a practical approach for the intensivist in different ICU ...

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Light sedation with dexmedetomidine: a practical approach for the intensivist in different ICU patients Stefano ROMAGNOLI, Angela AMIGONI, Ilaria BLANGETTI, Giampaolo CASELLA, Cosimo CHELAZZI, Francesco FORFORI, Cristiana GARISTO, Maria Cristina MONDARDINI, Marco MOLTRASIO, Daniela PASERO, Tiziana PRINCIPI, Zaccaria RICCI, Fabio TARANTINO, GIORGIO CONTI Minerva Anestesiologica 2018 Feb 05 DOI: 10.23736/S0375-9393.18.12350-9 Article type: Review Article © 2018 EDIZIONI MINERVA MEDICA Article first published online: February 05, 2018 Manuscript accepted: January 26, 2018 Manuscript revised: January 22, 2018 Manuscript received: August 6, 2017

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Light sedation with dexmedetomidine: a practical approach for the intensivist in different ICU patients

Stefano ROMAGNOLI 1*, Angela AMIGONI 2, Ilaria BLANGETTI 3, Giampaolo CASELLA 4, Cosimo CHELAZZI 1, Francesco FORFORI 5, Cristiana GARISTO 6, Maria Cristina MONDARDINI 7, Marco MOLTRASIO 8, Daniela PASERO 9, Tiziana PRINCIPI 10, Zaccaria RICCI 6, Fabio TARANTINO 11, Giorgio CONTI 12.

1

Department of Anesthesiology and Intensive Care.

Azienda OspedalieroUniversitaria Careggi Largo Brambilla, 3 – 50139 Florence, Italy Pediatric Intensive Care Unit Department of Woman's and Child's Health –University Hospital of Padova

2

Cardiothoracic and Vascular ICU Emergency and Critical Care Department Santa Croce and Carle Hospital

3

Cuneo, Italy 1° Service of Anesthesia and Critical Care Emergency Department, Intensive Care Unit, ASST Grande

4

Ospedale Metropolitano Ospedale Niguarda "Cà Granda" Milano Milano 20126, Piazza Ospedale Maggiore 3 5

Anesthesia and Critical Care University of Pisa – Pisa, Italy

6

Department of Cardiology and Cardiac Surgery, Pediatric Cardiac Intensive Care Unit, Bambino Gesù

Children’s Hospital, IRCCS, Piazza Sant'Onofrio, 4, 00165 Rome, Italy 7

Department of Paediatric Anaesthesia and Paediatric Intensive Care Unit Policlinico S. OrsolaMalpighi

University Hospital – Bologna, Italy 8

Cardiac Intensive Care Unit Centro Cardiologico Monzino, IRCCS Milan, Italy

9

Anesthesia and Critical Care 1, Department of Anesthesia and Critical Care AOU Città della Salute e della

Scienza di Torino Turin, Italy 10

Emergency Department, Clinic od Anesthesia and Critical Care, Ospedali Riuniti Ancona Ancona Italia Department of Anesthesia and Critical Care, Policlinico San Martino Hospital, Genova – Italy

11

12

Department of Pediatric ICU, Intensive Care and Anesthesia, Catholic University of Rome, Rome, Italy

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*Corresponding author Romagnoli Stefano Department of Anesthesiology and Intensive Care Azienda OspedalieroUniversitaria Careggi Largo Brambilla, 3 50139 Florence, Italy Phone +393356100535 Email: [email protected]



Abstract Light sedation, corresponding to a Richmond AgitationSedation Scale between 0 and 1 is a priority of modern critical care practice. Dexmedetomidine, a highly selective, central, 2adrenoceptor agonist, is increasingly administered in the intensive care units (ICUs) as an effective drug to induce light sedation, analgesia and a quasiphysiological sleep in critically ill patients. Although in general dexmedetomidine is well tolerated, side effects as bradycardia, hypertension, and hypotension may occur. Although a general dosing range is suggested, different ICU patients may require different and highly precise titration that may significantly vary due to neurological status, cardiorespiratory function, baseline blood pressure, heart rate, liver efficiency, age and coadministration of other sedatives. This review analyzes the use of dexmedetomidine in different settings including pediatric, adult, medical and surgical patients starting with some considerations on delirium prevention and sleep quality in critically ill patients and how dexmedetomidine may contribute to these crucial aspects. Dexmedetomidine use in specific subpopulations with unique characteristics will be detailed, with a special attention to a safe use.

