Executive Summary: Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

Abstract

Clinical practice guidelines are published and promoted, often by professional societies, because they provide a current and transparently analyzed review of relevant research and are written with the aim to guide clinical practice. The 2018 Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) (PADIS) guidelines (1) first 1) builds on this mission by updating the 2013 PAD guidelines (2); 2) by adding two inextricably related clinical care topics (immobility and sleep); 3) by including patients as collaborators and coauthors; and 4) by inviting panelists from high-income countries as an early step toward incorporating more diverse practices and expertise from the global critical care community. Readers will find rationales for 37 recommendations (derived from actionable Patient Intervention Comparison Outcome questions), two good practice statements, and 32 statements (derived from nonactionable, descriptive questions for which the Grading of Recommendations Assessment, Development and Evaluation methodology was not used) across the five guideline sections. Only two of the 37 recommendations are strong; most are conditional. Compared with a strong recommendation (most desirable to clinicians), conditional recommendations apply to most, but not all critically ill adults, and are made when evidence is conflicting, low quality, insufficient and/or applicable to just one patient subgroup, and/or when potential benefits require weighing almost equal risks. The supplemental digital figures and tables linked to the full guideline provide background on how the questions were established, profiles of the evidence, the “evidence to decision” tables used to develop recommendations, and voting results. We also describe the evidence gaps that prevented us from fully addressing all clinical priority questions. The five sections of this guideline are interrelated, and thus, the guideline should be considered in its entirety rather than as discrete or distinct recommendations. A separate PADIS guideline implementation and integration article (3) and a detailed description of the methodologic innovations that characterize these guidelines (4) have been published separately. This executive summary highlights the 18 recommendations the section leaders and guideline chair/vice-chair felt would be of greatest interest to ICU clinicians. All PADIS recommendations (including those highlighted in this executive summary) are found in Table 1. All descriptive questions and ungraded statements are found in Table 2.TABLE 1.: Summary of Actionable Patient Intervention Comparison Outcome Questions and RecommendationsTABLE 2.: Summary of Descriptive Questions and Ungraded StatementsRECOMMENDATIONS Pain Pain management is complex and has many origins. A consistent approach to pain assessment and management is paramount, particularly given the unique features inherent to critically ill adults. In this population, whose reference standard measure of pain is the patient’s self-report, the inability to communicate clearly does not negate a patient’s pain experience or the need for appropriate pain management (5). Severe pain negatively affects critically ill adults (6) beyond its unpleasant experience dimension. Implementation of assessment-driven and standardized pain management protocols improves ICU outcomes and clinical practice (5,6). Carefully titrated analgesic dosing is important in balancing the benefits versus risks of opioid exposure (7–10). Protocol-Based Pain Assessment and Management Question. Should we use a protocol-based (analgesia/analgosedation) pain assessment and management programs in the care of adult ICU patients when compared with usual care? Good practice statement. Management of pain for adult ICU patients should be guided by routine pain assessment and pain should be treated before a sedative agent is considered. Recommendation. We suggest using an assessment-driven, protocol-based, stepwise approach for pain and sedation management in critically ill adults (conditional recommendation, moderate quality of evidence). Remarks. For this recommendation, analgosedation is defined as either analgesia-first sedation (i.e., an analgesic [usually an opioid] is used before a sedative to reach the sedative goal) or analgesia-based sedation (i.e., an analgesic [usually an opioid] is used instead of a sedative to reach the sedative goal). The implementation of this recommendation infers that institutions should have an assessment-driven protocol that mandates regular pain and sedation assessment using validated tools, provides clear guidance on medication choice and dosing, and makes treating pain a priority over providing sedatives. Our pooled analysis suggests that protocol-based (analgesia/analgosedation) pain