Critical Care Medicine:
Creating and Implementing the 2013 ICU Pain, Agitation, and Delirium Guidelines for Adult Icu Patients
The Pain, Agitation, and Delirium Care Bundle: Synergistic Benefits of Implementing the 2013 Pain, Agitation, and Delirium Guidelines in an Integrated and Interdisciplinary Fashion
Barr, Juliana MD, FCCM1,2; Pandharipande, Pratik P. MD, MSCI, FCCM3
1Department of Anesthesia, Stanford University School of Medicine, Stanford, CA.
2Anesthesiology and Perioperative Care Service, VA Palo Alto Health Care System, Palo Alto, CA.
3Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN.
Dr. Barr has received speaking honoraria from the University of Hawaii, the American College of Chest Physicians, the Society of Critical Care Medicine, the Center for Quality Systems Improvement, the France Foundation, Sutter Health, and the Masimo Corporation. Dr. Pandharipande has received speaking honoraria from the France Foundation, Hospira, and Orion Pharma. He holds consultancies with Orion and Hospira and has research grants from the National Institutes of Health (HL111111) and Hospira.
For information regarding this article, E-mail: firstname.lastname@example.org
Objective: In 2013, the American College of Critical Care Medicine published a revised version of the pain, agitation, and delirium guidelines. The guidelines included an ICU pain, agitation, and delirium care bundle designed to facilitate implementation of the pain, agitation, and delirium guidelines.
Design: Review article.
Setting: Multispecialty critical care units.
Patients: Adult ICU patients.
Interventions: This article describes: 1) the ICU pain, agitation, and delirium care bundle in more detail, linking pain, sedation/agitation, and delirium management in an integrated and interdisciplinary fashion; 2) pain, agitation, and delirium implementation strategies; and 3) the potential synergistic benefits of linking pain, agitation, and delirium management strategies to other evidence-based ICU practices, including spontaneous breathing trials, ICU early mobility programs, and ICU sleep hygiene programs, in order to improve ICU patient outcomes and to reduce costs of care.
Results: Linking the ICU pain, agitation, and delirium management strategies with spontaneous awakening trials, spontaneous breathing trials, and early mobility and sleep hygiene programs is associated with significant improvements in ICU patient outcomes and reductions in their costs of care.
Conclusions: The 2013 ICU pain, agitation, and delirium guidelines provide critical care providers with an evidence-based, integrated, and interdisciplinary approach to managing pain, agitation/sedation, and delirium. The ICU pain, agitation, and delirium care bundle provides a framework for facilitating implementation of the pain, agitation, and delirium guidelines. Widespread implementation of the ICU pain, agitation, and delirium care bundle is likely to result in large-scale improvements in ICU patient outcomes and significant reductions in costs.
The American College of Critical Care Medicine recently published a revised version of the ICU pain, agitation, and delirium (PAD) guidelines (1). Readers are referred to a more in-depth description of the methodology used to develop the 2013 PAD guidelines published earlier in this supplement (2a). The PAD guidelines are the most extensive set of critical care clinical practice guidelines ever to be published. They focus only on adult ICU patients, with a separate set of PICU PAD guidelines in preparation. The PAD guidelines include both short- and long-term PAD management for both intubated and nonintubated ICU patients. They provide a more diverse set of recommendations for both medical and surgical ICU patients, and they include specific recommendations for using regional analgesia in ICU patients.
A central tenet of these PAD guidelines is the importance of managing pain, agitation/sedation, and delirium in critically ill patients in an integrated and interdisciplinary fashion. Compared with previous versions of these guidelines, the 2013 PAD guidelines are more evidence based and patient centered. There is a much greater emphasis on the need for better recognition and treatment of pain and delirium in critically ill patients and for minimizing the use of sedatives in ICU patients. The PAD guidelines include strong recommendations for the use of valid and reliable assessment tools for detecting significant pain, over- or under-sedation, and delirium in critically ill patients. PAD treatment strategies focus more on the process and approach to PAD management rather than making specific recommendations for using certain medications in different clinical situations. They include strong recommendations for assessing and treating pain first before administering sedatives and for maintaining a light level of sedation that allows for ICU patients to interact in a meaningful way with the ICU environment, without agitation. They include specific recommendations to both prevent and treat delirium in ICU patients, using both nonpharmacologic and pharmacologic strategies.
An ICU PAD care bundle was created as part of the PAD guidelines to help facilitate guideline implementation. The PAD care bundle focuses on assessing, treating, and preventing PAD in an integrated and interdisciplinary fashion. It also links PAD management to other evidence-based ICU practices, such as spontaneous awakening trials (SATs), spontaneous breathing trials (SBTs), ICU early mobility (EM) programs, and ICU sleep hygiene programs, in order to achieve synergistic benefits in ICU outcomes and to reduce costs. This article describes the ICU PAD care bundle in greater detail, along with PAD implementation strategies, and outlines the potential benefits of linking PAD management to other ICU best practices.
The 2013 PAD guideline recommendations have been incorporated into an ICU PAD care bundle (Fig. 1, A and B) that provides a systematic approach to help operationalize the PAD guideline recommendations in a stepwise fashion, integrating the assessment, treatment, and prevention of pain, agitation/sedation, and delirium in critically ill patients (1). The bundle also links PAD management strategies with other ICU interventions (i.e., SAT, SBTs, EM protocols, and sleep management strategies to preserve patients’ sleep-wake cycles), in order to achieve additional improvements in ICU patient outcomes.
Assessment of Pain, Agitation-Sedation, and Delirium
Pain assessments using valid and reliable assessment tools should provide the basis for the treatment of pain in critically ill patients. This includes using a numerical rating scale (NRS) (i.e., Likert scale) for patients who can self-report their pain and the use of one of the behavioral pain scales (BPSs) for those ICU patients who cannot. Most critically ill patients are likely to experience significant pain at some point during their ICU stay (2b) and identify it as a great source of stress and discomfort (3–6). Significant pain is not limited to surgical ICU patients; at least 50% of both medical and surgical ICU patients experience significant pain during their ICU stay (7, 8). Procedures are also a significant source of pain for critically ill patients, and inadequate treatment of procedural pain remains a significant problem for many ICU patients (9–16). In spite of the ubiquitous nature of pain in the ICU, many critically ill patients may be unable to self-report their pain, either verbally or with gestures, because of an altered level of consciousness, the use of sedatives or neuromuscular blocking agents, or mechanical ventilation (17).
The PAD guidelines make a strong recommendation for performing routine pain assessments in all ICU patients, regardless of whether patients can self-report their pain or not. Patients’ self-reporting is considered the “gold standard” in pain assessment. A recent study by Chanques et al (18) compared five commonly used self-report pain assessment tools in ICU patients and found that the 0–10 visually enlarged laminated NRS had the highest degree of sensitivity and specificity for detecting significant pain in critically ill patients who can self-report. In the absence of an objective method for measuring pain in critically ill patients who cannot self-report, a valid and reliable bedside pain assessment tool that incorporates patients’ behaviors as indicators of pain should be used. A rigorous psychometric analysis of six BPSs included in the PAD guidelines found that the BPS and the Critical-Care Pain Observation Tool (CPOT) are the most valid and reliable for use in ICU patients (1). A recently updated psychometric analysis of eight BPSs, including studies published since 2010, came to a similar conclusion (19).
Although NRSs or symbolic equivalents are commonly used as ICU pain assessment tools, BPSs have yet to be widely adopted in ICUs (20). In the absence of a BPS, pain assessments in nonverbal ICU patients are often left to self-interpretation by ICU nurses and physicians, who frequently use patients’ vital signs as a metric for untreated pain. But reliance on vital signs to predict pain may be misleading, since they correlate poorly with the presence or absence of pain in these patients (21–24). Because of this fact, the PAD guidelines recommend that changes in patients’ vital signs should only be considered as a cue to begin further pain assessments (1). Implementing BPSs (e.g., BPS or CPOT) improves both ICU pain management and clinical outcomes, including better use of analgesic and sedative agents, and shorter durations of mechanical ventilation and ICU length of stay (LOS) (20, 25, 26).
The ICU PAD care bundle mandates that pain assessments be performed and documented in ICU patients at least four times per nursing shift (i.e., q2–3 hr), and more frequently as needed. Patients are considered to be in significant pain if they self-report their pain intensity of 4 or greater (0–10 NRS) or have either a BPS score of 6 or greater (BPS range = 3–12) or CPOT score of 3 or greater (CPOT range = 3–8) if they cannot self-report.
Agitation and anxiety occur frequently in critically ill patients and can lead to adverse clinical outcomes (27–31). Common causes of agitation and anxiety in ICU patients include untreated pain, delirium, hypoxemia, hypoglycemia, hypotension, or withdrawal from alcohol and other drugs. Although prompt identification of the underlying cause of patient agitation is important, sedatives are commonly administered to these patients in order to prevent and treat agitation and its negative consequences (32).
The PAD guidelines strongly recommend the use of a valid and reliable sedation scoring system to routinely assess depth of sedation and agitation in ICU patients, and the results of these sedation/agitation assessments should provide the basis for the use of sedatives in critically ill patients (1). The administration of sedatives to critically ill patients without titrating these medications to a specific sedation scale endpoint often results in ICU patients becoming oversedated (33). This can result in prolongation of mechanical ventilation, an increased prevalence of ICU delirium and neuropsychological sequelae, increased ICU LOS, and an increased risk of death in these patients (34–39). The use of sedation scales, as part of an ICU sedation protocol, allows for ICU clinicians to administer and titrate sedative agents more appropriately in critically ill patients and results in significant improvements in these clinical outcomes (40–45).
The PAD guidelines included a rigorous psychometric analysis of 10 sedation scales and concluded that the Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) are the most valid and reliable sedation assessment tools for measuring quality and depth of sedation in adult ICU patients. A more recent analysis of the psychometric properties of 11 sedation scales, including studies published since 2010, came to a similar conclusion regarding the RASS and SAS scales (see article by Robinson et al  in this supplement).
The ICU PAD care bundle mandates that sedation/agitation assessments be performed and documented in all ICU patients, using either the RASS or SAS sedation scale, at least four times per nursing shift (i.e., q2–3 hr), and more frequently as needed. The RASS scale uses 10 discrete levels to define depth of sedation and agitation, ranging from –5 (unarousable) to +4 (combative) (47). By contrast, the SAS scale has seven discrete levels ranging from 1 (unarousable) to 7 (dangerously agitated) (48). Depth of sedation in patients using either of these scales is defined as follows: agitation if RASS = +1 to +4 or SAS = 5 to 7; awake and calm if RASS = 0 or SAS = 4; lightly sedated if RASS = –1 to –2 or SAS = 3; and deeply sedated if RASS = –3 to –5 or SAS = 1 to 2.