Key words: Dexmedetomidine; sedation; analgesia; intensive care medicine



Introduction Sedation and analgesia play fundamental roles in the management of critically ill patients who require close control of pain, agitation and anxiety. 1 Current guidelines and recommendations strongly advocate the transition from moderatedeep sedation with daily interruption to continuous light sedation, as it favors cooperation and comfort. 1–3 A crucial target in the modern approach to patients in the intensive care unit (ICU) is to have patients calm, cooperative, easily arousable and able to communicate and perform physiotherapy. Light sedation, defined as Richmond AgitationSedation Scale (RASS) between 0 (alert and calm) and 1 (not fully alert, but has sustained awakening [eye opening/eye contact] to voice [>10 seconds]) 4 has been recently proposed as a key component of a multiinterventional approach including optimal analgesia, goaldirected minimal sedation and a central role of relatives. 3 In this context, dexmedetomidine, a highly selective 2adrenoceptor agonist with sedative and analgesic effects, plays an important role in the short and longterm light sedation for critically ill patients. 5 The choice of sedative agents in ICU is a key factor for successful provision of light sedation and randomized controlled studies, although highly heterogeneous, suggest that dexmedetomidine could help to reduce ICU stay and time to extubation. 6–8 Continuous infusion of dexmedetomidine has a good tolerability profile that comprises rare, reversible and manageable side effects as hypotension and bradycardia. 9 In addition, dexmedetomidine induces sleep by acting on the locus ceruleus and, importantly, patients sedated with dexmedetomidine look clinically very similar to those under physiological sleep (i.e. easily aroused and more cognitively intact when aroused), as demonstrated by instrumental investigations, including electroencephalography (EEG) and functional magnetic resonance imaging. 10,11 Currently, dexmedetomidine is approved in Europe for sedation of ICU patients requiring a sedation not deeper than arousal in response to verbal stimulation. ICU patients may present highly heterogeneous features (e.g. respiratory failure, heart failure, liver dysfunction, age, surgical vs. medical admission, extracorporeal organ support) and the sedative and analgesic properties of dexmedetomidine, such as side effects, are dosedependent. Therefore, the present review, analyzes the use of dexmedetomidine in the different ICU settings focusing on specific sub populations of patients with unique characteristics. Finally, although this report is intended to suggest some This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


therapeuticsedative approaches to the new users whose decisions are complicated/hampered by the lack of experience and precise guidelines, it will also highlight the absence of studies exploring many clinical conditions in a number or different patient populations. Moreover, an initial paragraph has been dedicated to delirium prevention and sleep quality in ICU patients, a crucial aspect of ICU stay that is gaining more and more attention in everyday clinical practice.

Delirium, sleep and dexmedetomidine Delirium has been recently recognized as one of the most common “organ dysfunctions” complicating critically ill patients with rates ranging from 20% to 40%, with the higher rates of 60–80% observed in mechanically ventilated medical or surgical patients. 12 It is a strong independent predictor of prolonged MV and ICU length of stay, cost, and mortality. 12 Many nonmodifiable and modifiable risk factors for delirium development have been identified. Among those included in the latter group, the administration of psychoactive medications (particularly benzodiazepines) use, deep sedation and sleep disturbances are among the most important.1,13 In light of these strong evidences, with regards to pharmacological approaches to ICU patients, the Society of Critical Care Medicine guidelines 1 suggests the use of dexmedetomidine over benzodiazepines in MV patients as it may be associated with improved delirium outcomes. 5,14,15 In addition, dexmedetomidine, may promote sleep via more physiological pathways in comparison with GABAergic sedatives (i.e. benzodiazepines and propofol), favoring the N3 (or Slow Wave Sleep) stage. 16 Although the clear relationship between sleep and delirium still needs to be better understood, these findings suggest that dexmedetomidine may have an important role in the management of critically ill patients, by reducing the incidences of delirium and the degree of sleep disturbance. 17–19 Sleep is defined as a periodic, reversible state of disengagement from the environment and consists of an active process involving multiple mechanisms of the central nervous system (CNS). Normal sleep is divided into two states: rapid eyes movement (REM) and nonrapid eyes movement (NREM), the latter characterized by three stages that progress from 1 to 3 with the increase of sleep depth. Patients admitted to the ICU report sleep disorders, with fragmentation and disorganization. Sleep deprivation can cause physiological changes in the individual, such as abnormalities in the immune system, psychological disorders, changes in metabolism and reduced quality of life. The intensive care environment has been regarded as disturbing for the sleep patterns of patients. Individuals hospitalized in This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


the ICU are often treated with sedatives and analgesics, to decrease anxiety and pain, and promote sleep. Agitated delirium in intubated patients is a major problem, but it can be worse in the nonintubated ones. Standard ICU sedatives (midazolam, propofol and lorazepam) present, as a great disadvantage, the risk of respiratory depression. The most common classes of ICU sedatives used to promote sleep are benzodiazepine, propofol and, more recently, dexmedetomidine. 17,20–22 Midazolam and propofol infusion increase the total sleep time, but the quality of these pharmacological sedation (GABA agonists) is not the same as physiological sleep, showing disturbance of the architecture, decreased slow wave sleep (stage 2 and 3 SWS) and REM sleep. 23,24 Dexmedetomidine inhibits the release of norepinephrine in the locus ceruleus and enhances SWS, NREM sleep. Two recent clinical trials have demonstrated that dexmedetomidine improves sleep efficiency and quality. In a prospective crossover cohort study, Alexopoulou et al. evaluated the sleep efficiency of dexmedetomidine by polysomnography, in 13/16 enrolled patients, for three nights. Patients received no treatment on night 1 and 3, and, dexmedetomidine on night 2. Polysomnography showed that the sleep efficiency was improved upon dexmedetomidine (77.9%, SD 65.6–80.2%) vs no treatment (15.8%, 6.4– 51.6%, p=0.002). The sleep stage distribution was as follows: 16.1% in stage 1, 78.7% in stage 2, 0.0% in stage 3 and 0.0% in REM for the dexmedetomidine group, and 56.2%, 39.2%, 0.0% and 0.0%, respectively, for the untreated group. Moreover, sleep fragmentation was lower in the dexmedetomidine group (2.7 vs 7.6 arousals/hours). 17 Wu et al., in a pilot trial conducted in 76 adults admitted to the ICU after noncardiac surgery, administered lowdose dexmedetomidine or placebo for 15h. The polysomnogram was monitored throughout the whole study period. Dexmedetomidine increased stage 2 and decreased stage 1 sleep and increased the total sleep time, efficiency and subjective sleep quality. 22 In conclusion, dexmedetomidine could be useful for promoting sleep in both mechanically ventilated and nonventilated ICU patents. At the same time, dexmedetomidine could be part of a multimodal approach for the prevention of delirium. Doses should be set to reach a RASS 1.