and sedation assessment and management programs compared with usual therapy reduce sedative requirements, duration of mechanical ventilation, ICU length of stay (LOS), and pain intensity (5,11–31). Panel members issued a conditional recommendation because the benefits of a protocol-based approach were not observed across all critical outcomes. Pharmacologic Adjuvants to Opioid Therapy. Opioids remain a mainstay for pain management in most ICU settings; however, their side effects preoccupy clinicians because important safety concerns, such as sedation, delirium, respiratory depression, ileus, and immunosuppression, may increase ICU LOS and worsen post-ICU patient outcome. The panel generally supports the use of multimodal pharmacotherapy as a component of an analgesia-first approach to spare/minimize opioid and sedative use and optimize analgesia and rehabilitation (32), as described below. Acetaminophen Question. Should acetaminophen be used as an adjunct to an opioid (vs an opioid alone) for pain management in critically ill adults? Recommendation. We suggest using acetaminophen as an adjunct to an opioid to decrease pain intensity and opioid consumption for pain management in critically ill adults (conditional recommendation, very low quality of evidence). When compared with placebo in the perioperative period, use of IV acetaminophen 1 g every 6 hours was associated with reduced pain intensity and opioid consumption 24 hours after surgery (33,34). The risk for IV acetaminophen-associated hypotension may preclude its use in some patients (35). Given these findings, the panel suggests using acetaminophen (IV, oral, or rectal) to decrease pain intensity and opioid consumption when treating pain in critically ill patients, particularly in patients at higher risk for opioid-associated safety concerns. Nefopam Question. Should nefopam be used either as an adjunct or a replacement for an opioid (vs an opioid alone) for pain management in critically ill adults? Recommendation. We suggest using nefopam (if feasible) either as an adjunct or replacement for an opioid to reduce opioid use and their safety concerns when treating pain in critically ill adults (conditional recommendation, very low quality of evidence). Nefopam is a nonopioid analgesic; a 20-mg dose has an analgesic effect comparable to 6 mg of IV morphine (36). Nefopam has potential safety advantages over opioids and other nonopioid analgesics (e.g., cyclooxygenase 1 selective nonsteroidal anti-inflammatory drugs) because it has no detrimental effects on hemostasis, gastric mucosal integrity, renal function, vigilance, ventilatory drive, and intestinal motility. However, nefopam use can be associated with tachycardia, glaucoma, seizure, and delirium. Although not available in the United States or Canada, nefopam is a low-cost drug that is used in nearly 30 countries. In cardiac surgery patients, nefopam’s analgesic effect resembles IV fentanyl when delivered as patient-controlled analgesia, with less nausea (37). Ketamine Question. Should ketamine be used as an adjunct to an opioid (vs an opioid alone) for pain management in critically ill adults? Recommendation. We suggest using low-dose ketamine (1–2 µg/kg/hr) as an adjunct to opioid therapy when seeking to reduce opioid consumption in postsurgical adults admitted to the ICU (conditional recommendation, very low quality of evidence). IV ketamine, although shown to reduce opioid requirements among abdominal surgery patients admitted to the ICU, was not shown to improve patients’ self-reported pain intensity (38). Reduced opioid consumption is only a surrogate for better patient-centered outcomes. The frequency of side effects (i.e., nausea, delirium, hallucinations, hypoventilation, pruritus, and sedation) was similar between the ketamine and control groups. Although indirect evidence from randomized controlled trials (RCTs) in non-ICU patients supports a role for ketamine as an analgesic adjuvant to opioid therapy, evidence evaluating its role in the ICU for this indication currently remains limited. Neuropathic pain medications Question. Should a neuropathic pain medication (e.g., gabapentin, carbamazepine, and pregabalin) be used as an adjunct to an opioid (vs an opioid alone) for pain management in critically ill adults? Recommendations. We recommend using a neuropathic pain medication (e.g., gabapentin, carbamazepine, and pregabalin) with opioids for neuropathic pain management in critically ill adults (strong recommendation, moderate quality of evidence). We suggest using a neuropathic pain medication (e.g., gabapentin, carbamazepine, and pregabalin) with opioids for pain management in ICU adults after cardiovascular surgery (conditional recommendation, low quality of evidence). Neuropathic pain medications as an adjuvant to opioid