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Top 10 Myths Regarding Sedation and Delirium in
Gregory J. Peitz, PharmD, BCPS1,2; Michele C. Balas, PhD, RN, APRN-NP, CCRN3; Keith M. Olsen, PharmD, FCCP, FCCM2; Brenda T. Pun, RN, MSN, ACNP4; E. Wesley Ely, MD, MPH5,6 Abstract: The management of pain, agitation, and delirium in criti-cally ill patients can be complicated by multiple factors. Decisions Sedation and analgesia practices in conjunction with delirium reduction measures in critically ill patients have to administer opioids, sedatives, and antipsychotic medications been evolving processes. Over the last two decades, thera- are frequently driven by a desire to facilitate patients' comfort and peutic interventions have changed coinciding with new trials their tolerance of invasive procedures or other interventions within and published evidence. The positive benefits of spontaneous the ICU. Despite accumulating evidence supporting new strate- awakening trials (SATs), spontaneous breathing trials (SBTs), gies to optimize pain, sedation, and delirium practices in the ICU, and the implementation of early mobility in critically ill many critical care practition ers continue to embrace false per- patients have all been demonstrated (1–3). In addition, inves- ceptions regarding appropriate management in these critically ill tigators and clinicians have further defined the prevalence and patients. This article explores these perceptions in more detail and consequences of ICU-induced delirium (4–7).
offers new evidence-based strategies to help critical care practi- In January 2013, the American College of Critical Care tioners better manage sedation and delirium, particularly in ICU Medicine/Society of Critical Care Medicine (SCCM) released patients. (Crit Care Med 2013; 41:S46–S56) the pain, agitation, and delirium (PAD) guidelines that provide Key Words: agitation; analgesia; critical care medicine; delirium; a broad synopsis of PAD interventions aimed at improving evidence-based; myth; pain; sedation short- and long-term outcomes in ICU patients (8). Traditional approaches to managing pain, sedation, and delirium in ICU patients may be at odds with several of the PAD guideline rec- Department of Pharmaceutical and Nutrition Care, University of Nebraska Medical Center, Omaha, NE.
ommendations and can lead to poor ICU patient outcomes. 2Department of Pharmacy Practice, College of Pharmacy, University of Widespread adoption of the PAD guidelines will require sig- Nebraska Medical Center, Omaha, NE.
nificant efforts to overcome these perceptions or "myths" with 3The Ohio State University College of Nursing, Center for Critical and intensive provider education and retooling of ICU PAD prac- Complex Care, Columbus, OH.
tice patterns. The primary objective of this article is to explore 4Department of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt the basis of these myths regarding sedation and delirium in University Medical Center, Nashville, TN.
ICU patients and to provide alternative evidence-based strate- Department of Medicine, Division of Pulmonary and Critical Care, Vander- bilt University School of Medicine, Nashville, TN.
gies in order to help ICU clinicians improve the management 6VA-GRECC (Geriatric Research Education Clinical Center) for the VA of pain, sedation, and delirium in critically ill patients in an Tennessee Valley Healthcare System, Vanderbilt University Medical Cen- integrated and interdisciplinary fashion, based on the recom- ter, Nashville, TN.
mendations included in the 2013 ICU PAD guidelines.
Dr. Balas is currently a coinvestigator on a grant supported by the Alzheimer's Association, has received honoraria from the France Foun- dation and ProCE, and is a consultant for the Centers for Disease Con- trol and Cynosure Health. Dr. Olsen received honoraria from Covidien SEDATION AND ANALGESIA MANAGEMENT
and is a coinvestigator on a grant supported by the National Institutes of IN THE ICU
Health. Ms. Pun has received honoraria from the France Foundation and ProCE. Dr. Ely has a grant/grants pending from Lilly; received honoraria Myth 1: All Mechanically Ventilated ICU Patients
from Hospira, Orion, and Abbott; and is a consultant for Cumberland and Masimo. Dr. Peitz has disclosed that he does not have any potential conflicts of interest.
