Should acetaminophen be used as an adjunct to an opioid (vs an opioid alone) for pain management in critically ill adults?
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.
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?
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).
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.
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.
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).
Economic considerations surrounding sedative choice were not assessed as both propofol and dexmedetomidine acquisition costs are now lower than when they were initially studied. Incorporating both propofol and dexmedetomidine into practice was considered likely acceptable and feasible, whereas recognizing dexmedetomidine may not be the preferred unique sedative when deep sedation (with or without neuromuscular blockade) is required. Panel members judged that the desirable and undesirable consequences of propofol (vs dexmedetomidine) were balanced; therefore, they issued a conditional recommendation to use either agent for sedation of critically ill adults.
Should a multicomponent, nonpharmacologic strategy (vs no such strategy) be used to reduce delirium in critically ill adults?
We suggest using a multicomponent, nonpharmacologic intervention that is focused on (but not limited to) reducing modifiable risk factors for delirium, improving cognition, and optimizing sleep, mobility, hearing, and vision in critically ill adults (conditional recommendation, low quality of evidence).
These multicomponent interventions include (but are not limited to) strategies to reduce or shorten delirium (e.g., reorientation, cognitive stimulation, use of clocks), improve sleep (e.g., minimizing light and noise), improve wakefulness (i.e., reduced sedation), reduce immobility (e.g., early rehabilitation/mobilization), and reduce hearing and/or visual impairment (e.g., enable use of devices such as hearing aids or eye glasses).
The multicomponent intervention studies, many of which were not randomized, evaluated a bundle of interventions. Overall, the use of such strategies significantly reduced delirium (76, 80). Further, ICU duration of delirium in patients who developed it (79), ICU LOS (76), and hospital mortality all decreased (77). Another multiple intervention approach, the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle, was significantly associated with less delirium in a before-after study (81). When a revised and expanded ABCDEF bundle (which included a focus on “A,” assessment and treatment of pain, and “F,” family engagement) was evaluated in a larger, multicenter, before-after, cohort study, and where delirium was also assessed using the CAM-ICU, an adjusted analysis showed that improvements in bundle compliance were significantly associated with reduced mortality and more ICU days without coma or delirium (82). Adverse effects were not reported in the nonpharmacologic interventions studies.
We suggest not routinely using haloperidol, an atypical antipsychotic, or a 3-hydroxy-3-methylglutaryl coenzyme A reductase reductase inhibitor (i.e., a statin) to treat delirium (conditional recommendation, low quality of evidence).
Although this recommendation discourages the “routine” use of antipsychotic agents in the treatment of delirium, the short-term use of haloperidol or an atypical antipsychotic in patients may be warranted, despite a lack of evidence, for those patients who experience significant distress secondary to the symptoms of a delirium, such as hallucination and/or delusion-associated fearfulness or who are delirious and have agitation that may be physically harmful to themselves or others (88). However, all antipsychotic agents should be discontinued immediately following the resolution of the patient’s distressful symptoms.
A single randomized trial evaluated dexmedetomidine’s role as a treatment for agitation precluding ventilator liberation (89). It screened 21,500 intubated patients from 15 ICUs to enroll the 71 study patients and was terminated early because the allocated funding (from dexmedetomidine’s manufacturer) was expended (89). Although dexmedetomidine (vs placebo) was associated with a small, but statistically significant, increase in ventilator-free hours within 7 days of randomization, its use did not affect either ICU or hospital LOS, or patients’ disposition location at hospital discharge.
Survivors of critical illness frequently experience many long-term sequelae, including ICU-acquired muscle weakness (ICUAW). ICUAW can occur in 25–50% of critically ill patients (90) and is associated with impairments in patients’ long-term survival, physical functioning, and quality of life (91–93). One important risk factor for ICUAW is bed rest (91 , 94). The safety, feasibility, and benefits of rehabilitation and mobilization delivered in the ICU setting have been evaluated as potential means to mitigate ICUAW and impaired physical functioning. As highlighted in the 2013 guidelines (2), rehabilitation/mobilization may be beneficial as a delirium management strategy. Furthermore, important associations exist between analgesic and sedation practices, and pain and sedation status with whether patients participate in rehabilitation/mobilization in the ICU (95).
Rehabilitation is a “set of interventions designed to optimize functioning and reduce disability in individuals with a health condition.” Mobilization is a type of intervention within rehabilitation that facilitates the movement of patients and expends energy with a goal of improving patient outcomes. This recommendation supports performing rehabilitation/mobilization interventions over usual care or similar interventions with a reduced duration, reduced frequency, or later onset. The implementation of this recommendation will be influenced by feasibility-related issues, particularly related to variability in the availability of appropriate staffing and resources to perform rehabilitation/mobilization interventions across ICUs.
We make no recommendation regarding the use of dexmedetomidine at night to improve sleep (no recommendation, low quality of evidence).
One small RCT in open-heart surgery patients demonstrated that earplugs, eyeshades, and relaxing music improved self-reported sleep quality (129). Of the three observational before-and-after studies, one found an improvement in sleep in a mixed ICU population (131), whereas the other two did not (128 , 130). Pooled analysis of the three studies demonstrated an overall reduction in the prevalence of delirium with a sleep-promoting protocol. Which of the interventions, or combinations of interventions, are effective in improving sleep and reducing delirium cannot be discerned from the above studies.
Under the auspices of the Society of Critical Care Medicine, this executive summary aims to provide the most clinically meaningful and novel aspects, by section, of the PADIS guidelines that clinicians, stakeholders, and decision makers should consider using when improving care for critically ill adults. The recommendation rationales, fueled by rigorous data evaluation, debate, and discussion, circled back to the bedside experience—and the perspective of what was best for patient—held by the panelists and patients involved in producing the guidelines. We believe that the 2018 PADIS guideline (1) will foster the delivery of excellent care regarding pain, agitation/sedation, delirium, immobility, and sleep disruption and stimulate the completion of pragmatic, patient-centered research across each of these important critical care domains.
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