therapy have been evaluated in critically ill adults with Guillain-Barré syndrome or who have recently undergone cardiac surgery (39–42). Across both populations, their use significantly reduced opioid consumption within 24 hours of their initiation. Among cardiac surgery patients, neuropathic pain medication use did not affect time to extubation or ICU LOS (41,42). Panel members estimated that neuropathic agents had negligible costs and were widely available although the possible sedative and cognitive effects of these agents could preclude their use in some patients. These drugs require the ability for patients to swallow or have enteral access. Agitation/Sedation Sedatives are frequently administered to critically ill patients to relieve anxiety and prevent agitation-related harm (2). These medications may predispose patients to increased morbidity (43–46). In addition to the healthcare provider determining the specific indication for the sedative use, the patient’s current and subsequent sedation status should be continuously assessed using valid and reliable scales (47–49). The 2013 guidelines (2) suggested targeting light levels of sedation or using daily awakening trials (44,50–52), and minimizing benzodiazepines (53), to improve short-term outcomes (e.g., duration of mechanical ventilation and ICU LOS). In addition, sedation delivery paradigms and specific sedative medications can have an important effect on post-ICU outcomes including 90-day mortality, physical functioning, and neurocognitive and psychologic outcomes. Light Sedation Question. Does light sedation (vs deep sedation), regardless of the sedative agent(s) used, significantly affect outcomes in critically ill mechanically ventilated adults? Recommendation. We suggest using light sedation (vs deep sedation) in critically ill, mechanically ventilated adults (conditional recommendation, low quality of evidence). The 2013 guidelines’ ungraded statement associated maintaining a light level of sedation with shortened time to extubation and ICU LOS (2). Although the previous guideline defined light sedation as a Richmond Agitation-Sedation Scale (RASS) scale score of greater than or equal to –2 and eye opening of at least 10 seconds (50), this level of sedation is probably deeper than that required for mechanically ventilated patient management in an ICU. No universally accepted definition of light sedation exists. For studies that used scales, such as the RASS (48), a RASS score of –2 to +1 (or its equivalent using other scales) was defined as light sedation in the studies evaluated by this panel. The outcomes evaluated differ from the short-term outcomes assessed in the 2013 guidelines (2) in their consideration of post-ICU discharge measurements. Light sedation was associated with a shorter time to extubation (51,54,55) and a reduced tracheostomy rate (50). Light sedation was not associated with a reduction in 90-day mortality (44,50,53), delirium prevalence (44,54), posttraumatic stress disorder incidence (31,50), or self-extubation (44,50,53,55). No RCTs evaluated the impact of light versus deep sedation on cognitive or physical functioning. Choice of Sedative. Sedation indication, goal, clinical pharmacology, and acquisition cost are important determinants in choosing a sedative agent. The 2013 guidelines suggest (conditionally) that nonbenzodiazepine sedatives (either propofol or dexmedetomidine) are preferable to benzodiazepine sedatives (either midazolam or lorazepam) in critically ill, mechanically ventilated adults because of improved short-term outcomes, such as ICU LOS, duration of mechanical ventilation, and delirium (2). For the 2018 guidelines (1), we considered both short- and long-term outcomes as critical in our evaluation. Questions. Should propofol, when compared with a benzodiazepine, be used for sedation in critically ill, mechanically ventilated adults? Should dexmedetomidine, when compared with a benzodiazepine, be used for sedation in critically ill, mechanically ventilated adults? Should dexmedetomidine, when compared with propofol, be used for sedation in critically ill, mechanically ventilated adults? Recommendation. We suggest using either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults (conditional recommendation, low quality of evidence). We evaluated the effect of propofol versus a benzodiazepine, dexmedetomidine versus a benzodiazepine, and propofol versus dexmedetomidine in three separate analyses for the outcomes deemed critical. In most studies, benzodiazepines were administered as continuous infusions and not intermittent boluses. We combined studies using midazolam and lorazepam. A shortened time to light sedation of at least 4 hours and time to extubation of at least 8–12 hours (one nursing shift) were deemed clinically significant. Compared with a