A common perception concerning the critically ill is that all Address requests for reprints to: Gregory J. Peitz, PharmD, BCPS, patients who require mechanical ventilation should receive Department of Pharmaceutical and Nutrition Care, University of Nebraska sedative medications. Sedatives, including benzodiazepines, Medical Center, 981090 Nebraska Medical Center, Omaha, NE 68198- propofol, and dexmedetomidine, are routinely administered to ICU patients in conjunction with opioids in order to allay Copyright 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins patients' anxiety, reduce recall of unpleasant ICU experi- ences, improve patient tolerance of mechanical ventilation, www.ccmjournal.org September 2013 • Volume 41 • Number 9 (Suppl.) suppress hyperadrenergic responses, and provide treatment Although this study provided evidence of potential ben- for substance withdrawal (8–10). Additionally, sedatives may efits of a no-sedation (i.e., analgesia-first or analgosedation) also be indicated for treating patients with status epilepticus, approach, it had significant limitations. The study site located increased intracranial pressure, acute psychiatric illness, or in Denmark was already accustomed to a standard of care of for patients receiving neuromuscular blocking agents for any providing no sedation to ICU patients. Patients admitted to reason (9). But the administration of sedative agents is also this ICU were historically treated with as-needed IV morphine associated with undesirable short- and long-term outcomes boluses, with little utilization of continuous sedative or anal- in these patients. Short-term side effects include respiratory gesic infusions. The ICU nurse-to-patient ratio in this institu- depression, hemodynamic instability, or metabolic acidosis tion was also 1:1, and physical restraints were never used in ICU and vary with the type and dose of sedative used. Sustained patients. In those patients who displayed signs of discomfort, all use of sedatives can prolong mechanical ventilation, increase potential causes (i.e., pain, hypoxia, and tube obstruction) were ICU length of stay (LOS), and increase the likelihood of ICU systematically addressed. When an ICU patient became deliri- patients developing acute delirium (11, 12). A meta-analysis ous, a staff person was assigned to verbally comfort and reassure investigating outcomes related to ICU sedation showed that the patient until the was delirium resolved. Although all of these benzodiazepines (i.e., midazolam and lorazepam) are associ- confounding factors may limit the generalizability of this study's ated with a longer ICU LOS than nonbenzodiazepines (i.e., findings to other institutions with less rigorous delirium man- propofol and dexmedetomidine). An updated version of this agement methods and varying staffing levels, all of these points meta-analysis, published by Fraser et al (13) in this supple- are important contextual factors that may influence sedative ment, confirmed this finding, while simultaneously showing administration practices elsewhere. Other studies using analge- that benzodiazepines are associated with a prolonged duration sia-first strategies have also demonstrated improvements in ICU of mechanical ventilation compared to nonbenzodiazepines outcomes, particularly reducing the duration of mechanical when used for sedation. Benzodiazepine-based sedation in ventilation and ICU LOS, resulting in a PAD guideline recom-ICU patients has also been linked to long-lasting psychiatric mendation that "analgesia-first sedation be used in mechanically comorbidities, including posttraumatic stress disorder (PTSD) ventilated adult ICU patients (2B)" (8, 16, 17).
and depression. A study of 157 adult ICU patients found that the strongest clinical risk factor for developing PTSD after Myth 2: It Is Easier to Care for Deeply Sedated ICU
hospital discharge was the prolonged administration of seda- tive medications (14). Patients who received benzodiazepines Sedatives are often administered to critically ill patients in for sedation in particular were also more likely to experience order to facilitate patient care activities by ICU staff (18). In a depression at 3 months after they were discharged from the survey of 423 critical care nurses, nearly one third of respon- ICU. Given the risks associated with sedative medications in dents agreed or strongly agreed with the statement that all the ICU population, clinicians must carefully assess the risk/ mechanically ventilated patients should be sedated. Addition- benefit ratio of their use in these patients.
ally, 48% of those surveyed indicated their intention to sedate The question that this issue raises is: Can an ICU patient all of their mechanically ventilated patients (18). Coinciding receiving mechanical ventilation be safely managed primar- to these attitudes, the prevalence of mechanically ventilated ily using opioids with little, if any, sedative medications (i.e., patients receiving IV sedative infusions in the United States has an analgesia-first strategy)? Perhaps the best-known study doubled over the period 2001–2007 (19). These findings sug-designed to address this question was published by Strøm et gest a widespread culture of keeping mechanically ventilated al (15), who randomly assigned 140 medical and surgical ICU ICU patients at deep levels of sedation in order to facilitate patients undergoing mechanical ventilation to receive either ICU patient care activities. To address this notion that deeply a protocol of no sedation (primarily IV morphine boluses of sedating ICU patients facilitates easier patient care, one should 2.5–5 mg, with allowances for either IV haloperidol boluses first address the question, "easier for whom?" or rescue propofol infusions for 6-hr periods) or a regimen of Survey data have identified a number of factors that influ- sedation (IV propofol infusion titrated to a Ramsay score of 3–4 ence ICU nurses' decisions to administer sedative medica- for a maximum of 48 hr, followed by an IV midazolam infusion tions to critically ill patients. The primary indications listed by thereafter, with IV morphine boluses of 2.5–5 mg as needed), nurses for administering sedation are to provide patient com- with daily sedation interruptions until patients awoke. Patients fort, induce amnesia, and prevent self-injurious behaviors by in the no-sedation group had significantly more days without patients. Many nurses also believe that the overstimulation of mechanical ventilation than patients in the sedation cohort patients by family members is a valid rationale for administer-(mean difference = 4.2 d; 95% CI, 0.3–8.1; p = 0.02). Patients in ing additional sedative doses (9). Other potential benefits of the no-sedation group also experienced a significantly shorter deep sedation include enabling ICU nurses to be "more effi- ICU LOS (hazard ratio, 1.86; 95% CI, 1.05–3.23; p = 0.03), but cient" by facilitating their ability to safely multitask without they also experienced higher rates of hyperactive delirium (20% having to closely watch individual patients and to better man- vs 7%; p = 0.04) than patients in the sedation arm. There was no age nurse-to-patient staffing ratio (18).
difference in the prevalence of accidental extubation or ventila- From ICU patients' perspective, they might believe that it tor-associated pneumonia between the two groups.
would be "easier" for caregivers to care for them if they were Critical Care Medicine www.ccmjournal.org awake, alert, comfortable, and able to communicate effec- alterations in bowel motility, and increased release of inflam- tively with ICU staff. Presumably, unsedated or lightly sedated matory mediators, while also suffering from increased anxiety, ICU patients would be able to express their acute needs, lead- fatigue, sleep deprivation, and delirium (25). The causes of ing to a more positive experience for them during their ICU postoperative pain in surgical ICU patients are easily recogniz- stay. Additionally, being alert and interactive would also allow able (e.g., incisions and drains), but pain in the nonsurgical patients to participate in their own care decisions, including ICU patients often goes unrecognized. One study of 171 ICU making end-of-life decisions for themselves. ICU patients who patients, of which 34% were mechanically ventilated, found are able to interact in a meaningful way with ICU staff and at least 40% experienced significant pain during their ICU actively participate in their own care are also more able to par- care (26). Another study examined mechanically ventilated ticipate in activities such as SBTs and early mobility activities patients' physiologic responses to endotracheal suction by that will likely shorten their duration of mechanical ventilation measuring hemodynamic and respiratory variables, pupillary and ICU LOS.