Delirium is characterized by the acute onset of cerebral dysfunction, with a change or fluctuation in baseline mental status, inattention, and either disorganized thinking or an altered level of consciousness (49–54). Patients with delirium may either be agitated (i.e., hyperactive delirium), calm or lethargic (i.e., hypoactive delirium), or may fluctuate between the two subtypes. Hyperactive delirium is more often associated with hallucinations and delusions, whereas hypoactive delirium is more often characterized by confusion and sedation and is often undetected.
Delirium occurs commonly in critically ill patients. It is estimated that in up to 80% of critically ill patients delirium develops during their ICU stay (53, 55, 56). The presence of delirium in ICU patients is associated with significant negative outcomes, including prolonged duration of mechanical ventilation (57), prolonged hospital LOS (53, 56, 58), postdischarge institutionalization (59), long-term cognitive dysfunction (60, 61), an increased risk of death (56), and higher costs of care (62). ICU delirium has also recently been associated with a greater likelihood of patients developing long-term cognitive dysfunction (60). Hypoactive delirium occurs much more commonly than hyperactive delirium in ICU patients and is associated with a longer duration of mechanical ventilation and ICU LOS and a higher mortality risk than hyperactive delirium (63–67).
Reliable detection and diagnosis of delirium is essential for delirium treatment and for improving delirium-related ICU outcomes. Currently, only 25–59% of intensivists routinely screen their patients for delirium (68, 69), and 62% of intensivists in North America rely on a general clinical assessment to screen for delirium, which lacks sufficient sensitivity to detect delirium in these patients (70–72). Uninformed delirium assessments by ICU nurses are also notoriously unreliable for detecting delirium. One study comparing delirium observations by ICU nurses with delirium assessments performed by a trained ICU nurse using the Confusion Assessment Method for the ICU (CAM-ICU) delirium assessment tool showed poor agreement between the two, with a sensitivity of only 27% for casual assessments of delirium by untrained ICU nursing staff (73). ICU personnel often underestimate the presence of delirium in patients because it frequently presents as hypoactive rather than hyperactive form of delirium (74, 75).
The PAD guidelines make a strong recommendation for routinely monitoring ICU patients for delirium, using a valid and reliable delirium assessment tool (1). The PAD guidelines included a rigorous psychometric analysis of five delirium monitoring tools and concluded that the CAM-ICU (53) and the Intensive Care Delirium Screening Checklist (ICDSC) (54) are the most valid and reliable delirium monitoring tools for use in adult ICU patients.
The ICU PAD care bundle mandates that delirium assessments be performed and documented in all ICU patients, using either the CAM-ICU or the ICDSC tool, at least once a shift (i.e., q8–12 hr), and more often as needed. A patient is considered delirious if they are either CAM-ICU positive or their ICDSC score is greater than or equal to 4 (ICDSC scale range = 0–8).
PAD Treatment Strategies
The results of these PAD assessments should ultimately be incorporated into the daily discussions on interdisciplinary ICU rounds, with ICU teams addressing each patient’s current pain score and analgesia regimen, current and target sedation scores and sedation regimen, and current delirium score and delirium risk factors and treatment regimen. These assessments should then be incorporated into a treatment plan tailored to each patient for managing pain, agitation or oversedation, and delirium, using PAD protocols specific to the culture and formulary of each individual ICU. PAD protocols can help to facilitate the transfer of evidence-based “best practices” to the bedside, limit practice variation, and reduce treatment delays (20, 26). A protocolized approach to managing PAD can also significantly improve ICU patient outcomes and serve as a guide for quality assurance efforts (45, 76–78). The ICU PAD care bundle does not propose a one-size-fits-all drug treatment strategy for all ICU patients, but the treatment goals for all ICU PAD protocols should nevertheless be the same: 1) focus on patients’ pain management first, then sedate patients only if needed; 2) choose sedatives based on their pharmacologic profile and the individual sedation goals for each patient, using nonbenzodiazepines preferentially; 3) maintain a light level of sedation in ICU patients, which allows for patients to meaningfully interact with the ICU environment without agitation whenever possible; and 4) use both nonpharmacologic and pharmacologic treatment strategies to manage delirium in ICU patients.
Optimize pain management in critically ill patients by assessing and treating their pain first, then sedating them only if needed. It is important to recognize that ICU patients, even those who are mechanically ventilated, may require little or no sedative medications as long as their pain is well controlled (20, 79). And ICU patients who are managed with an analgesia-first (i.e., analgosedation) strategy have significant reductions in their duration of mechanical ventilation and ICU LOS (79, 80). Treat all significant pain in a timely fashion (i.e., < 30 min of diagnosing significant pain), employing patient-specific pain management strategies (i.e., opioids ± nonopioids for nonneuropathic pain, gabapentin or carbamazepine ± opioids for neuropathic pain, and epidural analgesia for postoperative pain and rib fractures) (1).
Opioids remain the primary analgesic of choice in critically ill patients with nonneuropathic pain, with all IV opioids being equally effective at equipotent doses (81–97). Oral opioids may be variably absorbed with reduced bioavailability in critically ill patients. Nonopioids (i.e., acetaminophen), nonsteroidal medications (i.e., ketorolac, ibuprofen), and ketamine can provide adjunctive pain relief, reduce overall opioid requirements, and help to minimize opioid side effects in critically ill patients (81, 84, 85, 93, 98). Either oral gabapentin or carbamazepine should be administered as first-line treatment of neuropathic pain in critically ill patients, using both nonopioids and opioids for adjunctive pain relief in these patients (82, 83). Neuraxial analgesia, specifically thoracic epidural analgesia, should be reserved for critically ill patients with rib fractures and in patients who have undergone abdominal aortic surgery (99–102). Lumbar epidurals provide no clear benefit over parenteral opioids for postoperative analgesia in patients who have undergone abdominal aortic surgery, and thoracic epidurals provide no clear benefit over parenteral opioids in patients who have undergone intrathoracic or nonvascular abdominal surgical procedures (100, 103–111). Once the appropriate pain medications have been administered, ICU patients should have their pain reassessed within 30 minutes using an appropriate pain assessment tool to determine analgesic efficacy.
Optimize sedation management by sedating ICU patients only as needed while maintaining a light level of sedation. A light level of sedation is defined in the PAD guidelines as a level of consciousness that allows for ICU patients to be responsive and aware, as demonstrated by their ability to follow three of five specific commands upon request (i.e., open eyes, maintain eye contact, squeeze hand, stick out tongue, and wiggle toes) (112–115). This degree of patient responsiveness and awareness is essential for the evaluation of pain through patients’ self-report, for assessing patients’ readiness to wean and extubate, for performing delirium assessments in patients, and for implementing EM efforts. Light sedation may be achieved using either targeted sedation strategies (TSSs) or daily sedation holidays.
The PAD guidelines did not recommend the use of daily sedation interruption (DSI) strategies that allows ICU patients to emerge from deeper levels of sedation to a light level of sedation on a daily basis over sedation protocol that routinely targets light sedation (i.e., TSS), due to the lack of high-quality studies comparing these two strategies. A more recent multicenter trial by Mehta et al (116) found no clear benefit of combining TSS with DSI to manage sedation in ICU patients. However, there are major shortcomings to this study. It is not clear from their results as to what percentage of time both the treatment and control groups achieved their target level of sedation (i.e., SAS = 3–4 or RASS = –3 to 0). In addition, both groups received moderate doses of sedatives and opioids throughout the study period. Specifically, the treatment group received an average sedative dose of 4.24 mg/hr, and the control group received an average of 3.4 mg/hr in terms of midazolam equivalents, and the treatment group received an average opioid dose of 74 μg/hr, whereas the control group received an average of 45 μg/hr in terms of fentanyl equivalents. Pharmacologic modeling of these doses of midazolam and fentanyl suggests that a significant number of patients in both the treatment and control groups were likely to be at a deeper level of sedation than the sedation protocol specified for much of the time, which may account for the lack of difference in outcomes between the two groups (117).
Sedative choice in ICU patients should be based primarily upon using sedatives that minimize side effects and improve patient outcomes. IV benzodiazepines, especially midazolam, are the most commonly used sedative-hypnotics for sedation of adult ICU patients, followed by propofol and dexmedetomidine (8, 68, 118–120). Barbiturates, diazepam, and ketamine are used rarely for sedation of adults in the ICU. Over the past decade, there is a growing body of evidence that the use of IV benzodiazepines for sedation of ICU patients, specifically midazolam and lorazepam, is associated with worse ICU outcomes than sedation with nonbenzodiazepines (specifically propofol and dexmedetomidine) (40–45, 121–126).
As part of the PAD guidelines, a meta-analysis was conducted of 13 studies (n = 1,551) comparing clinical outcomes in ICU patients sedated with either benzodiazepines (midazolam or lorazepam) or nonbenzodiazepines (propofol or dexmedetomidine) (1). Across all 13 studies, there was no significant difference in ICU LOS (127–139). But a more limited meta-analysis of 6 of the 13 studies that were of moderate to high quality demonstrated that benzodiazepines did increase ICU LOS by approximately 0.5 days compared with nonbenzodiazepines (127–139). Four studies suggested that mechanical ventilation is prolonged with benzodiazepine-based sedation (127–139), and four studies showed no apparent difference in mortality with benzodiazepine versus nonbenzodiazepine sedation (127–139).
An updated version of benzodiazepine versus nonbenzodiazepine meta-analysis published by Fraser et al (140) in this supplement supports the findings of the PAD guideline meta-analysis. This updated meta-analysis included a total of six ICU sedation outcome studies (n = 1,235) comparing midazolam versus dexmedetomidine (127–139, 141), lorazepam versus dexmedetomidine (139), midazolam versus propofol (128), and lorazepam versus propofol (127). This meta-analysis showed that the use of either dexmedetomidine or propofol for ICU sedation was associated with an even shorter ICU LOS (1.6 d) and a significant reduction in mechanical ventilation (1.9 d) than with benzodiazepine sedation. There was no effect on delirium prevalence or short-term mortality in this meta-analysis, though heterogeneity in the way delirium prevalence was measured in the two studies (139) may have resulted in these results given that both studies showed reductions in delirium prevalence over time (139).
There are several important differences between the two versions of these meta-analyses of sedative-related outcomes. The original meta-analysis included in the PAD guidelines was limited to assessing ICU LOS as the only outcome, and three of the six studies included in this meta-analysis were in cardiac surgery patients, a patient population with distinct clinical practices and generally a shorter ICU LOS (136–138). By contrast, the meta-analysis by Fraser et al excluded studies of cardiac surgery patients but included one high-quality multicenter trial (i.e., the Midazolam vs Dexmedetomidine for Sedation During Prolonged Mechanical Ventilation or MIDEX trial), which was published since the PAD guidelines meta-analysis was initially performed (141). The outcomes of interest in the MIDEX trial included duration of mechanical ventilation as well as ICU and hospital LOS, but not delirium prevalence or mortality. In addition to looking at ICU LOS, this newer meta-analysis also looked at duration of mechanical ventilation, delirium prevalence, and short-term mortality—outcomes, which were not included in the original PAD guideline meta-analysis due to an insufficient number of studies. The exact relationship between the use of benzodiazepines and delirium prevalence in ICU patients could not be answered in this meta-analysis, due to an insufficient number of high-quality studies designed to address this issue and the heterogeneity in these studies. The findings of the meta-analysis by Fraser et al nevertheless reinforce the PAD guideline recommendations for preferentially using nonbenzodiazepines for sedating adult ICU patients.