benzodiazepine, propofol use was associated with a shorter time to light sedation in seven RCTs (56–62) and a shorter time to extubation in nine RCTs (56,57,61, 67). Only one RCT assessed delirium and found no difference (61). No data were available for other critical outcomes. Although propofol was associated with a higher risk of self-extubation, the CI for this outcome was wide and it remains unclear if harm resulted (i.e., need for reintubation). Dexmedetomidine, when compared with a benzodiazepine infusion (one study used intermittent boluses), was associated with a shorter duration of mechanical ventilation in five RCTs (53,67–70) and ICU of stay in three RCTs (53,68,71). Delirium prevalence was evaluated in four RCTs (53,68,69,71); the Midazolam versus Dexmedetomidine (MIDEX) (69) trial data could not be pooled as delirium was assessed only once, 48 hours after sedation discontinuation. Dexmedetomidine was associated with a significant reduction in delirium in the three remaining pooled RCTs that evaluated delirium bid throughout the ICU stay (53, 68, 71). The Safety and Efficacy of Dexmedetomidine Compared With Midazolam (53) and Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) (68) studies both demonstrated a greater incidence of bradycardia in the dexmedetomidine group; neither study found that intervention was required for the bradycardia. We evaluated three RCTs comparing dexmedetomidine and propofol; none of the three demonstrated any difference in time to extubation (67, 69, 72). No data were available for other critical outcomes. A single RCT, the Propofol versus Dexmedetomidine (PRODEX) study, showed that delirium incidence was decreased with dexmedetomidine at the single time point of 48 hours after sedation cessation (69). Patients could communicate more effectively if sedated with dexmedetomidine when compared with propofol (69). No differences were reported in bradycardia or hypotension between patients sedated with propofol versus dexmedetomidine (69). sedative choice were not assessed as both propofol and dexmedetomidine acquisition costs are than when they were both propofol and dexmedetomidine practice was considered and dexmedetomidine may not be the unique sedative when deep sedation or is Panel members that the desirable and of propofol (vs dexmedetomidine) were they issued a conditional recommendation to use either agent for sedation of critically ill adults. Delirium Delirium is in critically ill adults. Delirium is a clinical most studies its using such as the Assessment for the ICU or the Delirium Delirium can be for patients and and is associated with cognitive increased ICU and LOS, and greater costs and Question. Should a (vs no such be used to reduce delirium in critically ill adults? Recommendation. We suggest using a intervention that is on not risk for delirium, and and in critically ill adults (conditional recommendation, low quality of evidence). Remarks. These are not to reduce or delirium (e.g., cognitive use of improve (e.g., minimizing light and improve (i.e., reduced sedation), reduce (e.g., early and reduce and/or (e.g., use of such as or eye The intervention studies, many of which were not evaluated a of the use of such significantly reduced delirium ICU duration of delirium in patients who it ICU LOS and mortality all decreased intervention the and Delirium and was significantly associated with less delirium in a study When a and a on assessment and of and was evaluated in a study, and delirium was also assessed using the an analysis showed that in were significantly associated with reduced mortality and more ICU or delirium effects were not reported in the Delirium Question. Should a agent (vs no use of this be used to delirium in all critically ill adults with Recommendation. We suggest not using an or a A (i.e., a to delirium (conditional recommendation, low quality of evidence). A of 2) and a 1) this This evidence suggests that the use of the an or a was not associated with a shorter duration of delirium, mechanical ventilation or ICU LOS, or decreased Although this recommendation the use of agents in the of delirium, the short-term use of or an in patients may be a of evidence, for those patients who experience significant to the of a delirium, such as and/or or who are and have that may be to or However, all agents should be the of the patient’s Dexmedetomidine Recommendation. We suggest using dexmedetomidine for delirium in mechanically ventilated adults is (conditional recommendation, low quality of evidence). A single randomized trial evaluated role as a for patients from to the study patients and was early because the was Although dexmedetomidine (vs was associated with a but increase in hours within of its use did not affect either ICU or LOS, or patients’ at Immobility and of critical frequently experience