responses, facial expressions, muscle tone, body movements, A growing body of evidence demonstrates that deep seda- and patients' RASS score (27). The responses were assessed tion of ICU patients is more harmful to patients than main- after endotracheal suction in ICU patients who were initially taining them at light levels of sedation. Shehabi et al (20, 21) sedated, then following the discontinuation of sedation, and reported that early deep sedation resulted in longer mechani- once again following opioid administration. Endotracheal suc- cal ventilation times and increased 6-month mortality. tioning induced signs of pain that included changes in hemo-Furthermore, because sedative medications are associated with dynamic and respiratory variables, muscle tone, and body the development of delirium, it is logical to assume that if these movements in all three groups, including those that received medications were targeted to maintain patients at lighter lev- an opioid dose after suctioning. The authors concluded that els of sedation, both the prevalence and duration of delirium endotracheal suctioning is a major source of physical discom- may be reduced. One recent study investigated the effects of fort in ICU patients, and despite analgesic therapy, standard maintaining mechanically ventilated patients with acute lung ICU doses of opioids were inadequate to attenuate the pain injury at a lighter level of sedation (i.e., a target Richmond response associated with endotracheal suctioning. Numerous Agitation-Sedation Scale [RASS] score of 0 [alert and calm]) other sources of painful stimuli in ICU patients have been using as-needed IV sedative boluses as first line, with continu- identified including mechanical ventilation and other routine ous sedative infusions used only if patients failed the bolus ICU procedures (e.g., needle sticks, urinary catheter insertions, treatment regimen (22). In addition, the trial implemented a central venous and arterial catheter placements, and bronchos- twice-daily delirium screening into routine practice using the copies) (8).
Confusion Assessment Method for the ICU (CAM-ICU). This In heavily sedated mechanically ventilated patients, it is integrated approach resulted in: 1) a reduced use of continuous often very difficult to adequately assess pain control, particu- opioid and sedative infusions in ICU patients (median propor- larly if validated pain score instruments are not used in patients tion of medical ICU days per patient: 33% vs 74% and 22% vs who cannot self-report their pain (28). A multicenter study of 70%, respectively, both p < 0.001); 2) an increase in ICU patient 44 ICUs in France and Luxembourg examined pain and seda- wakefulness (i.e., median RASS score per patient: –1.5 vs –4.0, tion practices in 1,381 mixed ICU patients (29). Despite over p < 0.001); and 3) an increase in the number of days that ICU 90% of patients receiving opioid analgesics, only 42% received patients were awake and not delirious (i.e., median proportion a documented pain assessment within 48 hours of ICU admis- of medical ICU days per patient: 19% vs 0%, p < 0.001). Since sion. In this study, adequate pain recognition was important delirious patients can be very difficult to care for and lead to because the subsequent secondary analysis showed that for increased healthcare costs (6), the prevention of delirium by those ICU patients who did receive pain assessment within 48 sedation reduction may actually make ICU patients easier to hours, they were more likely to receive targeted pain treatment care for in this instance. Perceived difficulty in taking care of and had a shorter duration of mechanical ventilation (i.e., 8 d lightly sedated patients notwithstanding, the evidence outlined vs 11 d; p < 0.01) and a significant reductions in ICU LOS (13 in the new PAD guidelines clearly favors keeping ICU patients d vs 18 d; p < 0.01) (30). These assessments held true regard- less sedated and more interactive, resulting in a strong recom- less of underlying diagnosis, including those patients with mendation that "sedative medications be titrated to maintain a nonoperative pain. In a separate study, 21 patients from vari- light rather than a deep level of sedation in adult ICU patients, ous diagnostic groups were assessed for recollection of painful unless clinically contraindicated (1B)." experiences if they regained consciousness prior to discharge from the ICU. Nearly 50% of these patients recalled experienc- Myth 3: Only Surgical ICU Patients Experience Pain
ing moderate to severe pain along with anxiety, fear, and sleep ICU patients routinely receive sedatives and analgesics during fragmentation during their ICU stay (31). From these data we their care, and yet 27–77% of all ICU patients still experience conclude that significant pain commonly occurs in both non- significant pain (23), with resulting negative alterations in phys- surgical and surgical ICU patients. Painful experiences often iologic and neurocognitive functions (24). Acutely ill patients go unrecognized and untreated in these patients, due to a lack experiencing untreated pain may develop tachycardia, tachy- of ICU provider recognition because patients are too sedated pnea, diaphoresis, increased myocardial oxygen consumption, to be able to self-report their pain, and because valid and www.ccmjournal.org September 2013 • Volume 41 • Number 9 (Suppl.) reliable behavioral pain assessment tools are not widely used in healthy subjects (40, 41). Based on currently available evi- in most ICUs. The undertreatment of pain in these patients dence, sleep disturbances in the ICU are poorly understood also increases the risk of them developing acute delirium dur- and may lead to grave consequences including a higher mor- ing their ICU stay and for developing symptoms of PTSD after tality (34). Equally important, the use of continuous sedative ICU discharge (32, 33). An analgesia-first strategy can improve infusions for sleep promotion is also associated with higher pain management and reduce the need for sedatives in criti- delirium rates, which is also associated with a higher risk of cally ill patients and is one of the key recommendations of the mortality in ICU patients. So the question must be asked: Does 2013 ICU PAD guidelines (8).