At the time of the initial literature review for the PAD guidelines, only two low-quality studies had been published comparing clinical outcomes in ICU patients receiving propofol versus dexmedetomidine for sedation (131, 132). Since that time, the results of a single large, multicenter study has been published (i.e., the Propofol vs Dexmedetomidine for Sedation During Prolonged Mechanical Ventilation or PRODEX trial), comparing ICU outcomes related to propofol versus dexmedetomidine for ICU sedation (141). In that study (n = 498), there were no differences observed in terms of duration of mechanical ventilation, ICU or hospital LOS, or mortality between the two treatment groups. Delirium prevalence was not an outcome measure in the PRODEX trial. More studies are needed to address this issue of delirium prevalence as it relates to sedative choice in ICU patients. Of note, there are currently no published studies comparing clinical outcomes in ICU patients sedated with ketamine versus other sedative agents.
In spite of the apparent benefits of using nonbenzodiazepines, it is important to note that the PAD guidelines do not specifically recommend that benzodiazepines should never be used for ICU sedation. Given their anxiolytic, amnesic, and anticonvulsant properties, benzodiazepines remain an important class of drugs for sedating critically ill patients. Benzodiazepines are still recommended as the sedative of choice for treating drug withdrawal syndromes in critically ill patients, especially ethanol or benzodiazepine withdrawal (142). Benzodiazepines may also be indicated for sedation of critically ill patients with intractable seizures. Finally, benzodiazepines can provide synergistic sedative effects in ICU patients who cannot otherwise be effectively sedated with propofol and/or dexmedetomidine alone or in whom required doses of each individual sedative cannot be reduced (120, 143).
Decisions regarding the choice of sedative agent to use in critically ill patients should ultimately be driven by: 1) the specific indications for sedation and the sedative goals for each patient; 2) the compatibility between the clinical pharmacology of a sedative, its side effect profile, and the relative contraindications for its use in a critically ill patient; and 3) the overall costs (not limited to pharmacy costs) associated with using a particular sedative.
The first step in treating delirium is to identify and eliminate potential contributing factors such as treatable disease states that can induce delirium (i.e., sepsis, shock states, glycemic dysregulation, electrolyte disorders, and hypoxia); inadequately treated pain; drug withdrawal; discontinuation of patients’ psychiatric medications; exposure to deliriogenic medications (i.e., benzodiazepines) or adverse drug effects; and environmental factors (i.e., sleep deprivation, disorientation, prolonged immobilization, and use of restraints). If delirium persists once identifiable causes have been eliminated, delirium treatment should include both nonpharmacologic and pharmacologic treatment strategies, with an emphasis on using nonpharmacologic interventions first. Proven nonpharmacologic delirium treatment strategies (some in non-ICU and others in ICU patients as well) include: 1) frequent reorientation of ICU patients, giving them access to their eyeglasses and hearing aids, if needed (144); 2) maintaining patients’ sleep-wake cycles by minimizing environmental and procedural disturbances at night (145); and 3) advancing patients’ mobility during the day as tolerated, with the ultimate goal of getting patients out of bed each day, even when they are intubated and mechanically ventilated (146, 147). Pharmacologic treatment of delirium should include: 1) adequate analgesia; 2) discontinuation of benzodiazepines (except in patients with suspected ethanol or benzodiazepine withdrawal); 3) resumption of patients’ psychiatric medications, if indicated; 4) treatment of drug withdrawal syndromes, if suspected; and 5) antipsychotics, if needed.
The 2013 PAD guidelines have a limited number of recommendations on the use of antipsychotics for the management of delirium in ICU patients, primarily due to a lack of clear evidence for the safety and efficacy of these medications in this patient population. A Cochrane review published in 2007 on the use of antipsychotics for the treatment of delirium did not specifically address their use in ICU patients (148). A more recent review of the literature published in 2012 concluded that the pharmacologic efficacy of antipsychotics for the treatment of ICU delirium is limited by “the small size of many studies, the inconsistency by which nonpharmacologic delirium prevention strategies were incorporated, the lack of a true placebo arm, and a failure to incorporate ICU and non-ICU clinical outcomes” (149). Robust studies of the treatment of delirium with haloperidol and other antipsychotics in non-ICU patients that could potentially be applied to ICU patients are also lacking. Nevertheless, antipsychotics, and haloperidol in particular, are commonly administered for the treatment of delirium in critically ill patients (68). The administration of antipsychotic medications for the treatment of delirium in ICU patients is also endorsed in several other clinical practice guidelines (150–158).
To date, there are only three published studies on the safety and efficacy of using antipsychotics for the treatment of delirium in ICU patients. The largest of these (n = 103), the Modifying the Incidence of Delirium trial, found that the number of delirium- or coma-free days was not different between ICU patients receiving ziprasidone (an atypical antipsychotic), haloperidol, or placebo for delirium (159). Devlin et al (160) compared delirium outcomes in ICU patients receiving haloperidol plus either quetiapine (atypical) or placebo (n = 36) and found that the addition of quetiapine to haloperidol was associated with a shorter duration of first episode of delirium, with no significant differences in ICU LOS or duration of mechanical ventilation. The shortcomings of this study were its small sample size and the fact that it did not reach its enrollment target. Skrobik et al (161) compared the safety and efficacy of olanzapine (atypical) versus haloperidol for the treatment of delirium in ICU patients (n = 73) and found improvements in the severity of delirium symptoms and a reduction in the need for sedatives over time, without significant differences between the two treatment groups. But patients treated with haloperidol in this study experienced more extrapyramidal side effects. Sufficiently powered and carefully designed, multicenter, placebo-controlled trials are needed to determine the safety and efficacy of using antipsychotics for the treatment of delirium in critically ill patients.
The PAD guideline recommendations for the use of antipsychotics in the treatment of delirium are limited to: 1) haloperidol for the treatment of delirium—no recommendation, due to a lack of evidence; 2) atypical antipsychotics may reduce the duration of delirium in ICU patients (based only on the study by Devlin et al ); 3) a strong recommendation against the use of rivastigmine (a cholinesterase inhibitor) for the treatment of delirium in ICU patients (based on a multicenter trial demonstrating that treatment of delirium in ICU patients with rivastigmine increases the severity and duration of delirium and the likelihood of death in these patients) (162); and 4) a weak recommendation against the use of antipsychotics in patients with prolonged Q-T interval or other risk factors for torsades de pointes (163–173).
PAD Prevention Strategies
The ICU PAD care bundle includes several important PAD prevention strategies. These include: 1) preemptively treating procedural pain in all ICU patients; 2) minimizing the need for sedation by linking SBTs with sedation protocols to facilitate patients’ weaning from mechanical ventilation; and 3) preventing delirium by promoting EM and preserving sleep-wake cycles in ICU patients.
Procedure-related pain occurs commonly in ICU patients, and inadequate treatment of procedural pain remains a significant problem for many of these patients (14, 174). Pain in ICU patients can trigger a significant stress response, leading to hemodynamic instability, impaired wound healing, hyperglycemia, and an increased risk of infections (175–179). Pain also has significant negative short- and long-term psychological consequences in ICU patients, including sleep deprivation during their stay in the ICU (180), persistent recollections of them experiencing significant pain in the ICU (6, 181–183), and a higher likelihood of patients developing chronic pain, Posttraumatic stress disorder symptoms, and a lower health-related quality of life after ICU discharge (184).
The prevalence and severity of procedural pain varies across ICU patient populations. Procedural pain varies with age (10, 12) and is more intense in non-Caucasians than in Caucasians (10, 12, 14). Differences in procedural pain between nonsurgical and surgical patients also vary according to the procedure (10, 12, 14).
In spite of its high prevalence, less than 25% of ICU patients receive analgesics prior to initiating procedures in the ICU (14). Preprocedural administration of analgesics, particularly opioids, significantly reduces the prevalence of significant procedural pain in ICU patients (185). Although opioids remain the systemic analgesics of choice for procedural pain, both nonopioids and relaxation therapy may provide adjunctive pain relief in these instances. The PAD guidelines recommend that procedural pain be preemptively treated in all ICU patients, given the prevalence of significant pain associated with invasive procedures, the short- and long-term negative consequences of untreated pain in these patients, and the minimal risks associated with preemptive analgesic therapy.
The best way to reduce the risks associated with ICU sedation is to reduce the need for sedation in these patients. Mechanical ventilation remains the major indication for the administration of sedative medications in the ICU, and ventilator weaning protocols that include daily SBTs can significantly reduce the duration of mechanical ventilation in critically ill patients (186). But it can be difficult to perform SBTs in ICU patients who are in a drug-induced coma, and deep sedation has been identified as an independent risk factor for both delaying the weaning and extubation of critically ill patients and prolonging their ICU LOS (38, 39, 43, 113, 187).
SATs or DSI, when performed in conjunction with SBTs, can help to facilitate the liberation of ICU patients from mechanical ventilation (187–189). Data from several studies suggest that DSI protocols significantly reduce the duration of mechanical ventilation and ICU LOS (113, 114, 187, 190). However, it may not be necessary to suspend sedative medications altogether before performing an SBT, as long as ICU patients are alert enough to cooperate (i.e., a baseline RASS of –3 to 0 or SAS of 3–4), and have a sufficient respiratory drive to breathe spontaneously when the SBT is performed. Data from studies assessing the impact of TSSs that maintain a light level of sedation without DSI have also been shown to be effective in facilitating weaning from mechanical ventilation in ICU patients (40–45, 121, 122, 191, 192). As previously discussed, it remains unclear as to whether combining a TSS sedation protocol with DSI has any synergistic benefit to facilitating SBTs in ICU patients; the one study designed to address this issue showed no benefit, but suffered from a number of methodological flaws (116). More research is needed to address this issue. Given the equivocal nature of the evidence, the PAD guidelines recommend that either DSI or TSS be used to facilitate daily SBTs in mechanically ventilated ICU patients, in order to shorten the duration of mechanical ventilation and reduce the need for continuous sedation in these patients (1). Of note, no study has demonstrated worsening of outcomes when combining DSI with TSS.
