International guidelines clearly recommend systematic assessment of pain, agitation/sedation, and delirium in all ICU patients, with validated tools [4–6]. They provide repeatable and comparable measurements, able to adequately titrate the analgesic, sedative, and antipsychotic therapy. The goal is to control the stress response and the neurological symptoms together keeping ARDS patients awake, cooperative, and well adapted to the necessary invasive procedures as soon as possible [28]. An excessive use of neuroactive drugs [26] correlates with longer mechanical ventilation and ICU stay, as well as with an increased risk of serious neurological consequences in both the short- and long-term [10, 29].

Among the validated tools, the scales with the highest psychometric properties [30] are the Verbal Numeric Rating (VNR), the Behavioral Pain Scale (BPS) [31], or the Critical-Care Pain Observation Tool (CPOT) [32] for the pain assessment, the Richmond Agitation-Sedation Scale (RASS) [33] and the Sedation-Agitation Scale (SAS) [34] for the agitation/sedation assessment, and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) [35] and the Intensive Care Delirium Screening Checklist (ICDSC) [36] for the delirium assessment.

Pain assessment has become culturally essential for intensivists, both nurses and physicians. Proper identification of pain symptoms in critically ill patients represents a challenge because of complexity in communication with patients needing endotracheal respiratory prostheses, because of altered state of consciousness or because of neuroactive drugs use. To address these issues, specific behavioral scales were designed and validated both in unconscious/sedated [37] and in conscious/awake patients [38] and established as a valid, reliable, and simple tool to be used in clinical practice.

Regarding sedative drugs, their under- or overuse may compromise clinical stability. Life-threatening side effects of untreated agitation and stress response are evident: self-removal of life-sustaining devices, tachypnea, tachycardia, hypertension, sustained hypoxemia, and hypercarbia due to uncoordinated mechanical ventilation [6]. At the same time, deeper-than-necessary sedation increases the length of ICU stay [5], the duration of mechanical ventilation [21], the sepsis severity [8], and the onset of new neurological failures both during hospitalization like delirium and after discharge [29] like the development of psychological reactions of traumatic nature (posttraumatic stress disorder, PTSD). In order to obtain the best sedative titration, the use of validated tools is mandatory. For example, the RASS describes ten levels of sedation/agitation through observation and verbal and physical stimulation. Scores range from −5 (unconscious, unresponsive to voice and physical stimuli) to + 4 (overtly combative, violent, immediate danger to staff), adequately describing the possible neurological condition needing an immediate intervention.

While regarding pain and agitation evaluation encouraging results are present in literature [39], delirium recognition [40] and assessment is more challenging, since its success is linked to an effective and lasting staff training [41]. Delirium has a very high prevalence in critically ill patients [42], with a direct relationship between increased morbidity and mortality and the duration (in days) of delirium [43, 44]. The presence and duration of delirium also correlates with a significant deterioration in the quality of life after ICU discharge [45]. Large literature recommends the use of validated tools [46], like the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). The CAM-ICU has excellent sensitivity and specificity and is based on only four items (acute modification of consciousness, inattention, disorganized thinking, altered level of consciousness). This allows a shorter training to teach ICU staff members a validated way to evaluate delirium.

All these measurements have to be reported in the clinical chart at least once per shift, together with an evaluation of adequacy of sedative treatment. The neurological monitoring plays a key role in ARDS patients, and it is quick to perform. A complete example of evaluations recommended by international guidelines is reported in Fig. 18.2. Physicians have to state the desired sedation target for that specific patient at that specific moment of clinical course; nurses, on their part, report the actual neurological state, describing pain, anxiety, agitation, sleep, need for physical restraints, and delirium, together with a comprehensive evaluation of sedative therapy, in order to get the most adequate treatment titration.

The appropriate target level of sedation primarily depends on a patient’s acute disease process and on the therapeutic and supportive interventions required. After the first few days of ICU stay, characterized by clinical stabilization and invasive procedures, the sedation target is a calm patient, awake during the day and asleep at night. The use of deep levels of sedation to facilitate mechanical ventilation or painful procedures should be minimized with ventilation setting optimization and adequate analgesia, rather than deepening unconsciousness [12, 47].