drug-induced sedation really benefit ICU patients in terms of facilitating sleep, or merely appear to mimic sleep? Due to Myth 4: Sedatives Help to Facilitate Sleep in ICU
potential undesirable side effects of sedation, promotion of sleep in ICU patients should focus more on environmental One of the perceived benefits of sedative therapy is the provi- sleep hygiene programs to facilitate natural sleep rather than sion of sleep in ICU patients. Sleep deprivation is associated drug-induced sedation that paradoxically impairs sleep in crit- with a higher risk of ICU patients developing delirium (31, ically ill patients. This would include strategies to control ICU 34, 35). Risk factors for sleep fragmentation in ICU patients light and noise at night, clustering ICU patient care activities include mechanical ventilation, untreated pain, ambient noise to be at specific times, and decreasing nighttime stimuli to pro- and light during nighttime hours, prior alcohol use, drug tect patients' sleep cycle (8, 42).
therapy before admission, and concurrent medication therapy (34). The "traditional" approach to overcome discordant ICU DELIRIUM MANAGEMENT IN ICU PATIENTS
sleep patterns was to heavily sedate critically ill patients with continuous sedative and opioid infusions, a practice previ- Myth 5: Delirium Is a Benign and Expected Side
ously endorsed in the 2002 version of the SCCM's ICU seda- Effect of Being in the ICU
tion and analgesia guidelines (36). But this practice of using Delirium is defined as an acute change in mental status accom- sedatives to facilitate sleep in ICU patients warrants further panied by inattention (43). It can manifest as one of three scrutiny (34, 37).
subtypes: hyperactive (e.g., restless, agitated, or combative), ICU patients typically experience only level I and II sleep hypoactive (e.g., lethargic, slow responses), or mixed (i.e., a patterns, with extended periods of wakefulness juxtaposed fluctuation between hyperactive and hypoactive subtypes). with brief periods of light sleep (34, 35). Rarely do ICU patients Historically, these types of mental status changes, especially progress to level III or IV (rapid eye movement [REM] or non- hyperactive delirium, were labeled as "ICU psychosis" and REM) sleep patterns for prolonged periods of time, thereby considered to be an ICU experience that would eventually depriving themselves of the physiologic and immunologic resolve when the patient was transferred with minimal impact benefits of deep sleep (34, 35). Similar patterns of sleep depri- on short- or long-term patient outcomes. A 2004 survey by vation and fragmentation in ICU patients or healthy subjects Ely et al (44) reported that only 23.7% of providers agreed result in similar patterns of cognitive impairment, disassoci- or strongly agreed that delirium was "normal" in the ICU, ated thought processes, and psychotic behaviors (34).
but more than 45% of the same respondents disagreed or The mechanisms that lead to normal sleep patterns are strongly disagreed that delirium caused long-term neurologic thought to involve circadian rhythms and the activation of or psychological defects. However, with the development of gamma-aminobutyric acid (GABA) and galananin inhibitory valid and reliable tools to detect delirium in ICU patients, we neurons (34, 35, 37). Benzodiazepines and propofol, the most have gained a greater understanding of the epidemiology of commonly used sedatives in ICU patients, interact with the delirium in ICU patients over the past decade. We now know GABA receptor to promote inhibitory effects that lead to cen- that acute delirium affects up to 80% of critically ill patients tral nervous system depression, followed by hypnotic effects and 10% of these patients remain delirious at the time of their (38). These agents promote level I and II non-REM sleep but hospital discharge (7, 45–47). ICU delirium is associated with suppress level III and IV sleep. Furthermore, benzodiazepines a longer duration of mechanical ventilation, longer ICU and reduce cerebral blood flow after just a single IV dose, and pro- hospital length of stay, and increases in-hospital mortality (4, pofol reduces cerebral glucose metabolism (35). In a small 5, 7). Pisani et al (48) determined that each day that a patient is study of healthy subjects receiving propofol, whole brain glu- delirious in the ICU increases the risk of death by 10%. There cose metabolic rates were depressed by 48–58% in subcorti- are also significant long-term consequences of ICU delirium, cal and cortical regions, respectively (39). Opioids also impact affecting patients long after their ICU and hospital discharge. sleep by inducing a dose-dependent effect on mu receptors, Delirium is associated with a three-fold increased risk of death resulting in a suppression of REM sleep. Thus, the combina- up to 6 months after hospital discharge (5). Delirium is also tion of sedatives as GABA receptor inhibitors administered in linked to the development of long-term, dementia-like cogni- conjunction with opioids may produce a multifactorial effect tive impairment. Girard et al (49) reported that an increase in on sleep and sleep patterns in ICU patients. Likewise, when delirium duration in the ICU from 1 day to 5 days was asso- these medications are rapidly withdrawn, a rebound surge ciated with nearly a five-point decline in cognitive battery in REM activity occurs that has been linked to nightmares scores 6 months after discharge. One ICU survivor describes Critical Care Medicine www.ccmjournal.org her experience, "One quite literally loses one's grip on what is of the time), less than half of the same respondents (47%) true and what is false because the true and the false are mixed would simultaneously perform a delirium assessment, despite together in a mess of experience" (50). The economic costs of this step being mandated by their own sedation protocol. Some ICU delirium are also considerable, resulting in an additional of this low compliance with delirium assessments may stem expenditure of $4–$16 billion in United States healthcare dol- from the fact that only 63% of respondents had ever received lars annually (6).