many long-term including can in of critically ill patients and is associated with in patients’ long-term physical functioning, and quality of important risk for is The and benefits of rehabilitation and delivered in the ICU have been evaluated as potential to and physical functioning. highlighted in the 2013 guidelines may be as a delirium management important between analgesic and sedation and pain and sedation status with patients in in the ICU Question. For critically ill adults, is rehabilitation or either or in or outcomes compared with usual a or Recommendation. We suggest rehabilitation or in critically ill adults (conditional recommendation, low quality of evidence). Remarks. is a of to optimize and reduce in with a is a of intervention within rehabilitation that the of patients and with a of patient outcomes. This recommendation supports over usual care or similar with a reduced reduced or The implementation of this recommendation will be by particularly related to in the of appropriate and to across We a of RCTs that our and reported on five critical outcomes. significantly improved at ICU discharge and significantly reduced duration of mechanical ventilation A but not in quality of using the within of discharge was observed across four RCTs had no effect on mortality or short-term physical The incidence of for patients was very low on five trials and outcomes function, and of to and related could not be evaluated to insufficient was assessed as to and to be on In addition, indirect evidence with a with panel members (including an ICU patient suggests that patients benefits Given the of either or and the low quality of evidence, panel members that the desirable for patients probably the Sleep is a and a of for many critically ill patients Sleep in the ICU can be and is by increased light and decreased and eye The of critical delirium, and is but it is important and is an of In addition to has been to to ICU delirium duration of mechanical ventilation and neurocognitive Pharmacologic Question. Should a medication (i.e., dexmedetomidine, or (vs no use of a be used to improve in critically ill adults? Recommendation. We no recommendation the use of to improve in critically ill adults recommendation, very low quality of evidence). randomized trials evaluating the of were of the studies reported a in quality, but the panel that the data were insufficient to a The of in the United States is not and concerns as to the quality and of the have prevented many from adding it to their however, associated with effects (e.g., sedation and and Dexmedetomidine Recommendation. We no recommendation the use of dexmedetomidine at to improve recommendation, low quality of evidence). randomized trials compared dexmedetomidine to placebo in critically ill mechanically ventilated and in critically ill, ventilated patients not a continuous sedative infusion Dexmedetomidine (vs increased and decreased 1 in both however, neither demonstrated a decrease in or an increase in deep or A not in our these with to and when dexmedetomidine was administered in mechanically ventilated ICU patients a sedative infusion is for a critically ill adult dexmedetomidine may be a because of its potential to improve Propofol Recommendation. We suggest not using propofol to improve in critically ill adults (conditional recommendation, low quality of evidence). RCTs compared propofol to benzodiazepines and one compared propofol to placebo No in with propofol compared with propofol was associated with side and respiratory depression, mechanical Although we recommend using propofol for the of in the critically ill, this recommendation does not to its use in patients or continuous Question. Should a protocol be used to improve in critically ill adults? Recommendation. We suggest using a protocol in critically ill adults (conditional recommendation, very low quality of evidence). The protocols for in their all and to patients and two use of Among the two a more complex of one a guideline that the use of medications to and/or delirium and in over a In all studies, protocols were to all ICU patients and did not a of patients to have RCT in surgery patients demonstrated that and improved self-reported quality the three studies, one found an in in a ICU the other two did not analysis of the three studies demonstrated an reduction in the prevalence of delirium with a of the or of are in and delirium be from the the of the of this executive summary to provide the most clinically and by of the PADIS guidelines that and should using when care for critically ill adults. The recommendation by data and to the the of was for by the panelists and patients in the We that the 2018 PADIS guideline (1) will the delivery of care delirium, and and the of patient-centered research across of these important critical care