been shown to improve outcomes in patients admitted to the intensive care unit (ICU) [1]. Many of these interventions are aimed at maintaining patient sensorium, while others focus on both short- and long-term mental and physical rehabilitation.  Non-pharmacologic strategies for optimizing the patient environment include reducing interruptions and ambient noise, promotion of the physiologic sleep-wake cycle, music and recreational therapy [2,3], and early mobilization and physical rehabilitation [4,5]. 


Minimization of sedative use and preference for opioid analgesics over traditional sedatives (e.g., propofol, benzodiazepines) as the first-line strategy for managing agitation.While agitation is common among patients requiring ventilator support and may complicate ongoing management [6], optimal strategies for managing analgesia and sedation have not been well-defined. Furthermore, uncontrolled discomfort and pain are the most common sources of agitation in critically ill patients, but many are incapable of accurately expressing or describing pain. A common misconception is that amnesia (i.e., not remembering an ICU stay) is helpful in the critically ill population; however, appropriate sensorium and memories have been shown to improve both short-term and long-term psychological outcomes [7].  Additionally, while sedated patients may not recall some details of their hospitalization, survivors of an ICU admission often recall inadequately controlled pain [8].

Although some patients may require the use of sedatives (e.g., propofol, benzodiazepines) for the management of agitation, these agents should be used sparingly, as they are associated with numerous complications in critically ill patients, including gastrointestinal hemorrhage, venous thromboembolism, ventilator-associated pneumonia, bacteremia, and post-traumatic stress disorder (PTSD) among ICU survivors [7,9]. While opioid analgesics are not without adverse effects, they have the advantage of providing both analgesia and sedation without amnestic effects.  In fact, when compared to a combination of opioid analgesics and sedatives (i.e., propofol, midazolam), the use of opioids alone has been shown to reduce duration of ventilator support, ICU length of stay, and overall hospital length of stay; the practice may also improve the ability to detect delirium among critically ill patients [10]. 

Preference for intermittent intravenous boluses over continuous intravenous infusions. Compared to intermittent intravenous boluses, the use of continuous infusion sedatives (including sedative doses of opioid analgesics) in critically ill patients is associated with worsening outcomes, including longer durations of ventilator support, ICU length of stay, and overall hospital length of stay [11,12]. Additionally, patients receiving sedation via continuous infusion are also more likely to be oversedated than those receiving intermittent boluses [13].

The pharmacologic advantages of continuous intravenous infusions (e.g., fentanyl, midazolam) are primarily intended for those patients in whom the duration of mechanical ventilation is expected to be very short (< 24-48 hours, i.e., surgical patients, post-operative cases), where rapid awakening is anticipated and desired.  However, the duration of ventilator support is typically longer in critically ill medical patients, due both to the severity of illness and irreversible nature of many of the concomitant disease states that characterize this patient population. As a result, the adverse effects of continuous intravenous infusions (e.g., accumulation of parent drug and active metabolites, tissue distribution, drug-specific infusion syndromes, oversedation) are more likely to outweigh their pharmacologic advantages.


Identification and management of delirium as an adjunct to analgesic and sedative therapy. Although it may be present in up to 80% of patients in the intensive care unit [1], ICU delirium often goes undiagnosed, where it contributes to a number of adverse outcomes, including both short and long-term psychiatric morbidity (e.g., cognitive impairment, functional disability) and mortality [14,15]. The identification and appropriate management of delirium is further complicated by the fact that many agents used for the management of analgesia and sedation not only mask delirium but may also contribute to it. As a result, routine evaluation for the presence of delirium in ICU patients is currently recommended [1]. The most well-validated scale for identifying delirium in critically ill patients is the Confusion Assessment Method for the ICU (CAM-ICU), where a diagnosis of delirium may be made in up to 90% of cases [16].

Neuroleptics are considered the agents of choice for the management of ICU delirium. Although some alternatives exist, haloperidol is the most extensively studied in the setting of agitated delirium.  Loading doses may be used for acutely agitated patients while lower doses may be scheduled every 4-6 hours once the acute episode is well-controlled. One of the most concerning adverse effects of haloperidol is its propensity to cause or contribute to QT-interval prolongation.  While caution should be exerted with the use of haloperidol in patients with a history of advanced heart disease, QT-interval prolongation is often dose-related, both in terms of cumulative dose (> 50 mg per day) and when high intermittent doses (e.g., > 20 mg) are given intravenously [17].  The risk of torsades de pointes is likely overestimated, as studies and case series suggest an incidence of < 4% [17-18]. While incidence of QT-interval prolongation is reportedly lower with atypical and other newer generation antipsychotics, this assertion is not well-supported by the literature. 


Daily interruption of sedative therapy as a strategy to wean pharmacologic therapy.  After it was shown to shorten the duration of ventilator support and ICU length of stay in a large randomized controlled trial, performing a daily interruption of sedative therapy (i.e., “daily awakening”) has been advocated as a standard of care for critically ill patients receiving mechanical ventilation [19]. While interruption of sedative therapy is an important component of assessing neurocognitive status in critically ill patients, it should also be used as a strategy to wean pharmacologic therapy when clinical condition permits.  In the landmark trial conducted by Kress et al [17], sedative therapy was discontinued if patients remained comfortable following the daily interruption; if ongoing sedation was required, it was restarted at half the previous dose and only up-titrated based on patient need.

References

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