Acute cerebrovascular events



Until 2010, dexmedetomidine was contraindicated in patients who had undergone cerebrovascular surgery or at risk of vasospasm (i.e. surgery for a cerebral aneurysm or arteriovenous malformations and up to 7 days after subarachnoid haemorrhage), but in the last few years several studies suggesting a neuroprotection role for dexmedetomidine have been published. Recent experimental studies showed a neuroprotective effect of dexmedetomidine against hypoxiainduced nervous system injury. 25,26 In an in vitro model of traumatic brain injury (TBI) dexmedetomidine showed a more pronounced protective effect than hypothermia on hippocampal cell cultures after mechanical trauma. 27 No synergistic effect of dexmedetomidine and hypothermia was observed. Moreover, the effect of dexmedetomidine was partially reversed by the simultaneous administration of the mitogenactivated protein kinase kinase 1 (MEK1) Inhibitor PD98059, suggesting the involvement of the extracellular signalregulated kinase (ERK) signalling pathway 27. Moreover two clinical studies assessed the effects of dexmedetomidine (bolus 1 g/kg over 10 min) on cerebral blood flow (CBF). 28,29 The first trial, performed at 0.4 g/kg/h following the bolus, showed a significant decrease in CBF in subjects without TBI (control group), with no change in the cerebral metabolic rate equivalent (CMRe) and CMRe/CBF ratio. In the TBI group, dexmedetomidine induced nonsignificant changes in CBF, CMRe and CMRe/CBF ratio. The percentage of CBF reduction was greater in the control group compared to the TBI group. 28 The second study tested the effects of a loading dose alone in patients without TBI. An increase in cerebral vascular resistance following the bolus has been suspected to be the cause of an increase in the pulsatility index (PI) and cerebral vascular resistance index. 29 Finally, Humble et al. demonstrated in 85 patients with severe TBI who received dexmedetomidine infusions, a significant decrease in the use of narcotics and sedatives combined with no decline in neurological function. 30 Clinical evidence on the use of dexmedetomidine in patients with TBI is lacking and new large trials are needed before principles of its use can be defined, then, indications cannot be obtained from literature so far.

Trauma Sedation and analgesia are central aspects in the care of traumatic critically ill patients. Commonly used sedative drugs in ICU patients include benzodiazepines, opioids, propofol and, more recently, dexmedetomidine. 31 Light sedation and adequate analgesia represent a useful strategy to obtain cooperation and neurological check combined with no pain and discomfort in trauma patients. This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


No RCTs have been published on the use of Dexmedetomidine in trauma patients in ICU so far. In 2011, Devabhakthuni et al. retrospectively analyzed 127 adult mechanically ventilated trauma patients who received either propofol, standarddose dexmedetomidine (0.7 g/kg/h) (HDD). 32 Patients in the HDD group displayed higher hypotension rate, longer median hospital length of stay and longer ventilator time. Moreover, an increased requirement for analgesic, sedative and antipsychotic drugs was found in HDD group. Weaknesses of this study are its retrospective design and the lack of a standardized sedation protocol. Furthermore, the time when dexmedetomidine was introduced was not clear, an important issue in an evolving critical illness as trauma. Another retrospective study compared opioid requirements in adult trauma patients receiving dexmedetomidine or propofol for sedation while being weaned from MV. 33 Results showed similar total analgesic requirements between the two groups within 48 h of sedative infusion. Further RCTs should be performed to investigate, not only analgesic requirements, but also other endpoints such as time to extubation, need for reintubation, ICU length of stay, and medicationrelated adverse effects during Dexmedetomidine sedation in trauma patients in ICU. Dexmedetomidine should be administered in wellstabilized (hemodynamic/ thermic control/ blood pH conditions) trauma patients, at the end of damage control procedures and in those not requiring acute resuscitation. Light sedation should facilitate comfort in awake patients and could be helpful in trauma management, allowing continuous central and peripheral neurological monitoring. Controversial results have been demonstrated in the only two retrospective studies analysing adult mechanically ventilated trauma patients. Further RCTs are needed to clarify the advantages of dexmedetomidine in critically ill trauma patients without severe head trauma.

Adult cardiac surgery and coronary ICU patients Neurological complications represent a major concern in patients undergoing cardiac surgery. 34 Despite new techniques and technologies are growing in this field, stroke, neurocognitive decline and delirium are still a critical issue. These conditions are associated with postoperative agitation, growing need for sedation and higher morbidity and mortality rates. 35