The PAD guidelines focus primarily on nonpharmacologic strategies preventing delirium, including recommendations for early mobilization and environmental management to promote sleep in ICU patients (1). Two studies have demonstrated that the institution of an ICU EM program is associated with significant reductions in the prevalence of delirium and other improvements in ICU outcomes (146, 147). In both of these studies, the functional status of patients admitted to a medical ICU was assessed on a daily basis by an interdisciplinary ICU team that included ICU physicians, nurses, respiratory therapists, physical therapists (PTs), and occupational therapists (OTs). ICU guidelines were developed for obtaining PT/OT consults on all patients, and PT and OT staff members were specifically assigned to the ICU. Sedation management practices were altered to ensure that patients were not deeply sedated, which might preclude them from participating in daily ICU EM activities. Activity levels ordered for all ICU patients were modified from “bed rest” to “as tolerated.” Specific criteria were developed as part of a safety screen to determine eligibility of patients for daily physical therapy and mobility. In the study by Needham et al (147), the prevalence of delirium in ICU patients decreased significantly, along with ICU sedative use. In addition, ICU LOS decreased by an average of 2.1 days, and hospital LOS decreased by an average of 3.1 days, while there was no significant change in hospital mortality. In the study by Schweickert et al (146), ICU patients who received routine physical therapy via an ICU EM protocol were more likely to: 1) achieve an independent functional status at the time of hospital discharge (59% vs 35% in the control group, p = 0.02); 2) have a shorter duration of delirium (2 d vs 4 d in the control group, p = 0.02); and 3) have more ventilator-free days (23.5 d vs 21.1 d in the control group, p = 0.05) than ICU patients who did not receive routine physical therapy. Effective strategies for creating and implementing an ICU EM program have been described in more detail elsewhere, including another article published by Engel et al (193) in this supplement (194). Readers are also referred to the Mobilization-Network (195) and Institute for Healthcare Improvement websites for additional details on how to implement an ICU EM program (196).
ICU patients frequently suffer from poor quality of sleep (197–202). The causes of sleep disturbances in critically ill patients are multifactorial and include round-the-clock environmental visual, auditory, and physical stimuli in the ICU, poorly treated pain (180), the use of sedatives and other medications, mechanical ventilation, and underlying disease processes (203, 204). Although sleep deprivation has been associated with delirium in ICU patients, the exact cause and effect relationship between sleep and delirium in these patients remains unclear (203, 205–208). Nevertheless, improving sleep hygiene in the ICU reduces both the prevalence and duration of delirium in critically ill patients (145).
The PAD guidelines include a strong recommendation for developing and implementing programs to promote sleep in ICU patients by using strategies to control light and noise, clustering ICU patient care activities, and decreasing stimuli at night to protect patients’ sleep cycles (1). Implementing quiet time on both day and night shifts and clustering patient care activities in the ICU result in both subjective and objective improvements in sleep in ICU patients (209–211). Sleep hygiene programs in non-ICU hospitalized patients have been associated with a reduced prevalence of delirium (212). A recent study by Kamdar et al (145) (n = 300) demonstrated that the implementation of an evidence-based sleep hygiene program in a medical ICU resulted in significant nighttime noise reductions in the ICU and a significant decrease in the prevalence of delirium in these patients as well. Nighttime ICU environmental interventions in this study included minimizing overhead pages, turning off patient televisions, dimming hallway lights, and grouping patient care activities at specific time intervals. Daytime interventions to promote normal circadian rhythms and nighttime sleep by ICU patients included raising the window blinds, preventing excessive napping, encouraging patient mobilization during the day, and minimizing caffeine intake in the evening. The use of earplugs by ICU patients has also been shown to improve sleep quality and to reduce the prevalence of delirium in these patients (213). Van Rompaey et al randomized adult ICU patients to the use of nighttime earplug or no earplugs. Patients sleeping with earplugs reported better sleep during the first night in the ICU, and fewer patients in this group subsequently developed delirium or mild confusion during the five-night study period. More broadly targeted, multifactorial programs that go beyond promoting sleep in non-ICU hospitalized patients have also been shown to be effective at preventing delirium (212, 214–216), but such multifaceted interventions have not been adequately studied in the ICU patient population. ICU light and noise reduction strategies including the use of earplugs, normalizing day-night illumination, minimizing ICU care-related interventions during normal sleeping hours, and interventions promoting ICU patient comfort and relaxation are low risk and inexpensive and should be implemented to prevent delirium in ICU patients.
At the time that the PAD guidelines were developed, there was no clear evidence that prophylactically administering either antipsychotics or dexmedetomidine for sedation was effective at preventing delirium in ICU patients. Thus, no recommendations were made for the use of one or more pharmacologic agents to prevent delirium in critically ill patients. A recent delirium prophylaxis study by van den Boogaard et al (217) in a mixed ICU patient population (n = 476 medical, surgical, trauma, and neurosurgical ICU patients) showed that the administration of haloperidol prophylactically to ICU patients who were at “high risk” for delirium (0.5–1 mg IV q8 hr, age adjusted) significantly reduced the prevalence of delirium in these patients (i.e., 65% vs 75% in the control group, p = 0.01). Haloperidol was stopped in 12 patients, however, because of QTc-time prolongation (n = 9), renal failure (n = 1), and neurological side effects (n = 2). Larger studies are needed to confirm the safety and efficacy of haloperidol and other antipsychotics for the prevention of delirium in critically ill patients.
PAD Care Bundle Implementation Strategies
Successful implementation of the ICU PAD care bundle requires an integrated and interdisciplinary team-based approach, led by an ICU clinician-champion (not necessarily a physician) and representative of all ICU stakeholders (i.e., physicians, nurses, respiratory therapists, pharmacists, PTs and OTs, hospital administrators, and ICU patients and families). Broadly targeted staff, patient, and family education on the PAD guidelines and the PAD care bundle elements will be important in order to gain widespread buy-in and support. It is also important to align the principles of family-centered care into the PAD care bundle implementation process, including shared decision making, early and frequent family communication about goals of care and daily care plans, and encouraging direct family involvement in patient care. Engagement and activation of ICU patients and their family members on the PAD care bundle elements will help to facilitate adoption of these practices and to sustain them (218).
ICUs vary in terms of the degree to which they are already incorporating elements of the PAD care bundle into their current ICU practices, so a baseline gap analysis can help ICUs to focus on those areas of the bundle that they have not yet implemented and integrate them with the bundle elements that they are already doing well. Identifying both process and outcome measures for each new PAD element initiative (i.e., pain and sedation protocols and EM) will help teams to better understand what works and what does not in their ICUs. Engaging frontline ICU staff in performing small tests of change, soliciting their feedback on how to further improve processes, measuring performance, and sharing results with all stakeholder groups will help to accelerate and sustain PAD improvements. Readers are referred to the Institute for Healthcare Improvement’s website for more details on effective improvement strategies they can use to facilitate implementation of the PAD care bundle in their ICUs (219).
ICUs should begin with implementing specific PAD assessment tools first and demonstrating that ICU staff are performing and interpreting these assessments in a consistent and reliable fashion before implementing PAD treatment and prevention protocols. This will enable ICU staff to correctly identify the need for pain, sedation, and delirium interventions in individual patients and forms the foundation for applying all other PAD care bundle elements to these patients. Otherwise, you do not know what you do not measure. The results of these PAD assessments should then be included in discussions on daily ICU rounds, incorporated into ICU patient goals sheets, checklists, and order sets, and become part of the daily PAD care plan for each patient.
PAD treatment and prevention protocols must be developed around existing ICU cultures and hospital formularies and individualized to the needs of each patient. But regardless of your approach to implementing the PAD care bundle in your ICU, the primary goals of any institutional PAD protocols should be to: 1) optimize pain management first; 2) make light sedation the norm; 3) move away from routinely using benzodiazepines, especially in ICU patients who are at risk for or those who already have delirium (note: benzodiazepines may be preferred medications, however, for treating anxiety, seizures, and alcohol or benzodiazepine withdrawal, or as adjunctive sedative therapy in ICU patients who cannot tolerate propofol and/or dexmedetomidine for sedation); 4) implement effective delirium prevention and treatment strategies, using both nonpharmacologic and pharmacologic approaches; and 5) use antipsychotics judiciously. All treatment interventions, whether they be pharmacologic or nonpharmacologic, should have corresponding safety screens applied to each patient beforehand—not all ICU patients will tolerate dexmedetomidine for sedation or be able to get out of bed to a chair. Readers are referred to a recent article by Pun et al (220) that includes a more in-depth description of these PAD implementation strategies.
The effects of implementing the ICU PAD care bundle in its entirety have yet to be fully measured in terms of its overall impact on ICU patient care. But individual elements have been shown to significantly improve both short- and long-term ICU patient outcomes and reduce costs of care (Table 1). When two or more of these elements have been combined with one another, additional synergistic benefits to ICU outcomes and cost reductions have been realized.
In 2008, Girard et al (187) published the Awakening and Breathing Coordination (ABC) Trial, which compared outcomes in ICU patients (n = 336) managed with SATs, coupled with SBTs, to ICU patients managed with SBTs alone and usual physician-directed sedative administration. The SAT + SBT treatment group had significantly better outcomes than the SBT-only treatment group, in terms of decreased duration of mechanical ventilation (↓ by 3.1 d, p = 0.02), shorter ICU LOS (↓ by 3.8 d, p = 0.01), and shorter hospital LOS (↓ by 4.3 d, p = 0.04). Although more ICU patients in the SAT + SBT group self-extubated than in the control group (16 vs 6 patients, p = 0.03), the number of ICU patients requiring reintubation after self-extubation was similar (five vs three patients, p = 0.47), as were total reintubation rates (13·8% vs 12·5%, p = 0·73) between the two groups. Furthermore, within the first year after study enrollment, patients in the SAT + SBT group were less likely to die than were patients in the SBT only group (HR, 0.68; 95% CI, 0.50–0.92; p = 0·01). So for every seven patients treated with the SAT + SBT protocol, one life was saved (note: number needed to treat was 7.4; 95% CI, 4.2–35.5).
Strong evidence also demonstrates that most ICU patients can be safely maintained at lighter sedation levels and actively mobilized, even while intubated. A study by Morris et al (221) showed that linking the ABC protocol with an ICU EM protocol in mechanically ventilated ICU patients (n = 330) reduced ICU and hospital LOS by an additional 1.4 days (p = 0.025) and 3.3 days (p = 0.006), respectively. In addition, ICU patients treated with ABC + EM had physical therapy initiated more frequently in the ICU (91% vs 13% usual care, p < 0.001) and were out of bed earlier (5 d vs 11 d, p < 0.001) than patients treated with the ABC protocol alone. Overall complication rates were similarly low in both groups, and there were no untoward events during any ICU mobility session in the treatment group. Including the costs of implementing the mobility team, there were no cost differences between the two treatment groups in this study. A 1-year follow-up of these patients showed that a lack of early ICU mobility therapy was a strong predictor of hospital readmission or death in these patients (odds ratio, 1.77; 95% CI, 1.04–3.01; p < 0.01) (222). Another study of mechanically ventilated ICU patients (n = 104) by Schweickert et al (146) demonstrated that linking SATs with an ICU EM protocol significantly reduced the duration of delirium (i.e., by 2 d, p = 0.02), increased the number of ventilator-free days (23.5 d vs 21.1 d, p = 0.05), and achieved nearly a three-fold increase in the likelihood that ICU patients would regain an independent functional status by the time of hospital discharge (p = 0.02) (i.e., patients were able to perform six activities of daily living and walk independently). In other words, more of these ICU patients could ultimately go home from the hospital instead of to a skilled nursing facility. A recent meta-analysis of ICU EM studies demonstrated that ICU EM programs improve quality of life, physical function, and peripheral and respiratory muscle strength in critically ill patients (223). ICU EM Programs also significantly reduce both ICU and hospital LOS and reduce the duration of mechanical ventilation.
