In the last decades, NIV has expanded greatly in several populations of patients with acute respiratory failure (ARF). As a result of emerging evidence, NIV has been shown to reduce the necessity of invasive ventilation and associated complications [1]. NIV is now considered the first-choice ventilator treatment for a large number of patients with ARF such as exacerbations of COPD along with a success percentage of 80–85% [2–5], acute cardiogenic pulmonary edema, pulmonary infiltrates in immunocompromised patients, and weaning from mechanical ventilation in COPD patients [1]. NIV success is strongly dependent on the patient’s degree of tolerance and collaboration during ventilation [3]. One of the most frequent causes of premature interruption of the NIV is mask intolerance due to pain, discomfort, or claustrophobia [6]. Relative contraindications to NIV are delirium and agitation [2]. Judicious sedation may play a crucial role in improving patient’s tolerance in selected cases at risk of endotracheal intubation due to NIV failure. Although the use of sedative drugs can reduce the risk of NIV failure, the possibility and suitability of sedating a patient during NIV remain a debated issue [7–10]. This chapter will focus on a practical overview of sedation and analgesia during NIV.

A survey published in 2007 [11] showed that in clinical practice, the use of sedatives varies according to the geographical location or by the type of hospital where the NIV is applied and by the specialist who prescribes it. This survey found that benzodiazepines were the most used drugs in North America, while opioids (morphine and fentanyl), although preferred in Europe, were only used in 29% of cases. In addition, sedation was usually administered as an intermittent intravenous bolus according to clinical experience rather than using standardized protocols.

Recently [12] a retrospective study evaluated the efficacy and safety of sedation in agitated patients treated with NIV after an episode of acute respiratory failure. Of 3506 patients 120 [81 patients with non-intubation code (DNI) and 39 non-DNI] were given sedatives to control agitation during NIV. Sedation was performed only intermittently in 72 (60%) patients, switched to continuously in 37 (31%), and provided only continuously in 11 (9%). The reasons for poor NIV tolerance were mask discomfort, pressure discomfort, or the combination of the two. Risperidone and haloperidol were the drugs of choice for the intermittent use; dexmedetomidine, midazolam, or propofol were chosen for continuous infusion. The Richmond Agitation-Sedation Scale (RASS) was used as an index of sedation level. Results suggest that sedation during NIV can be used to allow continuation of NIV in agitated patients with either a DNI or non-DNI status. Nevertheless 48% of patients in the study had diseases such as ARDS, severe pneumonia, and acute exacerbation of interstitial lung disease which have weak NIV recommendations.

Despite intolerance is commonly perceived as a reason for NIV failure that should respond to sedation and analgesia, recent studies suggest that they are not used very often for that indication. Muriel et al. found [13] that sedation and analgesia were used in only about 20% of patients using NIV, and they did not bring any benefit in terms of reduction of NIV failure. The level of evidence in favor of an extensive application of sedation during NIV is still limited, and further larger controlled trials are needed to clarify the indications of sedation during NIV.

Sedation and analgesia are commonly used in the ICU to improve quality of life in intubated and critically ill patients. Analgo-sedation increases tolerance to the endotracheal tube, reduces anxiety and reactions to painful stimuli, allows a better adaptation of the patient to the hospital environment, modulates patient respiratory effort and drive, and makes invasive procedures tolerable [14].

Additional goals of sedation include preserving day/night cycles, hemodynamic stability, conservation of diaphragmatic function, preservation of metabolic homeostasis, and attenuation of the stress/immune response.

In patients undergoing NIV, sedation should be administered by experienced staff using the minimum doses required to ensure a good control of agitation and to improve the patient-ventilator interaction, without inducing any respiratory drive depression. NIV is usually applied only in patients with a minimum spontaneous breathing capacity and able to trigger the ventilator and to protect the airway. The ideal sedative drug during NIV should have a rapid onset, a predictable duration of action, a constant half-life time, a no impact on the hemodynamic and respiratory drive, an organ-independent metabolism, a minimal drug interaction, and, finally, a low cost. However, no single sedative agent currently available fulfills the criteria for an ideal agent.

Morphine and synthetic molecules such as fentanyl and remifentanil are used in analgo-sedation procedures. Opioids are able to overcome the blood-brain barrier, interacting with a variety of central and peripheral receptors. In particular, they have an agonist action on opioid μ and κ receptors, producing analgesic action. Instead, the interaction with other receptors contributes to adverse events such as respiratory depression and hypotension. In particular, hypotension depends on different factor combinations that include sympathicolysis, bradycardia, and vagal stimulus for histamine release. Other side effects are depression level of consciousness and intestinal hypomobility. All these aspects should be considered when opioids are administered during NIV. Opioids are risky in patients with obstructive sleep apnea syndrome (OSA) because they can cause pharyngeal collapse and inhibition of the rapid eye movement (REM) phase. Naloxone and naltrexone are able to displace the molecules of morphine and analogues from the receptors, thus interrupting their action. Naloxone has an extreme short onset of action; it is indeed the drug of choice for acute opioid intoxication.