Risk factors for postoperative neurologic complications include comorbidities (e.g. vascular disease, diabetes and renal impairment), perioperative events (e.g. transfusions, hypotension and acidbase balance) and the use of cardiopulmonary bypass (e.g. timing and management). The incidence of delirium after cardiac surgery has been reported to be as high as 70%, depending on the methods employed to assess delirium 36; in particular, cardiopulmonary bypass and hypothermic circulatory arrest seem to play the main role in the development of postoperative delirium. Although our understanding of postoperative delirium is still incomplete, interventions to prevent and treat this disorder have been studied in postcardiac surgery patients, and sedation with dexmedetomidine seems to be associated with a lower risk of delirium 37 although controversial observations, in elderly population, have been recently observed 38. Nonetheless, evidence that dexmedetomidine might be suitable in post cardiacsurgical patients and can be considered for ICU management is quite consistent. 39–41 Postoperative pulmonary dysfunction is another frequent complication in patients recovering from cardiac surgery and when hypoxic respiratory failure occurs, NIV might be an important tool to improve oxygenation and prevent orotracheal intubation. Often, the main reason for NIV failure is the interface’s intolerance, which requires sedation with hypnotic drugs or opioids. However, the main drawback of these drugs is respiratory depression and the data available on the best drug to use are still poor. 42–44 As dexmedetomidine has minimal effects on the respiratory drive, it may be a promising drug to control agitation in extubated patients requiring NIV. It should remarked, however, that a reduced ventilatory responses to hypoxia and hypercapnia, similar to propofol infusion, has been observed in healthy male volunteers suggesting that attention should always be paid to respiratory drive during sedation. 45 In addition, renal and cardiac protection properties have been recently demonstrated in randomized controlled trials performed in patients undergoing cardiac surgery with cardiopulmonary bypass. 46,47 Special considerations should be pointed out in this setting of patients, where the hemodynamic assessment is crucial for postoperative management, and the dose of dexmedetomidine should be adjusted taking into account the following points: a) the needs for high dose of opioids to treat postsurgical pain; b) the use of cardiovascular drugs (i.e. beta blockers and calcium channel blockers), which both increase the risk of bradycardia.



In patients, already moderately/deeply sedated with propofol, a starting dose of dexmedetomidine between 0.40.7 g/kg/h, depending on the clinical evaluation, can be recommended with increasing or decreasing steps of 0.2 μg/kg/h every 3045 minutes (figure 3). The dose should be titrated to reach the effect. Similarly, in patients requiring NIV, we suggest a starting infusion dose of 0.2–0.7 g/kg/h, in association with analgesic drugs (remifentanil or morphine), with an increase of 0.1 g/kg/h every 4045 minutes if RASS is still >1. Patients admitted in the Coronary Intensive Care Unit (CICU) are a highly heterogeneous population characterized by acute, chronic, and acuteonchronic heart diseases, usually with several preexisting and progressive comorbidities. 48 In the last years, the characteristics of the CICU have changed by taking care of more complex patients with multiorgan failure. Therefore, patients often require advanced and invasive support, and the medical staff need advanced skills in handling analgesics and sedatives to implement the management of pain, agitation and delirium. 36 Dexmedetomidine has been investigated only in studies including mixed patients, whereas experience in “pure” cardiac patients is still lacking. In the acute cardiac setting, it is desirable that dexmedetomidine provides beneficial effects on pain with less nausea and respiratory depression in comparison with alternative drugs. 49 A sedation protocol targeted to light sedation with reduced benzodiazepines has been demonstrated to decrease the mechanical ventilation in medical patients with cardiogenic pulmonary oedema and after cardiac arrest. 50 In the management of CICU populations, dexmedetomidine is a useful drug to treat delirium in nonintubated patients after haloperidol failure. 51 Zhao Huang enrolled 62 patients with acute respiratory failure due to pulmonary oedema intolerant to noninvasive ventilation. 52 Those treated with dexmedetomidine vs midazolam were weaned from non invasive mechanical ventilation (NIV) faster (57.5±7.9 h vs 93.4±12.4 h, respectively, p=0.01). In the dexmedetomidine group, bradycardia developed more frequently but no patient required an intervention. 52 Besides sedation and analgesia, dexmedetomidine induces a reduction in BP and HR, which is often useful in the cardiac settings where hypertensive heart failure and myocardial ischemia are common. 53 The sedativebradycardic effects could be beneficial in lifethreatening medical emergencies to reduce circulating catecholamines 54, which along with enhanced vagal tone, reduced ischemiareperfusion injury and anti inflammatory properties, are underlying the speculative antiarrhythmic effects. 55 In a prospective randomized controlled clinical trial among 88 cardiac surgery patients without prior atrial fibrillation, dexmedetomidine reduced the incidence of newonset postoperative atrial fibrillation in comparison to propofol (respectively This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


13.6 % vs 36.4% odds ratio = 0.28; 95 % confidence interval, 0.10, 0.80; P = 0.025), finally shortening ICU stay. The greater rate of hypotension observed in dexmedetomidine than propofol group was managed overwhelmingly with fluid bolus or decreasing dexmedetomidine dose. 56 In conclusion, mostly available studies are based on mixed or small populations, so that the level of evidence in CV patients is low. However, dexmedetomidine represents a favorable profile in the context of cardiac critical ill: firstly, the cooperative and light sedation with minimal effects on the respiratory drive during invasive and noninvasive ventilation could be advantageous for ventilatory weaning, extubation and to reduce the duration of mechanical ventilation (MV) and the risk of delirium. Secondly, the hypotensive and negative chronotropic effects are often worthwhile in the cardiac setting while deleterious in other contexts where, up till now, the drug has been investigated. The potential supraventricular and ventricular antiarrhythmic properties, mainly observed in cardiac surgery patients could be useful also in other acute cardiac settings, when betablocking, sedative and/or antihypertensive effects are needed (i.e. electrical storm). 41 The spared analgesic effect could also reduce the use of morphine, which could delay the onset of action of oral antiplatelet agents. 57 Dexmedetomidine could be started at a low infusion rate mainly during noninvasive ventilation with caution in hemodynamically unstable patients, moreover in hyperacute phase of cardiac critical event which are unpredictable. Dexmedetomidine is contraindicated in atrioventricular blocks (i.e profound first, second, third degrees) and in other bradyarrhythmias associated to hypoperfusion. Future prospective trials are needed to define its role in this particular scenario.