In 2010, Vasilevskis et al (224) captured the essence of taking an integrated approach to ICU sedation, ventilator, and delirium management by coining the phrase “ABCDE bundle,” which stands for awakening and breathing coordination, delirium prevention and monitoring, and early mobility and exercise. Although the ABCDE bundle is arguably less comprehensive than the ICU PAD care bundle (i.e., most notably, it does not include strategies for pain management), it nevertheless captures the spirit of the PAD care bundle by linking sedation and delirium management in ICU patients with SATs, SBTs, and ICU EM programs. A recent study published by Balas et al (225) assessed the impacts of implementing the ABCDE bundle in seven mixed medical and surgical ICUs at a large, tertiary, academic medical center. Following widespread implementation of the ABCDE bundle at this facility, mechanically ventilated ICU patients were more likely to receive an SAT (71% vs 53%, p = 0.04), and an SBT (84% vs 71%, p = 0.03), and spent more days breathing without ventilator assistance (21 d vs 24 d, p = 0.04). The number of patients who self-extubated and who subsequently required reintubation did not differ significantly between the two groups. Implementation of the ABCDE bundle also decreased the duration of delirium in these patients by 50% (1 d vs 2 d, p = 0.004). The prevalence (20% vs 40%, p = 0.02) and duration of delirium were also significantly reduced in a separate analysis of nonmechanically ventilated ICU patients in this study (226). There were no significant differences observed in terms of ICU or hospital LOS, discharge disposition, or mortality between the pre- and postimplementation ABCDE bundle groups.
Implementation of the ICU PAD care bundle is also likely to result in considerable cost savings. Skrobik et al (76) implemented an integrated ICU PAD management protocol in a mixed medical-surgical ICU (n = 1,133). Their PAD protocol included patient assessments using valid and reliable PAD assessment tools (i.e., NRS [but none of the valid BPSs], RASS, and ICDSC tools), the results of which formed the basis of treatment with what was primarily a pharmacologically based PAD treatment protocol. Music therapy and patient reorientation were also included as part of their protocol, but PAD management was not specifically linked to SATs, SBTs, an ICU EM program, or any ICU sleep hygiene strategies. Nevertheless, implementation of this ICU PAD protocol resulted in significant reductions in patients’ pain scores and analgesic use, including a significant increase in the percentage of patients requiring no opioids, without a concomitant increase in nonopioid use. Benzodiazepine use decreased significantly as well, with a significant increase in the proportion of ICU patients sedated within their target RASS score range of –1 to +1. There was a lower prevalence of subsyndromal delirium (ICDSC > 0 but < 3) and iatrogenic coma, but no significant difference in antipsychotic use or the prevalence of delirium (i.e., ICDSC score ≥ 4) between the pre- and post-PAD protocol treatment groups. Finally, more patients in the PAD protocol treatment group remained cognitively intact during their ICU stay, and these patients were more likely to go home than patients with either subsyndromal delirium or delirium during their ICU stay. Implementation of this ICU PAD protocol significantly reduced ICU LOS (5.4 d vs 6.3 d, p = 0.009), hospital LOS (27.1 d vs 55 d, p < 0.0001), and the duration of mechanical ventilation (5.9 d vs 7.5 d, p = 0.01), while the percentage of ICU patients who were eventually discharged to home significantly increased (74.8% vs 68.2%, p = 0.05).
A cost analysis of this study published by Awissi et al (227) showed that the mean total cost of ICU hospitalization decreased from $6,212.64 per patient (in 2004 Canadian dollars) in the pre-PAD protocol group to $5,279.90 per patient in the post-PAD protocol group (p = 0.02), which represents an average total cost reduction of approximately 15% per patient. These modest cost reductions would likely have been much greater had the authors linked their PAD management protocol with SBTs, EM protocols, and ICU sleep hygiene programs.
A financial model recently developed by Lord et al (228), using published data, projected cost savings associated with implementing an ICU EM program, based on both conservative and best-case scenarios for estimated ICU and hospital LOS and cost reductions. It also included estimated cost reductions from an actual example of an ICU EM program implemented at their facility. Net cost savings generated from this example scenario, with 900 annual ICU admissions and actual LOS reductions of 22% and 19% for the ICU and floor, respectively, were $817,836 (in 2012 U.S. dollars). This was based on $1,176,312 of cost savings attributable to projected reductions in direct-variable costs due to reduced LOS, which was partially offset by an initial investment of $358,475 to implement the ICU early rehabilitation program. Hypothetical cost savings, based on an estimated reduction in both ICU and floor LOS ranging from 10% (conservative) to 25% (best-case scenario), ranged from $88,000 (net cost) to $3,763,000 (net savings), depending on the number of ICU admissions, direct-variable costs per day, and projected LOS reductions incorporated into the model. However, the model predicted a net cost savings in 20 of 24 possible scenarios. Under best-case scenario assumptions for LOS, the savings associated with implementing an ICU EM program were also projected to consistently increase with the number of ICU admissions (range, $260,000–$3,763,000). These model projections of cost savings associated with the implementation of an ICU EM program need to be tested prospectively at other institutions. But these results suggest that the up-front investment costs of implementing an ICU EM program are likely to be offset by significant cost savings resulting from reduced ICU and hospital LOS for patients.
Since the last version of these guidelines was published in 2002 (229), we have gained a greater understanding of how to better provide physical and psychological comfort for critically ill patients. The development of valid and reliable bedside assessment tools to measure pain, sedation, agitation, and delirium separately in ICU patients has allowed clinicians to better assess and manage these patients. Our increased understanding of the clinical pharmacology of medications commonly administered to treat PAD in ICU patients has given us greater insight to both the short- and long-term consequences of prolonged exposure to these agents. And how we administer these medications can affect patient outcomes as much as drug choice. Contrary to conventional wisdom in ICU sedation management, maintaining a light level of sedation while also ensuring patient comfort is associated with improved ICU clinical outcomes in most patients. Finally, our understanding of the risk factors and long-term consequences of delirium in ICU patients has also expanded.
But many important questions remain unanswered in the 2013 ICU PAD guidelines due to significant gaps in the evidence. Nevertheless, we believe that these guidelines, including the ICU PAD care bundle, provide a clearer road map for clinicians to better manage PAD in critically ill patients. And given the ubiquitous nature of PAD in ICU patients, we believe that these guidelines will be transformative in terms of their impact on ICU care, perhaps even more so than the sepsis guidelines have been (230).
The full impact of the ICU PAD care bundle on ICU patient outcomes and costs of care has yet to be tested and measured. But strong evidence indicates that linking PAD management strategies with ventilator weaning, EM, and sleep hygiene protocols in ICU patients results in significant synergistic benefits to clinical outcomes and reductions in costs of care. This suggests that widespread adoption of the ICU PAD care bundle will have a profound and positive effect on a variety of clinical and economic metrics related to care of critically ill patients.
An interdisciplinary team-based approach, using proven model improvement strategies, and ICU patient and family activation and engagement will help to ensure broad implementation of the PAD care bundle across diverse ICUs. Implementing the PAD guidelines gives ICU practitioners the opportunity to bring the humanity of critically ill patients back into practice and to significantly improve lives beyond the ICU stay. The past decade of critical care medicine has focused on implementing the sepsis care bundle (231). Let this be the decade of the ICU PAD care bundle.