formal training in delirium assessments, and more than 40% Given these significant risks and costs associated with the of all respondents indicated that neither the CAM-ICU nor development of delirium in critically ill patients, ICU teams ICDSC tools were ever mentioned or employed at their institu- should view delirium as a form of acute brain dysfunction tion. Other studies illustrate similar findings, describing both and give it the same attention as other organ system failures low prevalences of delirium screening and low confidence in in ICU patients (45), beginning with accurate delirium detec- the ability to accurately recognize delirium in ICU patients tion. Without using a standardized delirium assessment tool, (58, 59). This question of caregivers' ability to appropriately ICU clinicians may underestimate the presence of delirium identify delirium when present was studied in more detail in critically ill patients (51–53). For this reason, the ICU PAD by Spronk et al (7). Using CAM-ICU scores performed by a guidelines (8) recommend that all ICU patients be routinely group of independent study-specific nurses to verify actual screened for delirium using a valid and reliable assessment caregivers' assessment of delirium status, the study's results tool, such as the Confusion Assessment Method for the ICU demonstrated that there is an identification deficit pertaining (CAM-ICU) (47, 54) or the Intensive Care Delirium Screening to accurate delirium diagnosis. The study's observations con- Checklist (ICDSC) (55). All ICU patients should be systemati- cluded that only 28% of delirium days were correctly identified cally evaluated for delirium with institutional strategies imple- by intensivists; ICU nurses faired slightly better in this study mented to prevent and reduce the occurrence and impact of with a delirium detection rate of only 35%.
delirium, such as ICU early mobility, sleep hygiene programs, The aforementioned misunderstanding and poor recogni- and the minimization of benzodiazepine use in patients who tion of delirium prompts investigation into the rationale for are at risk for delirium (3, 12, 56, 57).
low compliance with delirium assessments. Several barriers to performing appropriate delirium screening may currently exist Myth 6: Delirium Assessment and Recognition Is
for healthcare providers. Potential limitations to using delir- Consistent and Uniform
ium assessment tools include difficulty in assessing delirium Given that delirium is a common problem in the ICU and in intubated or sedated patients, assessment tool complexity, associated with worse clinical outcomes (4–6, 48), it is impera- and caregivers' perception of unimportant results (53, 60). tive to reliably detect delirium in order to minimize risk fac- Despite these barriers, institutionally driven educational pro- tors or initiate appropriate treatment interventions. Of the grams have been shown to improve delirium screening accu-screening tools available for delirium, the most reliable scoring racy and compliance rates, while maintaining them for several indicators are the previously mentioned CAM-ICU and the years (61–64). These studies support the PAD guidelines' claim ICDSC (47, 55), both of which are recommended by the PAD that systematic ICU delirium screening is feasible and promote guidelines (8). Despite the endorsement for the use of these efforts to boost staff education and the monitoring of delirium tools, available literature suggests suboptimal compliance and screening implementation programs. As efforts to improve reliability with the performance of delirium screenings.
outcomes related to delirium in intensive care patients become Survey data demonstrate a wide range of delirium screen- more widely accepted, it is important that delirium monitor- ing practices, perceptions, and attitudes across multiple health- ing be performed regularly in the ICU, as early detection of care disciplines, with low adherence and familiarity with ICU delirium could lead to faster resolution in these patients.
delirium screening. In a survey of 912 healthcare professionals including 753 physicians, only 32% of the survey respondents Myth 7: All ICU Delirium Is Similar and Can Be
believed that the routine monitoring of delirium was sup- Managed Effectively by Medications
ported by evidence, and only 40% of those surveyed routinely Risk factors for delirium have been described as the manifes- assessed for delirium (44). Additionally, these same survey par- tation of an acute illness, a preexisting patient specific factor, ticipants estimated that they had properly diagnosed delirium or exposure to a modifiable risk factor such as medications only 22% of the time. The survey also identified that a wide or environmental components (8, 65). Specific risk factors variety of delirium screening tools were being used. Only 7% for delirium include baseline dementia, increased age, hyper- of the respondents indicated using CAM-ICU for their obser- tension, sepsis, hypoalbuminemia, prior alcohol abuse, and vatory method, whereas none listed the ICDSC. In a similar benzodiazepines (46, 56, 66). These factors and others trigger study (53), surveys were specifically disseminated to ICU complex interacting neurotransmitter systems and pathologic nurses to determine their perceptions of delirium in the ICU. processes leading to the fluctuating mental status or disorga- All of the 331 nurses surveyed practiced in ICUs that used a nized thinking accompanied by the acute onset of delirium. sedation protocol that instituted a delirium assessment com- Although hyperactive delirium is more easily recognized due ponent. Interestingly, respondents indicated that even though to outward symptoms of restlessness, agitation, combative- ICU nurses frequently assessed patients' sedation status (98% ness, and sometimes hallucinations and delusions, hypoactive www.ccmjournal.org September 2013 • Volume 41 • Number 9 (Suppl.) delirium is frequently missed by caregivers, especially in those should be used cautiously when administered in conjunction patients who are heavily sedated. Hypoactive delirium, which with other QC interval corrected for heart rate prolonging presents as inattentiveness or a disorganized thought process, medications (e.g., methadone, moxifloxacin, and amioda- is prevalent in 43–60% of all delirium cases and is associated rone). Antipsychotics can also cause significant extrapyramidal with greater mortality than hyperactive delirium (67). Regard- symptoms in these patients, even in small doses (74). Since data less of delirium classification, practitioners are often eager to remain sparse on the use of antipsychotics for the treatment implement both pharmacologic and nonpharmacologic inter- of delirium, modifiable risk factors should first be minimized, ventions to treat delirious patients, given the negative conse- and nonpharmacologic interventions should be implemented quences of the disorder in the ICU (44, 53, 58, 59, 68).
before any pharmacologic treatment of delirium is considered.