Sepsis Increasing evidence suggests that dexmedetomidine could be a promising sedative agent in septic patients, related to the effects on apoptosis and the modulation of the immune system. 58 Xiang et al. showed that, in a murine model of lipopolysaccharide(LPS) induced endotoxemia, the pre emptive administration of dexmedetomidine significantly attenuated the cytokine response and increased the survival rate. 59 Similar results were published by Hofer et al. reporting that the preemptive administration of dexmedetomidine or clonidine successfully improved survival and suppressed the overproduction of the proinflammatory mediators in experimental sepsis induced by cecal ligation and puncture. 60



The main mechanism responsible for the antiinflammatory effects of dexmedetomidine may involve the modulation of cytokine production by the activation of the parasympathetic nervous system (cholinergic anti inflammatory pathway). Dexmedetomidine may also attenuate LPSinduced epithelial cell death in endotoxemic rats protecting against gut barrier dysfunction. 61 As a consequence, intestinal microcirculation is improved, and intestinal epithelial cell death, tight junction damage, and intestinal bacterial translocation to the spleen are reduced. 61 In addition, the observation that this agent may reduce the levels of serum endocan suggests its protective action against endothelial dysfunction. 61 In clinical practice few studies examined the effect of dexmedetomidine as sedation strategy in patients with sepsis. In the Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM) trial, critically ill patients sedated with dexmedetomidine had reduced number of secondary infections, enhancing the immunological effect of the drug. 62 Although patients with septic shock receiving dexmedetomidine may experience hypotension and bradycardia, a reduction in proinflammatory cytokines seems to outweigh any direct hypotensive effect of the drug. 63 In a subgroup analysis from the MENDS doubleblind randomized controlled trial, septic patients receiving dexmedetomidine had more days free from brain dysfunction and MV and were less likely to die than those that received a lorazepambased sedation regimen, supporting the hypothesis that sedation with dexmedetomidine may lead to better outcomes for patients with sepsis than benzodiazepine sedation. 63 A systematic review evaluated the effect of dexmedetomidine use for sedation in patients with sepsis, severe sepsis, or septic shock comparing to other sedatives commonly used in ICU. The systematic review (including 6 studies; 242 patients) showed that in patients with sepsis the administration of dexmedetomidine exerts a beneficial effect on 28day mortality and delirium/coma (moderate quality of evidence based on the GRADE approach) but has no significant effect on the length of ICU stay or duration of MV (moderate quality of evidence). The survival benefit was prominent in comparison with lorazepam but not with propofol. 64 No adverse events (with the exception of bradycardia) in using of dexmedetomidine were observed. 64 In a recent randomized clinical trial that included patients with sepsis undergoing ventilation, the use of dexmedetomidine did not result in statistically significant improvement in mortality or ventilation freedays. 65 In the study, with systematic protocolised sedation, dexmedetomidine treatment was associated with better



sedation but not with delirium reduction enhancing the importance of having a systematic sedation protocol as the main effective strategy for reducing delirium. 65 Currently, the small number of available studies with limited sample size warrants further trials to evaluate the longterm and shortterm outcomes of dexmedetomidine sedation in patients with sepsis, and to compare its effects with different types and doses of sedative agents. So finally, further trials are required to evaluate the beneficial effects of dexmedetomidine in comparison to other different sedative agent in patients with sepsis. Although dexmedetomidine seems to exert an effect on apoptosis and on modulation of the immune system which might be particularly important in the pathogenesis of sepsis its potential benefits and risks in patients with sepsis remains a controversy. Patients with oncohematologic diseases that develop infections are being increasingly admitted in ICUs for respiratory failure needing NIV or invasive MV. In the last years, the short and mediumterm outcomes of these patient have been slowly improving. 66 ICU standard practice should be the same as for other critically ill patients, and sedation is not an exception. Dexmedetomidinedriven light sedation retains its potential advantages in these patients and can be used during NIV, highflow oxygen therapy, insertion of catheters/drains and overnight sedation. Specific literature is scarce and, uptodate, data may be inferred by general papers on sedation and expertopinion. Nonrenal elimination of dexmedetomidine can favour its use in these patients, who often exhibit variable degrees of kidney injury, due to chemo or antiinfective therapy, whilst caution must be taken in case of hepatic failure. 67 NIV is the most common form of respiratory support for ICUoncohematologic patients and, as for the general ICUpopulation, it should target sound clinical endpoints in a due time (e.g. PaO 2/FiO2 or respiratory rate): ventilator settings and optimization/rotation of interfaces are essential to maximise the chances of success 68. In this context, light sedation may provide better patient comfort and increased tolerance to NIV as well as reduced oxygen demand and respiratory workload. 44 The clinical target should be a better oxygenation and a reduced rate of tracheal intubation, with a potential positive effect on the outcome. This is particularly important in the oncohematologic patients, in which invasive MV is related to high rates of infective/bleeding complications and ventilatorinduced lung injury. 68 The link between sedation and respiratory drive during NIV is complex and any approach should be strictly tailored on each single patient. A general consideration is that deep sedation during NIV should be avoided since it exerts depressive effects on forebrain. A poor neurologic status counterindicates NIV and a deeply This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


sedated patient is at increased risk of respiratory acidosis, hypoxia and inhalation. 68 This is particularly true for oncohematologic patients, who can spend days or weeks on NIV due to persistent respiratory failure. In summary, data on dexmedetomidine use in oncohematologic ICUpatients are still lacking. Due to its pharmacodynamics, dexmedetomidine may be helpful in the complex management of those patients, particularly during NIV. Due to its pharmacokinetics, its use can be considered in patients with acute kidney injury and could be considered a helpful sedative to provide light sedation in oncohematologic patients due to the minimal effects on respiratory drive.