1. Barr J, Fraser GL, Puntillo K, et al.American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263–306
2a. Barr J, Kishman CP Jr, Jaeschke R. The Pain, Agitation, and Delirium Care Bundle: Synergistic Benefits of Implementing the 2013 Pain, Agitation, and Delirium Guidelines in an Integrated and Interdisciplinary Fashion. Crit Care Med. 2013;41:S1–S15
2b. Erstad BL, Puntillo K, Gilbert HC, et al. Pain management principles in the critically ill. Chest. 2009;135:1075–1086
3. Ballard KS. Identification of environmental stressors for patients in a surgical intensive care unit. Issues Ment Health Nurs. 1981;3:89–108
4. So HM, Chan DS. Perception of stressors by patients and nurses of critical care units in Hong Kong. Int J Nurs Stud. 2004;41:77–84
5. Hweidi IM. Jordanian patients’ perception of stressors in critical care units: A questionnaire survey. Int J Nurs Stud. 2007;44:227–235
6. Rotondi AJ, Chelluri L, Sirio C, et al. Patients’ recollections of stressful experiences while receiving prolonged mechanical ventilation in an intensive care unit. Crit Care Med. 2002;30:746–752
7. Chanques G, Sebbane M, Barbotte E, et al. A prospective study of pain at rest: Incidence and characteristics of an unrecognized symptom in surgical and trauma versus medical intensive care unit patients. Anesthesiology. 2007;107:858–860
8. Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology. 2007;106:687–695; quiz 891–892
9. Stanik-Hutt JA, Soeken KL, Belcher AE, et al. Pain experiences of traumatically injured patients in a critical care setting. Am J Crit Care. 2001;10:252–259
10. Stotts NA, Puntillo K, Stanik-Hutt J, et al. Does age make a difference in procedural pain perceptions and responses in hospitalized adults? Acute Pain. 2007;9:125–134
11. Stotts NA, Puntillo K, Bonham Morris A, et al. Wound care pain in hospitalized adult patients. Heart Lung. 2004;33:321–332
12. Arroyo-Novoa CM, Figueroa-Ramos MI, Puntillo KA, et al. Pain related to tracheal suctioning in awake acutely and critically ill adults: A descriptive study. Intensive Crit Care Nurs. 2008;24:20–27
13. Puntillo K, Ley SJ. Appropriately timed analgesics control pain due to chest tube removal. Am J Crit Care. 2004;13:292–301; discussion 302; quiz 303–304
14. Puntillo KA, White C, Morris AB, et al. Patients’ perceptions and responses to procedural pain: Results from Thunder Project II. Am J Crit Care. 2001;10:238–251
15. Puntillo KA. Dimensions of procedural pain and its analgesic management in critically ill surgical patients. Am J Crit Care. 1994;3:116–122
16. Puntillo KA. Effects of interpleural bupivacaine on pleural chest tube removal pain: A randomized controlled trial. Am J Crit Care. 1996;5:102–108
17. Shannon K, Bucknall T. Pain assessment in critical care: What have we learnt from research. Intensive Crit Care Nurs. 2003;19:154–162
18. Chanques G, Viel E, Constantin JM, et al. The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales. Pain. 2010;151:711–721
19. Gélinas C, Puntillo KA, Joffe AM, et al. A validated approach to evaluating psychometric properties of pain assessment tools for use in nonverbal critically ill adults. Semin Respir Crit Care Med. 2013;34:153–168
20. Payen JF, Bosson JL, Chanques G, et al.DOLOREA Investigators. Pain assessment is associated with decreased duration of mechanical ventilation in the intensive care unit: A post hoc analysis of the DOLOREA study. Anesthesiology. 2009;111:1308–1316
21. Aïssaoui Y, Zeggwagh AA, Zekraoui A, et al. Validation of a behavioral pain scale in critically ill, sedated, and mechanically ventilated patients. Anesth Analg. 2005;101:1470–1476
22. Gélinas C, Johnston C. Pain assessment in the critically ill ventilated adult: Validation of the Critical-Care Pain Observation Tool and physiologic indicators. Clin J Pain. 2007;23:497–505
23. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29:2258–2263
24. Gélinas C, Arbour C. Behavioral and physiologic indicators during a nociceptive procedure in conscious and unconscious mechanically ventilated adults: Similar or different? J Crit Care. 2009;24:628.e7–628.e17
25. Arbour C, Gélinas C, Michaud C. Impact of the implementation of the critical-care pain observation tool (CPOT) on pain management and clinical outcomes in mechanically ventilated trauma intensive care unit patients: A pilot study. J Trauma Nurs. 2011;18:52–60
26. Chanques G, Jaber S, Barbotte E, et al. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med. 2006;34:1691–1699
27. Fraser GL, Prato BS, Riker RR, et al. Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU. Pharmacotherapy. 2000;20:75–82
28. Atkins PM, Mion LC, Mendelson W, et al. Characteristics and outcomes of patients who self-extubate from ventilatory support: A case-control study. Chest. 1997;112:1317–1323
29. Vassal T, Anh NG, Gabillet JM, et al. Prospective evaluation of self-extubations in a medical intensive care unit. Intensive Care Med. 1993;19:340–342
30. Fraser GL, Riker RR, Prato BS, et al. The frequency and cost of patient-initiated device removal in the ICU. Pharmacotherapy. 2001;21:1–6
31. Conti J, Smith D. Haemodynamic responses to extubation after cardiac surgery with and without continued sedation. Br J Anaesth. 1998;80:834–836
32. Cohen D, Horiuchi K, Kemper M, et al. Modulating effects of propofol on metabolic and cardiopulmonary responses to stressful intensive care unit procedures. Crit Care Med. 1996;24:612–617
33. Botha JA, Mudholkar P. The effect of a sedation scale on ventilation hours, sedative, analgesic and inotropic use in an intensive care unit. Crit Care Resusc. 2004;6:253–257
34. Roberts DJ, Haroon B, Hall RI. Sedation for critically ill or injured adults in the intensive care unit: A shifting paradigm. Drugs. 2012;72:1881–1916
35. Shehabi Y, Bellomo R, Reade MC, et al.Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724–731
36. Agarwal V, O’Neill PJ, Cotton BA, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res. 2010;31:706–715
37. Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma. 2008;65:34–41
38. Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541–548
39. Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37:2527–2534
40. Arabi Y, Haddad S, Hawes R, et al. Changing sedation practices in the intensive care unit—Protocol implementation, multifaceted multidisciplinary approach and teamwork. Middle East J Anesthesiol. 2007;19:429–447
41. Arias-Rivera S, Sánchez-Sánchez Mdel M, Santos-Díaz R, et al. Effect of a nursing-implemented sedation protocol on weaning outcome. Crit Care Med. 2008;36:2054–2060
42. Brattebø G, Hofoss D, Flaatten H, et al. Effect of a scoring system and protocol for sedation on duration of patients’ need for ventilator support in a surgical intensive care unit. Qual Saf Health Care. 2004;13:203–205
43. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27:2609–2615
44. Quenot JP, Ladoire S, Devoucoux F, et al. Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia. Crit Care Med. 2007;35:2031–2036
45. Robinson BR, Mueller EW, Henson K, et al. An analgesia-delirium-sedation protocol for critically ill trauma patients reduces ventilator days and hospital length of stay. J Trauma. 2008;65:517–526
46. Robinson BRH, Berube M, Barr J, et al. Psychometric Analysis of Subjective Sedation Scales in Critically Ill Adults. Crit Care Med. 2013;41(Suppl):S16–S29
47. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166:1338–1344
48. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27:1325–1329
49. Meagher DJ, Leonard M, Donnelly S, et al. A longitudinal study of motor subtypes in delirium: Relationship with other phenomenology, etiology, medication exposure and prognosis. J Psychosom Res. 2011;71:395–403
50. Gupta N, de Jonghe J, Schieveld J, et al. Delirium phenomenology: What can we learn from the symptoms of delirium? J Psychosom Res. 2008;65:215–222
51. American Psychiatric Association:. . Delirium, dementia and amnestic and other cognitive disorders. Diagnostic and Statistical Manual of Mental Disorders.. 1994 Washington, DC American Psychiatric Association
52. American Psychiatric Association:. . Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156:1–20
53. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286:2703–2710
54. Bergeron N, Dubois MJ, Dumont M, et al. Intensive Care Delirium Screening Checklist: Evaluation of a new screening tool. Intensive Care Med. 2001;27:859–864
55. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: Occurrence and clinical course in older patients. J Am Geriatr Soc. 2003;51:591–598
56. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–1762
57. Lat I, McMillian W, Taylor S, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med. 2009;37:1898–1905
58. Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892–1900
59. McAvay GJ, Van Ness PH, Bogardus ST Jr, et al. Older adults discharged from the hospital with delirium: 1-Year outcomes. J Am Geriatr Soc. 2006;54:1245–1250
60. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513–1520
61. Jackson JC, Gordon SM, Hart RP, et al. The association between delirium and cognitive decline: A review of the empirical literature. Neuropsychol Rev. 2004;14:87–98
62. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955–962
63. Guenther U, Popp J, Koecher L, et al. Validity and reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU patients. J Crit Care. 2010;25:144–151
64. McPherson JA, Wagner CE, Boehm LM, et al. Delirium in the cardiovascular ICU: Exploring modifiable risk factors. Crit Care Med. 2013;41:405–413
65. Stransky M, Schmidt C, Ganslmeier P, et al. Hypoactive delirium after cardiac surgery as an independent risk factor for prolonged mechanical ventilation. J Cardiothorac Vasc Anesth. 2011;25:968–974
66. Sharma A, Malhotra S, Grover S, et al. Incidence, prevalence, risk factor and outcome of delirium in intensive care unit: A study from India. Gen Hosp Psychiatry. 2012;34:639–646
67. van den Boogaard M, Schoonhoven L, van der Hoeven JG, et al. Incidence and short-term consequences of delirium in critically ill patients: A prospective observational cohort study. Int J Nurs Stud. 2012;49:775–783
68. Patel RP, Gambrell M, Speroff T, et al. Delirium and sedation in the intensive care unit: Survey of behaviors and attitudes of 1384 healthcare professionals. Crit Care Med. 2009;37:825–832
69. Mac Sweeney R, Barber V, Page V, et al.Intensive Care Foundation. A national survey of the management of delirium in UK intensive care units. QJM. 2010;103:243–251
70. van Eijk MM, van Marum RJ, Klijn IA, et al. Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med. 2009;37:1881–1885
71. Devlin JW, Fong JJ, Fraser GL, et al. Delirium assessment in the critically ill. Intensive Care Med. 2007;33:929–940
72. Devlin JW, Marquis F, Riker RR, et al. Combined didactic and scenario-based education improves the ability of intensive care unit staff to recognize delirium at the bedside. Crit Care. 2008;12:R19
73. Mistarz R, Eliott S, Whitfield A, et al. Bedside nurse-patient interactions do not reliably detect delirium: An observational study. Aust Crit Care. 2011;24:126–132
74. Guenther U, Popp J, Koecher L, et al. Validity and reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU patients. J Crit Care. 2010;25:144–151
75. Peterson JF, Pun BT, Dittus RS, et al. Delirium and its motoric subtypes: A study of 614 critically ill patients. J Am Geriatr Soc. 2006;54:479–484
76. Skrobik Y, Ahern S, Leblanc M, et al. Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg. 2010;111:451–463
77. Banerjee A, Girard TD, Pandharipande P. The complex interplay between delirium, sedation, and early mobility during critical illness: Applications in the trauma unit. Curr Opin Anaesthesiol. 2011;24:195–201
78. Sessler CN, Pedram S. Protocolized and target-based sedation and analgesia in the ICU. Crit Care Clin. 2009;25:489–513, viii
79. Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet. 2010;375:475–480