The appropriate balance of sedation and analgesia is difficult to be achieved and maintained. Without a rational agreement upon “target levels” of sedation, different members of the healthcare team will have disparate treatment goals, increasing the chance for iatrogenic complications and potentially delaying recovery [48].

The target level of sedation should be discussed and defined at the beginning of each staff shift and reevaluated regularly as the clinical condition of the patient changes. The pharmacological treatment should be planned with the appropriate flexibility to allow titration to the desired endpoint, anticipating fluctuations in sedation requirements throughout the day. Frequent monitoring with validated tools improves communication among clinicians and plays an important role in detecting and treating pain, agitation, and delirium while avoiding excessive or prolonged sedation [25].

Recognition that heavy sedation may increase mortality and morbidity has led to a new approach that maximizes the comfort of the patients while they remain awake, interactive, and oriented. This new approach relies on strategies such as daily interruptions of sedation, analgesia-based sedation, enteral sedation, avoidance of paralytic agents, early mobilization, and use of validated tools for sedation assessment [1]. In recent years, many guidelines have been proposed [4–6], representing a guide to symptom-oriented prevention, diagnosis, and treatment of delirium, anxiety, stress, and protocol-based analgesia, sedation, and sleep management. They comprehensively describe all attentions to be paid to perform the best neurological treatment. Nevertheless, even in guidelines with a high-quality rating, numerous recommendations have moderate or low levels of evidence [65].

Overall, the principal recommendation regarding analgesia is to evaluate pain and maintain its level ≤ 4/10, by beginning early than late the treatment of pain, and by using opioid drugs first, together with non-opioid and multimodal analgesia techniques. A simple and practical flowchart at the bedside is presented in Fig. 18.4.

Regarding sedation, a target RASS of 0/−1 is recommended for all ICU patients, with the use of deep sedation reserved only for patients with specific indications (e.g., early ARDS patients, requiring neuromuscular blocking or prone positioning). In particular, intensivists should consider the specific indication and individual goal of sedation and the pharmacokinetics/pharmacodynamics of each drug used. Non-benzodiazepine drugs, such as propofol or dexmedetomidine, have to be preferred. The need for sedation varies widely among different patients and with the illness course, and it has to be defined among “deep sedation”, “cooperative/awake sedation,” and “no sedation,” always preferring superficial levels of sedation and promoting early mobilization. The use of containment measures in episodes of severe agitation has to be performed in this order: first verbal, then pharmacological, and finally physical, considering that neuroactive drugs should not be administered in excess as a form of “chemical immobilization.” In the sedation flowchart (Fig. 18.5), it is clear that defining a target and evaluating the actual level of sedation or agitation with validated tools are absolute priorities. The choice of the specific sedative drug, albeit important, comes only after a clinical reasoning focused on managing the organic/metabolic causes and the problems that may be caused by adjustable invasive devices.

Recommendations about delirium are prescribed first to identify modifiable risk factors (Fig. 18.6) and to detect regularly the appearance of delirium by using the CAM-ICU. In case of delirium appearance, it is indicated to use a non-pharmacological protocol first, along with the suspension or decreasing of deliriogenic therapies, and then to select the most appropriate drug (haloperidol, atypical antipsychotics, or dexmedetomidine; avoid the use of benzodiazepines) and titer its dose to the lowest effective dose.

Beyond the choice of the specific drug [66–68], the most frequently used method for administering sedatives is the continuous intravenous route, because of its pharmacokinetic properties [63]. Intravenous infusions present predictable and easy to handle onset/offset properties, justifying the search for an early goal-directed sedation strategy [69]. Although these characteristics are necessary in short ICU stays, they may be useless, or even dangerous, for patients requiring more than 3 days of mechanical ventilation [27]. When using potent drugs, it is easy to incur in overadministration albeit goals are established and adequate [25]. Moreover, daily awakening trials produce far-from-physiological neurological fluctuations [70], and continuous deep sedation does not permit patients to recall factual memories, which has been proven effective in preventing PTSD [71].