Pediatric critically ill patients The first experience about dexmedetomidine use in pediatric population was published in 2002 by Tobias et al. in three different settings, following the studies performed in adult populations: in pediatric ICU (PICU), to provide sedation in mechanically ventilated patients, intraoperatively, to control hypertension during orthopedic surgery, and during a procedure to provide sedation. 69 After this preliminary report, a large body of literature has been produced on the preoperative and periprocedural applications in the operative room, outside the operative room and in the ICU. 70–72 Dexmedetomidine was effectively adopted in children during diagnostic, airway, and painful procedures. 73 The larger experience was reported on the use of this drug for Nuclear Magnetic Resonance sedation, where it was found effective and safe either alone or with midazolam, versus propofol or midazolam itself. 74–76 In PICU, this agent was firstly administered to spare other analgesic and sedative drugs. 77,78 Data in this setting are poor, as few randomized controlled trials (RCTs) were conducted. 79 A study by Tobias et al. comparing dexmedetomidine to midazolam in 10 versus 10 patients reported a better sedation and fewer analgesic doses in the dexmedetomidine group. 80 Recently, a large analysis showed that dexmedetomidine was effective as primary sedative in obtaining adequate sedation in low criticality patients. Moreover, this study demonstrated a decreased duration of MV weaning in patients intolerant of an awake intubated state. 81

Encouraging results have recently emerged from a cohort observational study on the use of

dexmedetomidine as a single continuous agent for sedation during NIV on 202 critically ill children (not neonates) with acute respiratory insufficiency. It is currently the largest pediatric report regarding this specific use.82



In neonates, dexmedetomidine was safely used also in term newborn babies and preterms ages, without serious adverse effects or severe haemodynamic changes. 83 Many offlabel indications exist in nonoperative room anesthesia and in PICU settings due to the advantages of this drug, especially considering the negligible effect on the respiratory function and the comfort achieved by patients, but also because this drug does not promote delirium and may help to prevent it. 84 Dexmedetomidine may be used moving forward to the early Comfort using Analgesia, minimal Sedatives and maximal Human Care (eCASH) concept proposed for adult critically ill patients 3 and the so called pediatric goaloriented sedation. 85 However, no study supports an evidencebased effect of this drug in promoting early mobilization and better outcome in PICU patients. Finally, published data indicate that dexmedetomidine may be useful in PICU during withdrawal from opioids and benzodiazepines 86, but no conclusive studies have been published. In nonoperating room sedation, a bolus of 0.52 g/Kg in 10 minutes (repeatable) was used, followed by an infusion of 0.53 g/Kg/h 73 (table 1). Pain should be managed before and during sedation with dexmedetomidine at any time especially during painful procedures. In PICU, a loading dose is not recommended (figure 2). The initial infusion dose ranges from 0.2 g/Kg/h up to a maximum of 1.4 g/Kg/h, titrating it based on the patient response. Dexmedetomidine has been safely used in longterm infusion. Yet, in case of drug infusion interruption, patients need to be monitored due to the risk of developing withdrawal symptoms, like tremors, agitation and insomnia. 87,88 Dexmedetomidine should be avoided in children treated with digoxin, betaadrenergic blockers, calcium channels blockers and agents that cause bradycardia or hypotension. We conclude that dexmedetomidine is effective and safe in providing sedation during nonoperating room procedures (bolus of 0.52 g/Kg followed by infusion of 0.53 g/Kg/h), but the association with an opioid/ketamine medication is necessary during the painful phases. In PICU, dexmedetomidine is indicated for difficult analgesia and sedation but some of its most important advantages are the protection from delirium and the facilitator effect during weaning from analgosedative therapy and the extubation phase. The recommended dose for initial infusion ranges from 0.2 g/Kg/h up to a maximum of 1.4 g/Kg/h.

Pediatric cardiac surgery This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