80. Rozendaal FW, Spronk PE, Snellen FF, et al.UltiSAFE investigators. Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: A centre randomised, cross-over, open-label study in the Netherlands. Intensive Care Med. 2009;35:291–298
81. Memis D, Inal MT, Kavalci G, et al. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25:458–462
82. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: A double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95:1719–1723
83. Pandey CK, Raza M, Tripathi M, et al. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg. 2005;101:220–225
84. Rapanos T, Murphy P, Szalai JP, et al. Rectal indomethacin reduces postoperative pain and morphine use after cardiac surgery. Can J Anaesth. 1999;46:725–730
85. Hynninen MS, Cheng DC, Hossain I, et al. Non-steroidal anti-inflammatory drugs in treatment of postoperative pain after cardiac surgery. Can J Anaesth. 2000;47:1182–1187
86. Machata AM, Illievich UM, Gustorff B, et al. Remifentanil for tracheal tube tolerance: A case control study. Anaesthesia. 2007;62:796–801
87. Krishnan K, Elliot SC, Berridge JC, et al. Remifentanil patient-controlled analgesia following cardiac surgery. Acta Anaesthesiol Scand. 2005;49:876–879
88. Dahaba AA, Grabner T, Rehak PH, et al. Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: A randomized double blind study. Anesthesiology. 2004;101:640–646
89. Karabinis A, Mandragos K, Stergiopoulos S, et al. Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: A randomised, controlled trial [ISRCTN50308308]. Crit Care. 2004;8:R268–R280
90. Chinachoti T, Kessler P, Kirkham A, et al. Remifentanil vs morphine for patients in intensive care unit who need short-term mechanical ventilation. J Med Assoc Thai. 2002;85(Suppl 3):S848–S857
91. Soltész S, Biedler A, Silomon M, et al. Recovery after remifentanil and sufentanil for analgesia and sedation of mechanically ventilated patients after trauma or major surgery. Br J Anaesth. 2001;86:763–768
92. Breen D, Wilmer A, Bodenham A, et al. Offset of pharmacodynamic effects and safety of remifentanil in intensive care unit patients with various degrees of renal impairment. Crit Care. 2004;8:R21–R30
93. Guillou N, Tanguy M, Seguin P, et al. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003;97:843–847
94. Frakes MA, Lord WR, Kociszewski C, et al. Efficacy of fentanyl analgesia for trauma in critical care transport. Am J Emerg Med. 2006;24:286–289
95. Carrer S, Bocchi A, Candini M, et al. Short term analgesia based sedation in the Intensive Care Unit: Morphine vs remifentanil + morphine. Minerva Anestesiol. 2007;73:327–332
96. Maddali MM, Kurian E, Fahr J. Extubation time, hemodynamic stability, and postoperative pain control in patients undergoing coronary artery bypass surgery: An evaluation of fentanyl, remifentanil, and nonsteroidal antiinflammatory drugs with propofol for perioperative and postoperative management. J Clin Anesth. 2006;18:605–610
97. Guggenberger H, Schroeder TH, Vonthein R, et al. Remifentanil or sufentanil for coronary surgery: Comparison of postoperative respiratory impairment. Eur J Anaesthesiol. 2006;23:832–840
98. Schmittner MD, Vajkoczy SL, Horn P, et al. Effects of fentanyl and S(+)-ketamine on cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with intracranial pathologies: A pilot study. J Neurosurg Anesthesiol. 2007;19:257–262
99. Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: A randomized, controlled Veterans Affairs cooperative study. Ann Surg. 2001;234:560–569
100. Nishimori M, Ballantyne JC, Low JH. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev. 2006;3:CD005059
101. Bulger EM, Edwards T, Klotz P, et al. Epidural analgesia improves outcome after multiple rib fractures. Surgery. 2004;136:426–430
102. Carrier FM, Turgeon AF, Nicole PC, et al. Effect of epidural analgesia in patients with traumatic rib fractures: A systematic review and meta-analysis of randomized controlled trials. Can J Anaesth. 2009;56:230–242
103. Rigg JR, Jamrozik K, Myles PS, et al.MASTER Anaethesia Trial Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: A randomised trial. Lancet. 2002;359:1276–1282
104. Peyton PJ, Myles PS, Silbert BS, et al. Perioperative epidural analgesia and outcome after major abdominal surgery in high-risk patients. Anesth Analg. 2003;96:548–554
105. Luketich JD, Land SR, Sullivan EA, et al. Thoracic epidural versus intercostal nerve catheter plus patient-controlled analgesia: A randomized study. Ann Thorac Surg. 2005;79:1845–1849; discussion 1849–1850
106. Ali M, Winter DC, Hanly AM, et al. Prospective, randomized, controlled trial of thoracic epidural or patient-controlled opiate analgesia on perioperative quality of life. Br J Anaesth. 2010;104:292–297
107. Rudin A, Flisberg P, Johansson J, et al. Thoracic epidural analgesia or intravenous morphine analgesia after thoracoabdominal esophagectomy: A prospective follow-up of 201 patients. J Cardiothorac Vasc Anesth. 2005;19:350–357
108. Wahlander S, Frumento RJ, Wagener G, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19:630–635
109. Turker G, Goren S, Bayram S, et al. Comparison of lumbar epidural tramadol and lumbar epidural morphine for pain relief after thoracotomy: A repeated-dose study. J Cardiothorac Vasc Anesth. 2005;19:468–474
110. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: A meta-analysis. Anesth Analg. 2001;93:853–858
111. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: A meta-analysis. JAMA. 2003;290:2455–2463
112. Kress JP, Vinayak AG, Levitt J, et al. Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease. Crit Care Med. 2007;35:365–371
113. Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471–1477
114. Mehta S, Burry L, Martinez-Motta JC, et al.Canadian Critical Care Trials Group. A randomized trial of daily awakening in critically ill patients managed with a sedation protocol: A pilot trial. Crit Care Med. 2008;36:2092–2099
115. Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Crit Care. 2008;12(Suppl 3):S6
116. Mehta S, Burry L, Cook D, et al.SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: A randomized controlled trial. JAMA. 2012;308:1985–1992
117. Barr J, Zomorodi K, Bertaccini EJ, et al. A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model. Anesthesiology. 2001;95:286–298
118. Mehta S, McCullagh I, Burry L. Current sedation practices: Lessons learned from international surveys. Anesthesiol Clin. 2011;29:607–624
119. Salluh JI, Dal-Pizzol F, Mello PV, et al.Brazilian Research in Intensive Care Network. Delirium recognition and sedation practices in critically ill patients: A survey on the attitudes of 1015 Brazilian critical care physicians. J Crit Care. 2009;24:556–562
120. Wunsch H, Kahn JM, Kramer AA, et al. Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009;37:3031–3039
121. Bucknall TK, Manias E, Presneill JJ. A randomized trial of protocol-directed sedation management for mechanical ventilation in an Australian intensive care unit. Crit Care Med. 2008;36:1444–1450
122. Elliott R, McKinley S, Aitken LM, et al. The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit. Intensive Care Med. 2006;32:1506–1514
123. Mascia MF, Koch M, Medicis JJ. Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care. Crit Care Med. 2000;28:2300–2306
124. Marshall J, Finn CA, Theodore AC. Impact of a clinical pharmacist-enforced intensive care unit sedation protocol on duration of mechanical ventilation and hospital stay. Crit Care Med. 2008;36:427–433
125. DuBose JJ, Inaba K, Shiflett A, et al. Measurable outcomes of quality improvement in the trauma intensive care unit: The impact of a daily quality rounding checklist. J Trauma. 2008;64:22–27; discussion 27–29
126. Devlin JW, Holbrook AM, Fuller HD. The effect of ICU sedation guidelines and pharmacist interventions on clinical outcomes and drug cost. Ann Pharmacother. 1997;31:689–695
127. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. 2006;34:1326–1332
128. Weinbroum AA, Halpern P, Rudick V, et al. Midazolam versus propofol for long-term sedation in the ICU: A randomized prospective comparison. Intensive Care Med. 1997;23:1258–1263
129. Riker RR, Shehabi Y, Bokesch PM, et al.SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009;301:489–499
130. Pandharipande PP, Sanders RD, Girard TD, et al.MENDS investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38
131. Ruokonen E, Parviainen I, Jakob SM, et al.“Dexmedetomidine for Continuous Sedation” Investigators. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med. 2009;35:282–290
132. Maldonado JR, Wysong A, van der Starre PJ, et al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009;50:206–217
133. Fong JJ, Kanji S, Dasta JF, et al. Propofol associated with a shorter duration of mechanical ventilation than scheduled intermittent lorazepam: A database analysis using Project IMPACT. Ann Pharmacother. 2007;41:1986–1991
134. Esmaoglu A, Ulgey A, Akin A, et al. Comparison between dexmedetomidine and midazolam for sedation of eclampsia patients in the intensive care unit. J Crit Care. 2009;24:551–555
135. Anis AH, Wang XH, Leon H, et al.Propofol Study Group. Economic evaluation of propofol for sedation of patients admitted to intensive care units. Anesthesiology. 2002;96:196–201
136. Hall RI, Sandham D, Cardinal P, et al.Study Investigators. Propofol vs midazolam for ICU sedation: A Canadian multicenter randomized trial. Chest. 2001;119:1151–1159
137. Huey-Ling L, Chun-Che S, Jen-Jen T, et al. Comparison of the effect of protocol-directed sedation with propofol vs. midazolam by nurses in intensive care: Efficacy, haemodynamic stability and patient satisfaction. J Clin Nurs. 2008;17:1510–1517
138. Searle NR, Côté S, Taillefer J, et al. Propofol or midazolam for sedation and early extubation following cardiac surgery. Can J Anaesth. 1997;44:629–635
139. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA. 2007;298:2644–2653
140. Fraser GL, Devlin JW, Worby CP, et al. Benzodiazepine Versus Nonbenzodiazepine-Based Sedation for Mechanically Ventilated, Critically Ill Adults: A Systematic Review and Meta-Analysis of Randomized Trials. Crit Care Med. 2013;41(Suppl):S30–S38
141. Jakob SM, Ruokonen E, Grounds RM, et al.Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA. 2012;307:1151–1160
142. Awissi DK, Lebrun G, Coursin DB, et al. Alcohol withdrawal and delirium tremens in the critically ill: A systematic review and commentary. Intensive Care Med. 2013;39:16–30
143. Carrasco G, Cabré L, Sobrepere G, et al. Synergistic sedation with propofol and midazolam in intensive care patients after coronary artery bypass grafting. Crit Care Med. 1998;26:844–851
144. Colombo R, Corona A, Praga F, et al. A reorientation strategy for reducing delirium in the critically ill. Results of an interventional study. Minerva Anestesiol. 2012;78:1026–1033
145. Kamdar BB, King LM, Collop NA, et al. The effect of a quality improvement intervention on perceived sleep quality and cognition in a medical ICU. Crit Care Med. 2013;41:800–809
146. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet. 2009;373:1874–1882
147. Needham DM, Korupolu R, Zanni JM, et al. Early physical medicine and rehabilitation for patients with acute respiratory failure: A quality improvement project. Arch Phys Med Rehabil. 2010;91:536–542
148. Lonergan E, Britton AM, Luxenberg J, et al. Antipsychotics for delirium. Cochrane Database Syst Rev. 2007;2:CD005594
149. Devlin JW, Al-Qadhee NS, Skrobik Y. Pharmacologic prevention and treatment of delirium in critically ill and non-critically ill hospitalised patients: A review of data from prospective, randomised studies. Best Pract Res Clin Anaesthesiol. 2012;26:289–309
150. Martin J, Heymann A, Bäsell K, et al. Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care—Short version. Ger Med Sci. 2010;8:Doc02
151. Michaud L, Büla C, Berney A, et al. Delirium: Guidelines for general hospitals. J Psychosom Res. 2007;62:371–383
152. Silva JA, Romera MA, Chamorro C, et al. Sedo-analgesia in neurologically ill patients: Guidelines revisited. Stroke. 2008;39:e67; author reply e68