Nonpharmacologic interventions that are effective in treat- The choice of sedative used in ICU patients may also decrease ing and preventing delirium include minimizing risk factors the prevalence of delirium. In one large multicenter trial (Safety and initiating early progressive mobility in ICU patients (3, 8, and Efficacy of Dexmedetomidine Compared with Midazolam 69). But pharmacologic intervention is often the first therapy [SEDCOM] study), there was a lower prevalence of delirium in initiated in these patients. Survey data indicate consistent atti- mechanically ventilated ICU patients receiving dexmedetomi- tudes among ICU clinicians that pharmacologic treatment dine compared with those who received midazolam for seda-is an appropriate strategy for the management of delirium, tion (12). In a subgroup analysis of the Maximizing Efficacy with antipsychotic drugs frequently administered to treat ICU of Targeted Sedation and Reducing Neurological Dysfunction patients with delirium (44, 59, 68). One particular survey of (MENDS) study, delirium outcomes were compared in 103 U.S. pharmacists from 45 hospitals in eight states illustrates mechanically ventilated ICU patients with sepsis (n = 63) or that 85% of respondents believe that delirium should be phar- without sepsis (n = 40), who received either IV dexmedetomi- macologically managed, with 65% of responses indicating the dine or lorazepam for sedation (75). Septic patients receiving need for dual medication regimens. Haloperidol was the treat- dexmedetomidine had more delirium/coma-free days, more ment of choice by 85% of those surveyed (68). Results from delirium-free days, and more ventilator-free days than patients another survey also demonstrate that antipsychotics are fre- receiving lorazepam for sedation. Across all patients evaluated, quently administered for treatment of delirium, with haloperi- those sedated with dexmedetomidine had a 70% lower likeli- dol again being the drug of choice in these patients (44). Given hood of having delirium on any given treatment day compared these survey results, it is no surprise then that haloperidol with patients sedated with lorazepam. To date, however, there utilization increases in institutions as ICU delirium screening are no published studies demonstrating that dexmedetomi- increases (70). However, despite the perceived benefit of giving dine reduces either the duration or severity of delirium in ICU an antipsychotic to treat delirium, there is a paucity of evidence patients. The PAD guidelines include a weak recommenda- to support the safety and effectiveness of this practice. Studies tion for avoiding benzodiazepines in ICU patients who are at evaluating haloperidol use in the management of delirious risk for delirium, and those who are diagnosed with delirium patients lack uniformity, have mixed efficacy results, mixed should receive dexmedetomidine for sedation rather than a safety results, and include few, if any, ICU patients. Although benzodiazepine. But the PAD guidelines do not recommend recent studies suggest the value of low-dose haloperidol for avoiding the use of benzodiazepines as sedative agents in ICU delirium prophylaxis, each trial employed a nonrigorous study patients altogether. In fact, benzodiazepines remain the seda- design and screened for and treated only high-risk patients (71, tive of choice for treatment of drug and alcohol withdrawal 72). The evidence for using other atypical antipsychotic medi- symptoms in ICU patients (76). Benzodiazepines may also be cations to both treat and prevent delirium in ICU patients is indicated for sedation of critically ill patients with intractable also sparse. In one randomized placebo-controlled pilot trial seizures and can provide synergistic sedative effects in ICU comparing quetiapine versus placebo given in conjunction patients who cannot otherwise be effectively sedated with pro-with haloperidol for the treatment of delirium in ICU patients, pofol and/or dexmedetomidine (19, 77). There are no large, there was a reduction in duration of delirium and shortened well-designed studies comparing the prevalence and duration time to delirium resolution, but the sample size in this study of delirium in ICU patients receiving propofol versus dex- was small (n = 36) (73). A larger study is needed to validate medetomidine. More study is needed to address these issues these results. Given the limited data regarding the safety and related to sedative choice and delirium in critically ill patients.
efficacy of administering antipsychotics for the treatment of
delirium in ICU patients, the current ICU PAD guidelines UNTOWARD EFFECTS OF ICU SEDATION
provide no recommendation on their use in this instance (8). Nevertheless, antipsychotics are likely to continue to be used commonly for the treatment of delirium in these patients, and Myth 8: Daily Interruptions of Sedative Medications
providers should be familiar with the inherent risks and lack of Are Unsafe
evidence when administering antipsychotics. Both traditional Sedative and opioid analgesic medications are intermittently or antipsychotics (e.g., haloperidol) and atypical antipsychotics continuously administered to facilitate patients' comfort and (e.g., quetiapine) pose a significant cardiac risk and should improve mechanical ventilation synchrony (29, 78). However, be avoided in patients with underlying QTc prolongation and these agents do not come without undesirable adverse effects. Critical Care Medicine www.ccmjournal.org Continuous sedative regimens have resulted in prolonged receiving benzodiazepines for alcohol withdrawal or intrac-mechanical ventilation times, increased LOS, greater organ table seizures). Broad educational efforts among ICU staff failure, and increased likelihood of reintubation (79). In 2000, and family members regarding the safety and efficacy of per- Kress et al (1) first introduced the concept of daily interruption forming DIS/SATs will be necessary in order to get widespread of sedation (DIS), otherwise referred as SATs, as a means of buy-in and support for DIS/SATs (81, 82). Finally, DIS/SAT reducing sedative use and improving patient outcomes in the protocols should include careful coordination of sedative ICU. Although the use of DIS is one strategy recommended suspension by nursing staff in order to synchronize this with by the PAD guidelines to improve ICU outcomes, widespread efforts by respiratory therapists to conduct SBTs and physical reluctance on the part of ICU practitioners to routinely sus- therapists to perform mobility exercises in order to maximize pend sedative medications in critically ill patients still persists. the benefits of DIS/SATs. Thoughtfully implemented, DIS can A 2009 survey of 1,384 healthcare professionals found that only be performed safely in most ICU patients and is one of the key 44% of respondents believed that DISs (SATs) were performed strategies recommended for minimizing the use of sedatives at least 50% of the time in their mechanically ventilated ICU and maintaining light levels of sedation in critically ill patients patients despite simultaneously reporting that 71% of the in the new PAD guidelines (the other being to continuously respective institutions used sedation protocols that included target a light level of sedation) (8).