Dexmedetomidine is mainly administered to pediatric cardiac surgery patients with 2 indications: sedation in pediatric cardiac ICU (pCICU) and sedation during minimally invasive procedures (i.e. in the catheterization laboratory). 89 A special mention is reserved to the intraoperative use of dexmedetomidine to prevent arrhythmic complications during surgical correction of congenital heart disease. In the pCICU, dexmedetomidine is typically administered to maintain an adequate sedation level and an anxiolytic effect in association with a mild analgesic effect, without depressing the respiratory drive. This allows patients to easily awake and collaborate upon verbal stimulation, and an optimal compliance with medical and nursing procedures. 90 Specific indications to dexmedetomidine administration in the pCICU are: application of NIV either with facial or nasal masks; occurrence of delirium in spontaneously breathing patients: these children present a neurological condition characterized by agitation or irritability determined by termination of prolonged deep sedation, environmental reasons (eg. absence of parents) or low systemic and cerebral oxygenation in low cardiac output syndromes (e,g, children with dilative cardiomyopathy); patients with difficult respiratory weaning: the addition of dexmedetomidine to other sedative drugs allows to reduce the overall sedation dose (sparing effect) and side effects (e.g. respiratory depression upon opioids, dysphoria and delirium upon benzodiazepines); 77,91,92 patients who need prolonged sedation: in case of rotation of sedative drugs acting on different receptors (e.g. propofol, opioids, benzodiazepines), the infusion of 2 agonists might be recommended to prevent or treat tachyphylaxis. Several studies have supported the use of dexmedetomidine during catheterization of congenital heart disease patients 70,93,94, to possibly maintain the patient in light sedation and spontaneously breathing in order to eventually achieve more realistic hemodynamic catheterization laboratory results than during deep sedation and MV. In this case, dexmedetomidine can be used in combination with other drugs (e.g. propofol, ketamine, opioids, benzodiazepines) or as a single sedative medication, especially in older children to induce a light sedation and improve tolerance to the catheterization procedures. In patients undergoing heart surgery with high risk of arrhythmias secondary to surgical damage of the conduction tissue (eg. in tetralogy of Fallot), the sympatholytic effect of dexmedetomidine and the reduced



release of catecholamines induce a chronotropic and dromotropic negative effect that can facilitate the management of the tachyarrhythmia.70,71 Pediatric patients excluded from the use of dexmedetomidine:

patients with liver dysfunction, as the drug is metabolized almost exclusively via the liver, with the

production of inactive metabolites subsequently excreted by the kidneys. Hence, liver but not renal dysfunction may alter the metabolism of dexmedetomidine, whereas it is not affected by renal dysfunction;

patients affected by atrioventricular block or sick sinus syndrome.

Dexmedetomidine has to be administered as a continuous infusion (0.21.4 g/kg/h) potentially preceded by a loading dose of 0.61 g/kg to obtain a more rapid sedative effect, especially when the drug is used as the unique sedative. 96–98 The interruption of dexmedetomidine administration requires slow deescalation to avoid the occurrence of withdrawal symptoms. The dose is reduced by 25% every 2 hours until the complete stop of administration within 8 hours. In fact, in case of abrupt discontinuation of prolonged dexmedetomidine infusion, symptoms such as agitation, hypertension, tachycardia, vomiting, sneezing and seizures have been described. 99–101 The side effects expected during dexmedetomidine administration are bradycardia and hypotension. As both seem to be dosedependent, particular attention should be paid when using the drug in patients with marked hemodynamic instability. 77,102,103 In conclusion, dexmedetomidine could be a promising help in the management of children with heart disease, to achieve an adequate sedation level. Although it seems safe at the recommended doses, pediatric cardiac surgery patients may be at higher risk of developing dexmedetomidine related hemodynamic side effects.

Takeoff and cruise speed: start and titrate the infusion rate Currently, a loading dose of dexmedetomidine is not recommended in clinical practice due to the high risk of adverse effects (hypotension/hypertension, bradycardia). 9 An initial dose of 0.7 g/Kg/h is advised in patients already intubated and sedated, who require a switch to light sedation. Thereafter, the sedation has to be titrated within the wide range of 0.2 to 1.4 g/Kg/h. 9 Nonetheless, due to the wide range of doses, different patient response or sensitivity to the drug and, especially, different baseline neurological and cardiovascular (CV) conditions, a personalized approach to choose the starting dose could/should be adopted by the This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


caregiver (figure 1). Moreover, studies have shown than even lowdose of dexmedetomidine (i.e. 0.1 g/Kg/h) might be efficacious in selected population of patients. 104 Some crucial aspects that should be considered before setting the infusion pump are: 1) the pharmacokinetic profile (onset time and metabolism); 2) the effects on blood pressure (BP) and heart rate (HR); 3) the state of agitation (sometimes delirium); 4) the effects on respiratory function.

1) A linear pharmacokinetics has been demonstrated for dexmedetomidine doses ranging from 0.2 to1.4 g/Kg/h. 9,105 The onset and peak of sedation occur within 15 and 45 min and 1 h, respectively, from the start of intravenous (IV) infusion. 1,106 Therefore, it may take up to 1 h to reach a new steadystate sedation level after having increased the continuous infusion. 9 The terminal elimination halflife is approximately 1.53 h in patients with normal liver function, while in case of severe hepatic dysfunction, dexmedetomidine clearance can be impaired, thus prolonging the emergence and

2)

requiring lower doses. 1,9 Dexmedetomidine has sympatholytic activity. A reduction in norepinephrine and epinephrine levels has been demonstrated in healthy volunteers and postoperative patients. 9,53 The effects on BP are biphasic, with decrease at low doses and increase at high doses. 9,53 For instance, infusion of dexmedetomidine 0.20.7 g/Kg/h without a loading dose resulted in BP decrease of 16% within 2 hours in critically ill patients requiring sedation for >24 h. 107 In the absence of a loading dose, an average 10% fall in systolic BP, HR and cardiac output (CO) has been observed following a dose of 1 μg/kg/h. 106 Published studies have shown that BP, even decreased during dexmedetomidine infusion, may remain within normal limits. 107 In contrast, a transient increase in BP, due to peripheral vasoconstriction, has been demonstrated in patients receiving a loading dose of 1 g/Kg followed by continuous infusion of 0.20.7 g/Kg/h. 9 HR decrease commonly occurs in healthy volunteers and critically ill patients. Indeed, infusion of dexmedetomidine 0.20.7 g/Kg/h without a loading dose resulted in HR decrease of 21% within 12 hours in critically ill patients requiring sedation. 9,53,107 Based on the documented effects of dexmedetomidine on BP and HR, an individualized approach to select the starting dose, always avoiding a loading dose, is suggested (figure 1).