153. Tropea J, Slee JA, Brand CA, et al. Clinical practice guidelines for the management of delirium in older people in Australia. Australas J Ageing. 2008;27:150–156
154. Kessler P, Martin J. [Optimisation of sedation practice in ICU by implementing of S2e Guidelines]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2008;43:38–43
155. Playfor S, Jenkins I, Boyles C, et al.United Kingdom Paediatric Intensive Care Society Sedation; Analgesia and Neuromuscular Blockade Working Group. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med. 2006;32:1125–1136
156. Potter J, George JGuideline Development Group. . The prevention, diagnosis and management of delirium in older people: Concise guidelines. Clin Med. 2006;6:303–308
157. American College of Critical Care Medicine of the Society of Critical Care Medicine, American Society of Health-System Pharmacists, American College of Chest Physicians:. . Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Am J Health-Syst Pharm. 2002;59:150–178
158. O’Mahony R, Murthy L, Akunne A, et al.Guideline Development Group. Synopsis of the National Institute for Health and Clinical Excellence guideline for prevention of delirium. Ann Intern Med. 2011;154:746–751
159. Girard TD, Pandharipande PP, Carson SS, et al.MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428–437
160. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38:419–427
161. Skrobik YK, Bergeron N, Dumont M, et al. Olanzapine vs haloperidol: Treating delirium in a critical care setting. Intensive Care Med. 2004;30:444–449
162. van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: A multicentre, double-blind, placebo-controlled randomised trial. Lancet. 2010;376:1829–1837
163. Hunt N, Stern TA. The association between intravenous haloperidol and Torsades de Pointes. Three cases and a literature review. Psychosomatics. 1995;36:541–549
164. Sharma ND, Rosman HS, Padhi ID, et al. Torsades de Pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol. 1998;81:238–240
165. Metzger E, Friedman R. Prolongation of the corrected QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol. 1993;13:128–132
166. Tisdale JE, Rasty S, Padhi ID, et al. The effect of intravenous haloperidol on QT interval dispersion in critically ill patients: Comparison with QT interval prolongation for assessment of risk of Torsades de Pointes. J Clin Pharmacol. 2001;41:1310–1318
167. Perrault LP, Denault AY, Carrier M, et al. Torsades de pointes secondary to intravenous haloperidol after coronary bypass grafting surgery. Can J Anaesth. 2000;47:251–254
168. Tisdale JE, Kovacs R, Mi D, et al. Accuracy of uncorrected versus corrected QT interval for prediction of torsade de pointes associated with intravenous haloperidol. Pharmacotherapy. 2007;27:175–182
169. Heinrich TW, Biblo LA, Schneider J. Torsades de pointes associated with ziprasidone. Psychosomatics. 2006;47:264–268
170. Tei Y, Morita T, Inoue S, et al. Torsades de pointes caused by a small dose of risperidone in a terminally ill cancer patient. Psychosomatics. 2004;45:450–451
171. Pham CP, de Feiter PW, van der Kuy PH, et al. Long QTc interval and torsade de pointes caused by fluconazole. Ann Pharmacother. 2006;40:1456–1461
172. Gilchrist NA, Asoh I, Greenberg B. Atypical antipsychotics for the treatment of ICU delirium. J Intensive Care Med. 2012;27:354–361
173. Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy. 2005;25:8S–18S
174. Siffleet J, Young J, Nikoletti S, et al. Patients’ self-report of procedural pain in the intensive care unit. J Clin Nurs. 2007;16:2142–2148
175. Akça O, Melischek M, Scheck T, et al. Postoperative pain and subcutaneous oxygen tension. Lancet. 1999;354:41–42
176. Hedderich R, Ness TJ. Analgesia for trauma and burns. Crit Care Clin. 1999;15:167–184
177. Beilin B, Shavit Y, Hart J, et al. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg. 1996;82:492–497
178. Pollock RE, Lotzová E, Stanford SD. Mechanism of surgical stress impairment of human perioperative natural killer cell cytotoxicity. Arch Surg. 1991;126:338–342
179. Peterson PK, Chao CC, Molitor T, et al. Stress and pathogenesis of infectious disease. Rev Infect Dis. 1991;13:710–720
180. Jones J, Hoggart B, Withey J, et al. What the patients say: A study of reactions to an intensive care unit. Intensive Care Med. 1979;5:89–92
181. Gélinas C. Management of pain in cardiac surgery ICU patients: Have we improved over time? Intensive Crit Care Nurs. 2007;23:298–303
182. Schelling G, Richter M, Roozendaal B, et al. Exposure to high stress in the intensive care unit may have negative effects on health-related quality-of-life outcomes after cardiac surgery. Crit Care Med. 2003;31:1971–1980
183. Granja C, Gomes E, Amaro A, et al.JMIP Study Group. Understanding posttraumatic stress disorder-related symptoms after critical care: The early illness amnesia hypothesis. Crit Care Med. 2008;36:2801–2809
184. Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med. 1998;26:651–659
185. Puntillo KA, Wild LR, Morris AB, et al. Practices and predictors of analgesic interventions for adults undergoing painful procedures. Am J Crit Care. 2002;11:415–429; quiz 430–431
186. Macintyre NR. Evidence-based assessments in the ventilator discontinuation process. Respir Care. 2012;57:1611–1618
187. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): A randomised controlled trial. Lancet. 2008;371:126–134
188. Luetz A, Goldmann A, Weber-Carstens S, et al. Weaning from mechanical ventilation and sedation. Curr Opin Anaesthesiol. 2012;25:164–169
189. Hooper MH, Girard TD. Sedation and weaning from mechanical ventilation: Linking spontaneous awakening trials and spontaneous breathing trials to improve patient outcomes. Anesthesiol Clin. 2011;29:651–661
190. Anifantaki S, Prinianakis G, Vitsaksaki E, et al. Daily interruption of sedative infusions in an adult medical-surgical intensive care unit: Randomized controlled trial. J Adv Nurs. 2009;65:1054–1060
191. De Jonghe B, Bastuji-Garin S, Fangio P, et al. Sedation algorithm in critically ill patients without acute brain injury. Crit Care Med. 2005;33:120–127
192. MacLaren R, Plamondon JM, Ramsay KB, et al. A prospective evaluation of empiric versus protocol-based sedation and analgesia. Pharmacotherapy. 2000;20:662–672
193. Engel HJ, Needham DM, Morris PE, et al. ICU Early Mobilization: From Recommendation to Implementation at Three Medical Centers. Crit Care Med. 2013;41(Suppl):S69–S80
194. Hopkins RO, Spuhler VJ. Strategies for promoting early activity in critically ill mechanically ventilated patients. AACN Adv Crit Care. 2009;20:277–289
197. Redeker NS. Sleep in acute care settings: An integrative review. J Nurs Scholarsh. 2000;32:31–38
198. Fontana CJ, Pittiglio LI. Sleep deprivation among critical care patients. Crit Care Nurs Q. 2010;33:75–81
199. Lawson N, Thompson K, Saunders G, et al. Sound intensity and noise evaluation in a critical care unit. Am J Crit Care. 2010;19:e88–e98; quiz e99
200. Dunn H, Anderson MA, Hill PD. Nighttime lighting in intensive care units. Crit Care Nurse. 2010;30:31–37
201. Tembo AC, Parker V. Factors that impact on sleep in intensive care patients. Intensive Crit Care Nurs. 2009;25:314–322
202. Xie H, Kang J, Mills GH. Clinical review: The impact of noise on patients’ sleep and the effectiveness of noise reduction strategies in intensive care units. Crit Care. 2009;13:208
203. Trompeo AC, Vidi Y, Locane MD, et al. Sleep disturbances in the critically ill patients: Role of delirium and sedative agents. Minerva Anestesiol. 2011;77:604–612
204. Andersen JH, Boesen HC, Skovgaard Olsen K. Sleep in the intensive care unit measured by polysomnography. Minerva Anestesiol. 2013;79:804–815
205. Sanders RD, Maze M. Contribution of sedative-hypnotic agents to delirium via modulation of the sleep pathway. Can J Anaesth. 2011;58:149–156
206. Weinhouse GL, Schwab RJ, Watson PL, et al. Bench-to-bedside review: Delirium in ICU patients—Importance of sleep deprivation. Crit Care. 2009;13:234
207. Sanders RD. Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses. 2011;77:140–143
208. Figueroa-Ramos MI, Arroyo-Novoa CM, Lee KA, et al. Sleep and delirium in ICU patients: A review of mechanisms and manifestations. Intensive Care Med. 2009;35:781–795
209. Li SY, Wang TJ, Vivienne Wu SF, et al. Efficacy of controlling night-time noise and activities to improve patients’ sleep quality in a surgical intensive care unit. J Clin Nurs. 2011;20:396–407
210. Dennis CM, Lee R, Woodard EK, et al. Benefits of quiet time for neuro-intensive care patients. J Neurosci Nurs. 2010;42:217–224
211. Faraklas I, Holt B, Tran S, et al. Impact of a nursing-driven sleep hygiene protocol on sleep quality. J Burn Care Res. 2013;34:249–254
212. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340:669–676
213. Van Rompaey B, Elseviers MM, Van Drom W, et al. The effect of earplugs during the night on the onset of delirium and sleep perception: A randomized controlled trial in intensive care patients. Crit Care. 2012;16:R73
214. Inouye SK, Baker DI, Fugal P, et al.HELP Dissemination Project. Dissemination of the hospital elder life program: Implementation, adaptation, and successes. J Am Geriatr Soc. 2006;54:1492–1499
215. Lundström M, Edlund A, Karlsson S, et al. A multifactorial intervention program reduces the duration of delirium, length of hospitalization, and mortality in delirious patients. J Am Geriatr Soc. 2005;53:622–628
216. Milisen K, Lemiengre J, Braes T, et al. Multicomponent intervention strategies for managing delirium in hospitalized older people: Systematic review. J Adv Nurs. 2005;52:79–90
217. van den Boogaard M, Schoonhoven L, van Achterberg T, et al. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Crit Care. 2013;17:R9
220. Pun BT, Balas MC, Davidson J. Implementing the 2013 PAD Guidelines: Top ten points to consider. Semin Respir Crit Care Med. 2013;34:223–235
221. Morris PE, Goad A, Thompson C, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med. 2008;36:2238–2243
222. Morris PE, Griffin L, Berry M, et al. Receiving early mobility during an intensive care unit admission is a predictor of improved outcomes in acute respiratory failure. Am J Med Sci. 2011;341:373–377
223. Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: A systematic review and meta-analysis. Crit Care Med. 2013;41:1543–1554
224. Vasilevskis EE, Ely EW, Speroff T, et al. Reducing iatrogenic risks: ICU-acquired delirium and weakness—Crossing the quality chasm. Chest. 2010;138:1224–1233
225. Balas M, Olsen K, Gannon D, et al. Safety and efficacy of the abcde bundle in critically-ill patients receiving mechanical ventilation. Crit Care Med. 2012;40:U18
226. Olsen K, Burke W, Peitz G, et al. The abcde bundle reduces the incidence of delirium in non-mechanically ventilated patients. Crit Care Med. 2012;40:U19
227. Awissi DK, Bégin C, Moisan J, et al. I-SAVE study: Impact of sedation, analgesia, and delirium protocols evaluated in the intensive care unit: An economic evaluation. Ann Pharmacother. 2012;46:21–28
228. Lord RK, Mayhew CR, Korupolu R, et al. ICU early physical rehabilitation programs: Financial modeling of cost savings. Crit Care Med. 2013;41:717–724
229. Jacobi J, Fraser GL, Coursin DB, et al.Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119–141
230. Levy MM, Dellinger RP, Townsend SR, et al.Surviving Sepsis Campaign. The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38:367–374
231. Surviving Sepsis Campaign. . The Society of Critical Care Medicine, Mount Prospect, IL, and the European Society of Intensive Care Medicine, Brussels, Belgium Available at: http:///www.survivingsepsis.org/Pages/default.aspx
. Accessed July 19, 2013
232. Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes after discharge from intensive care unit: Report from a stakeholders’ conference. Crit Care Med. 2012;40:502–509
agitation; critical care; delirium; implementation; intensive care; outcomes; pain; pain, agitation, and delirium care bundle; pain, agitation, and delirium guidelines; sedation
© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
Highlight selected keywords in the article text.