If continuous intravenous infusion is used, the daily interruption of sedatives and analgesics is recommended in order to reduce the total administered dosage and to perform a spontaneous breathing trial, if allowed by the respiratory condition of the patient. The purpose is to reduce the development of complications and the duration of mechanical ventilation [17]. This strategy may prove less effective if specific and ICU team-shared protocols are used [72].

Many quite different sedation protocols have been presented in literature [10, 73, 74]. Some of them essentially rely on the use of different drug doses [75], with the aim to different sedation levels [56, 76]. Other protocols are based on nursing-implemented algorithms [13, 77–79] or on analgesia-first sedation [21, 80]. Moreover, tested ways to optimize sedation management in ICU are patient-controlled sedation [81] or automated sedation in patients needing deep sedation [82], the use of inhaled halogenates [83, 84], or the enteral administration of drugs [28, 85]. All these protocols rely on the continuous and adequate neurological assessment made with validated tools, in order to measure not only pain, agitation, and delirium but also level of consciousness and patient mobilization.

The most promising protocol, in terms of efficacy, recommends to join the sedation strategies with early physiotherapy [86], mobilization [87], and occupational therapy [88, 89], also engaging patient families. Even if implementing such protocols is not simple [90], from the first presentation made in 2010 [91, 92], it has offered the best results in terms of effectiveness [93]. Briefly, following the acronym ABCDEF, the authors made these suggestions:

Regarding ARDS patients needing extracorporeal life support systems (ECLS), there is a gray area about sedation, where safety aspects and the ability to positively influence recovery must be balanced. Patients on ECLS have numerous risk factors to develop both delirium during the ICU stay and PTSD after discharge. Hyperactive delirium or agitation can be life-threatening for these patients, so that a consequent monitoring and a symptomatic therapy of stress, anxiety, delirium, pain, and insomnia is essential to safely achieve a target RASS of 0. The higher level of alertness allows the patient to actively partake in physical exercises [94] that is considered a feasible and safe goal [95, 96]. International guidelines recommend a strict definition of sedation targets for patients on ECLS, including frequent clinical monitoring and continuous adjustment of the level of sedation required [4].

Positioning therapy has been demonstrated effective in ameliorating prognosis of severe ARDS patients. It is used for prophylaxis and treatment of respiratory dysfunctions and requires an individual sedation target. Changes of the position frequently represent a challenge for the symptomatic treatment of anxiety, stress, and pain. Therefore, a symptom-orientated therapy should be adapted for changing demands during positioning therapy. Though a deep sedation may be indicated for patient repositioning [97], an excessive sedation should be avoided through the use of objective tools based on EEG analysis, as previously described.

The use of non-depolarizing neuromuscular blockers in patients with severe ARDS is suggested during the first 48 ICU hours. Despite this practice, it is suggested not to routinely increase the dose of sedatives, when accompanied by an infusion of opiates, even in patients subjected to permissive hypercapnia [98]. To control respiratory rate, fentanyl is recommended as the analgesic of choice in patients with hemodynamic instability, bronchial asthma, or COPD, with respect to the other opiates. Methadone via the enteral route could be used in patients receiving opiates for more than 5 days, but still needing mechanical ventilation. Once tracheostomy is performed, it is advisable to consider a decrease in sedative and analgesic regimens.

After the hyperacute phase of respiratory failure, a defined sedation and analgesia monitoring and dose adjustment protocol is recommended, to shorten the weaning process. This protocol should include daily evaluation of sedation, an awakening test and a spontaneous breathing test. It is advisable not to use benzodiazepines in the withdrawal of MV. Dexmedetomidine is recommended in case of weaning difficulties, in patients with withdrawal syndrome, or after failed attempts of weaning secondary to agitation and delirium [67]. Low-dose remifentanil in continuous infusion is another effective alternative during weaning process. Music therapy is a possible non-pharmacological adjuvant to sedation [99]. Melatonin supplementation could be useful to decrease the need for sedative drugs, then shortening the ventilation length [100], and to restore the sleep-wake rhythm.