SATs (59). Furthermore, many clinicians believe that lighten-ing sedation predisposes critically ill patients to hemodynamic Myth 9: Sedative and Analgesic Medications Do Not
instability, increased oxygen requirements, increased risk of Accumulate With Prolonged Use
self-extubation, or untoward long-term psychological defects Opioids and sedative hypnotics commonly administered to (18, 80). Similarly, ICU nurses are more likely to perform an ICU patients each have their own unique pharmacologic pro- SAT in ICU patients with favorable respiratory variables (e.g., file and vary considerably in terms of their volumes of distri- Fio < 50% or positive end-expiratory pressure < 5 mm Hg), bution, elimination half-lives, potencies, onset and offset of who are receiving propofol rather than a benzodiazepine, or if action, and side effects. These differences should influence the the nurse had prior favorable experiences performing SATs (81, choice of agent(s) used for each patient rather than having a 82). The presence or absence of interdisciplinary communica- "one-size-fits-all approach" (38). All of these drugs can accu- tion may also play a role as SATs are more likely to happen for mulate in tissues when administered over extended periods, ICU patients whose multidisciplinary care team incorporates resulting in prolonged emergence from sedation when these sedation goals in its daily discussions on ICU rounds (81).
drugs are discontinued (29, 38, 78, 87–90). Some drugs, such Since the goal of SATs is to reduce sedative use and to facili- as midazolam and morphine, have active metabolites (i.e., tate ventilator weaning, it is intuitive to think that by stopping α-hydroxymidazolam and morphine-6-glucoronide, respec- these medications in conjunction with SBTs that outcomes tively) that are excreted by the kidneys and can accumulate in could be improved. This hypothesis was tested in the Awakening ICU patients with renal insufficiency (91, 92). Emergence from and Breathing Controlled (ABC) (2) trial, where the linking of sedation is also dependent on the baseline depth of sedation, daily SATs with SBTs shortened mechanical ventilation time by such that patients who are sedated more deeply will take lon- more than 3 days, and reduced ICU and hospital LOS by 3.8 ger to regain consciousness than those who are maintained at days and 4.3 days, respectively, when compared to performing lighter levels of sedation (88, 89, 93). Finally, larger volumes of daily SBTs alone. The study also demonstrated that the SAT + distribution and/or reduced clearance of medications may fur- SBT group had a significantly reduced mortality risk at 1 year ther delay emergence from sedation in critically ill patients. It (HR, 0.68; 95% CI, 0.5–0.92; p = 0.01). Despite safety concerns is therefore important to use analgesia and sedation strategies for ICU patients awakening from sedation, the implementa- that minimize the total dose of opioids and sedatives adminis- tion of a daily DIS does not have untoward consequences in the tered to critically ill patients, in order to reduce the likelihood cardiac patient (83), nor does it lead to long-term neurocogni- of delayed emergence from sedation and perhaps resulting in tive effects (84, 85). In the ABC trial, though the combination failed attempts at DIS/SATs (18, 59, 82).
of an SAT with an SBT resulted in more self-extubations, there was no statistical difference in reintubation rates between the Myth 10: Deep Sedation and Amnesia Derived From
intervention and control groups. Despite similar mechanical Sedative Administration in ICU Patients Result in
ventilation times and LOS between those patients receiving Improved Psychological Outcomes, Especially PTSD
lighter targeted sedation and patients receiving DIS, a recent For decades, the treatment and management of critically ill trial has shown no difference in adverse events between the patients has focused primarily on ensuring patient survival. cohorts (86). These results provide additional evidence that Advancements in therapies, technology, and novel medications performing DIS in appropriate patients is safe.
have all resulted in improved survival, thus compelling critical The implementation of DIS should include a safety screen care staff to look beyond hospital discharge data and consider with clear exclusion criteria for performing DIS to avoid pos- the long-term impact of therapies and treatments adminis- sible adverse events (e.g., avoid in patients receiving neuro- tered to these patients during their ICU stay (94). There has muscular blocking agents, patients about to undergo invasive been a recent explosion in research focused on identifying procedures or transports outside the ICU, or in those patients and describing the long-term complications following critical www.ccmjournal.org September 2013 • Volume 41 • Number 9 (Suppl.) illness, including long-term impacts on physical and psycho- SATs paired with SBTs experienced no difference in cognitive, logical recovery, cognition, and quality of life. The foundation psychological (including PTSD), or functional outcomes at for understanding these relationships between in-hospital either 3 or 12 months after hospital discharge (2, 85). These management strategies and long-term patient outcomes is to studies provide clear and compelling evidence that maintain- be able to identify modifiable risk factors that can be influ- ing lighter levels of sedation by using either targeted sedation enced during each patient's ICU stay.