3) Dexmedetomidine is commonly administered to provide anxiolysis, sedation, and moderate analgesia in patients admitted to the ICU. In addition, this agent has been shown to reduce the incidence of delirium 14 and to be a potential rescue drug for treating deliriuminduced agitation after haloperidol failure in nonintubated patients. 51 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


4) Dexmedetomidine has minimal effects on the respiratory function in both healthy volunteers and ICU patients. 9,53,108,109 It can reduce the oropharyngeal muscle tone, thus increasing the risk of airway obstruction in nonintubated patients. Therefore, continuous respiratory monitoring is indicated. Nonetheless, the absence of significant effects of dexmedetomidine on respiratory drive makes this agent particularly safe in nonintubated patients, compared to other sedatives (see below). The choice of the starting dose and timing for reset the posology should take into account all the above mentioned key features of dexmedetomidine. For instance, a higher starting dose (e.g. 1 g/Kg/h) could be administered in an agitated patient with high BP and HR (figure. 1). Other adjuvant temporary sedatives (e.g. propofol or midazolam) could be considered when starting sedation with dexmedetomidine according to its pharmacokinetics. On the contrary, a low dose (e.g. 0.3 g/Kg/h) could be more appropriate for those patients requiring light sedation to promote sleep and/or prevent delirium.

Conclusions Dexmedetomidine is approved for sedation of adult ICU patients in Europe, and for procedural sedation use in USA and other countries. Sedation occurs via the activation of adrenoceptors at the site that physiologically controls vigilance, thus ensuring a unique sedative profile characterized by a calm but alert state, in which patients are sedated but easily arousable and able to cooperate. Although a dose regimen of administration is actually suggested (0.21.4 μg/kg/h), ICU patients may differ for a number of aspects, including neurological state, hemodynamic conditions and acute and chronic diseases. During the last years, dexmedetomidine became a popular sedative agent for critically ill patients because of its unique properties able to keep patients sedated but cooperative and able to communicate their needs. Moreover, the minimal interference with the respiratory drive, hence facilitating weaning from ventilator in intubated patients, also keep dexmedetomidine particularly safe for nonintubated ones. In addition, dexmedetomidine effects on sleep quantity and architecture could be of particular advantage in preserving a physiological sleep and preventing delirium. Although dexmedetomidine has these desirable properties, side effects should always be taken into serious account. Hypotension and bradycardia during continuous infusion are the most commonly described side effects although reduction in BP is commonly restrained. Different subgroups of patients have their own clinical characteristics and require different doses and sometime personalized administration strategies. Careful drug titration should be applied in terms of sub This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.


group clinical differences, e.g. adult cardiac surgery vs. pediatric patients, desired drug effect, e.g. light sedation when used alone vs. deep sedation in combination with other drugs, patient individual response, e.g. high doses vs. low doses, but also in terms of intragroup differences, e.g. agitated patients with tachycardia and hypertension vs. non hyperdynamic/hyperactive patients. In closing, dexmedetomidine is becoming the most promising candidate as first line sedation in critically ill patients requiring RASS levels between 2 and 0 for its unique capability of providing light sedation, analgesia, physiologiclike sleep, and potentially helping in preventing delirium, potentially optimizing cooperation of mechanically ventilated and nonmechanically ventilated ICU patients.

Key messages



Dexmedetomidine represents an optimal choice for sedation of critically ill patients for its unique properties to keep the patients calm and cooperative by providing (light) sedation and analgesia



Dexmedetomidine could be a fundamental support for prevention and treatment of delirium of critically ill patients.



The induction and maintenance of a quasiphysiologic sleep, provided by dexmedetomidine, may be of great advantage in promoting patients’ recovery and preventing delirium occurrence.



ICU patients present highly heterogeneous clinical features. These should be taken into close consideration in order to take advantage of the good tolerability profile of this sedative and analgesic agent and to limit, at the same time, the occurrence of its hemodynamic side effects.



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Table 1 – Pediatric patients requiring Non-Operating Room Anesthesia Not painful Painful Note

Dexmedetomidine loading dose: 0.5-1 g/Kg in 10 min, possibly associated with midazolam 0.1-0.2 mg/Kg; then continuous infusion: 0.5-1 g/Kg/min Dexmedetomidine loading dose: 0.5-2 g/Kg in 10 min + ketamine 2 mg/Kg (or fentanyl 2 g/Kg) repeatable. Then dexmedetomidine continuous infusion: 0.5-3 g/Kg/h. Note: pay attention to cardiovascular adverse effects like bradycardia and hypotension. Reduce the dose if any of these occur.




Figure 1 - Posology scheme for dexmedetomidine administration depending of patients’ baseline neurologic and hemodynamic characteristics.


Figure 2 – Patients requiring sedation in pediatric ICU or pediatric cardiac ICU. before and during sedation with dexmedetomidine at any time.

110

Pain should be managed




Figure 3 – Protocol of transition from propofol sedation regimen.

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