delivery (103) or daily sedative interruption (84, 85) results in PTSD is one specific long-term outcome that affects a sub- improved in-hospital outcomes, such as shorter ICU length of set of ICU survivors. PTSD is a psychiatric condition that stay and shorter ventilator time, without causing long-term develops from exposure to a traumatic event and is character- psychological harm in ICU survivors. As a result, the ICU ized by intrusive recollections (e.g., recurrent dreams, night- PAD guidelines recommend that most ICU patients should be mares, or flashbacks), avoidant/numbing symptoms, and maintained at a light level of sedation that allows for patients hyperarousal symptoms (e.g., sleep disruption, hypervigilance, to interact in a meaningful way with the ICU environment and and exaggerated startle response) (95). Systematic reviews to participate in their ICU care (8).
indicate a wide prevalence of PTSD ranging from 2% to 66% following ICU discharge (96, 97). This is likely due to varia- tions in study methodology including poor patient follow-up, A growing body of evidence published over the past decade selection bias, and heavy reliance on screening questionnaires challenges widely held beliefs regarding the prevalence and rather than diagnostics interview, making it difficult to know management of pain, agitation/sedation, and delirium in the true prevalence of PTSD in ICU survivors (96, 97). A sys- adult ICU patients. Several new PAD treatment strategies have tematic review of 15 studies looking at the prevalence and emerged in recent years, which have led to significant improve- risk factors for PTSD in ICU survivors and its impact on their ments in both short- and long-term outcomes in these patients quality of life concluded that the median point prevalence of and significant reductions in their costs of care. The 2013 ICU questionnaire-ascertained "clinically significant" PTSD symp- PAD guidelines provide a clear, evidence-based road map for toms was 22% (n = 1,104), and the median point prevalence of optimizing the management of pain, agitation/sedation, and clinician-diagnosed PTSD was 19% (n = 93). Risk factors for delirium in ICU patients in an integrated and interdisciplin- post-ICU PTSD included prior psychopathology, greater ICU ary fashion, based on the most recent evidence. But widespread benzodiazepine administration, and post-ICU memories of adoption and implementation of these guidelines is likely to be in-ICU experiences which were either frightening and/or psy- impeded by long-held beliefs and "myths" that have ingrained chotic (98). Not surprisingly, post-ICU PTSD was associated existing PAD practice patterns among ICU providers.
with substantially lower health-related quality of life in these Knowledge of the most current evidence behind the best practices recommended in the PAD guidelines will help to There is a long-held belief that deeply sedated patients will debunk these myths, but a single strategy education alone be spared from remembering specific ICU events while pro- will be ineffective in promoting widespread adoption of tecting them from developing psychological stress (99, 100). the PAD guidelines. Current PAD management habits trig- In reality, sedation itself is thought to be a significant risk fac- gered by the interpretation of existing cues (i.e., the patient is tor for the development of PTSD in ICU survivors. Girard et agitated!) and followed by traditional routines (turn up the al (101) found an association between ICU patients receiving sedatives!) lead to perceived rewards (i.e., the patient is calm high doses of benzodiazepines for sedation and the develop- now!). But many of these cue-routine-rewards in managing ment of PTSD in ICU survivors. Jones et al (11) hypothesized PAD in ICU patients are based on false assumptions about that depth and length of sedation could result in greater oppor- the risks and benefits of current PAD management strate- tunities to form delusional memory and thus be associated gies. What is needed here is a new set of habits based on new with PTSD in ICU survivors. They demonstrated that delusion cues (or new interpretations of old cues), new routines, and memory is more strongly associated with the development of new rewards (104). Routine assessments of patients to detect PTSD following the ICU rather than factual memory (11, 102).
significant pain, over- or under-sedation, and delirium using In a study comparing light sedation with deep sedation, valid and reliable assessment tools will help to form new "cues" Treggiari et al (103) reported that the patients receiving deep to help change clinical practice. ICUs will then need to decide sedation had more trouble remembering important parts of how to incorporate these PAD assessments into the broader their ICU stay and more disturbing memories of the ICU, but framework of their PAD management protocols in such a way scored similar to the light sedation group on the PTSD ques- that they become part of the everyday workflow in the ICU tionnaire screen. Two studies investigating potential long-term as new "routines." Finally, regulatory bodies and third-party neurologic consequences from daily sedation interruption and payers will need to incentivize and reward hospitals in order lighter sedation levels found no negative psychological impact. to encourage widespread adoption of these guidelines in their Kress et al (84) reported that ICU patients who received DIS ICUs in order to create new "rewards." But knowledge is the experienced less PTSD and had fewer PTSD symptoms at principle driver of change, and this article attempts to debunk 6-month follow-up. In a follow-up investigation to the ABC many current beliefs regarding current ICU practices in pain, trial, it was found that ICU patients who experienced daily agitation/sedation, and delirium management and to promote Critical Care Medicine www.ccmjournal.org a greater understanding of the benefits of implementing the 20. Shehabi Y, Bellomo R, Reade MC, et al; Sedation Practice in Intensive 2013 ICU PAD guidelines.
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The role of the consultant pharmacist in long-term-care

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