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Considerations in the delivery of optimized ICU sedation Riku Aantaa Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Turku, Finland Dan Longrois Department of Anesthesia and Intensive Care, Hôpital Bichat-Claude Bernard,Assistance Publique-Hôpitaux de Paris, Université Paris 7, INSERM U698, Paris, France Jean Mantz Department of Anesthesia, Critical Care and Emergency Medicine INSERM U 676,Neurobiology Unit, Beaujon University Hospital, University of Paris, Clichy, France Peter H Tonner KlinikfürAnästhesie, operative und allg. Intensivmedizin, Notfallmedizin, Klinikum Links der Weser GmbH, Bremen, Germany perspectives on which see, among Separately, it needs to be noted that others, Lo et al.6, Levy et al.7 and developments in ventilator technology The spectacle of the intensive care Rietjens et al.8), but the significance have exerted a marked influence on unit (ICU) patient sedated to the point of such uses must be acknowledged.
sedation practice. One consequence of appearing moribund is familiar to of these advances is that we consider viewers of TV hospital dramas.
One other point to be acknowledged that the phrase ‘adaptation to a Unhappily, this parody has had (and immediately is that several of our ventilator' should cease to be part of retains) some basis in fact1,2 and ideas and suggestions require active clinical vocabulary: it is wholly should receive greater attention and continuing scrutiny of patients.
feasible now to think and speak in because there is now a widely agreed That, in turn, often implies or terms of adapting the ventilator to the consensus that inappropriate sedation requires a patient:staff ratio as close patient, a change in terminology that (meaning levels of sedation too far as possible to 1:1. There are obvious may seem trivial but which is, in fact, either above or below constantly cost implications in such a of great significance. Indeed, the varying goals) in the ICU may requirement: we do not claim to have feasibility of delivering mechanical contribute in a detrimental way to the solutions to the challenges of funding.
ventilation without the need for longer-term health and well-being of wholesale use of neuromuscular many patients.3–5 blockade is essential to the realization Our aim in this position paper is to of the cooperative and awake patient.
examine current themes, unmet (or (In Germany and elsewhere the The goals of analgesia and sedation under-appreciated) needs and avoidance of neuromuscular blockade (especially those of analgesia) are opportunities in sedation practice for is a measure of the quality of care.) perceived differently by the patient, adult ICU patients. Our method is to his/her family and the medical Additional medical goals include identify the goals of sedation and then profession. From the patient's point of haemodynamic stability, preservation discuss the procedures for the view, analgesia, comfort, preservation of metabolic homeostasis, immobility, attainment of those goals, bearing in of day/night cycles (including natural muscular relaxation, preservation of mind that the goals themselves may sleep), lack of nuisances such as diaphragmatic function and vary from patient to patient and for ambient light and noise, and concerns modulation of the stress/immune any individual patient according to such as quality of bed are important.
response, the facilitation of diagnostic their clinical course and progress.
Physicians and nursing staff are also and therapeutic interventions as well Our perspectives and ideas are based committed to providing analgesia and as considerations such as on personal and shared experiences of comfort, but other considerations may programmed withdrawal from ICU practice but in many cases are shape their perspectives. A simple sedation. This last may be directed not supported by a great weight of example of the non-congruence of toward the end of sedation but may evidence from controlled trials. This views is offered by perceptions of also be directed at other goals; for essay is thus a subjective – but we mechanical ventilation: for staff there example, the neurological evaluation hope thought-provoking – assessment is an emphasis on optimizing patient- of a patient who will thereafter of sedation practice; it is not a ventilator synchrony whereas for continue to be sedated. One systematic analysis. Sedation practice many patients the dominating feature additional item that deserves attention in the paediatric ICU will not be of ventilation is the discomfort is the short- and long-term effect of examined in detail and there will be associated with the endotracheal sedation on factual recollection. It no discussion of sedation as an might be anticipated that deeper element in end-of-life palliation (for Intensetimes, Issue 14: October 2011 levels of sedation are associated withless factual recollection. Whether ornot this is a good thing is an open Haemodynamic stability question. There are claims that better Suitability for use after extubation factual recall may reduce the risk of later deleterious psychological effects of an ICU stay.10 However, not all Non-accumulative PK research into that subject reaches the same conclusion,11 and the parallelwidespread evidence that excessive sedation has inherent deleterious effects thus creates a tension betweentwo goals for which at present there isno universal response.
Promotion of natural sleep Preservation of ventilatory drive Figure 1 illustrates our view of someareas of therapeutic priority in Metabolic stability Avoidance of PONV sedation. This is an extensive set ofcriteria but by no means exhaustive:consideration of only the desirable Fig. 1. The 'web of priorities' in ICU sedation: factors relevant to the clinical profile of drugs that
features of candidate drugs would may be used for sedation in the adult ICU. Higher scores in any domain indicate greater fulfilment include: rapid onset/offset of action; of the desired therapeutic effect. PK: pharmacokinetics; PONV: postoperative nausea and vomiting.
minimal or no adverse effects; and no Organ protection refers to the possibility of modulating tissue/organ ischaemia–reperfusion. Non-accumulative PK refers both to relatively short contextual half-lives (minutes to hours but not days) increase in overall costs of care. No and to the absence of active metabolites that prolong the pharmacodynamic effect of the parent existing or emerging sedative or drug. Metabolic stability refers to the lack of interference with nutritional substrates (e.g. lipids are sedation regimen fulfils all of these provided by propofol) and also to the lack of effect on other metabolic processes as encountered inthe propofol infusion syndrome (disruption of fatty acid oxidation and the mitochondrial electron transport chain). Several important points emerge fromthis depiction. The first is that noexisting or emerging drug or regimen 2. Knowledge is incomplete and from their effects in healthy fulfils all of the requirements. A further research is required before volunteers or less ill patients: second implicit consideration is that robust principles of good practice a. Development of tolerance to drugs, the hierarchy of requirements may can be developed: development of dependence to vary according to the stage of a. Prevention of delirium. Progress in drugs, and withdrawal reactions.
sedation. Thirdly, the issue of unmet this area may be especially needs in ICU sedation cannot be b. Delayed emergence from sedation challenging because ‘delirium' is limited to the pharmacology of (including build up of active drug not a single entity and its causes sedative drugs. The origins of metabolites in renal failure, etc.) are numerous, ranging from unfulfilled needs may be systemic or withdrawal from drugs (medical and c. Non-availability of drugs (or organizational, and not only recreational) to postoperative regimens) relevant to needs of ICU delirium, and to confusion in the patients identified in (2) above.
For instance: From theory to actions 1. Adequate knowledge exists and b. Sleep disturbances, prevention and recommendations for best practice No matter how much knowledge is have been formulated, but accumulated in one domain, c. Postoperative/post-ICU cognitive implementation of this knowledge practitioners are faced with the and guidance is suboptimal.
question: "What should we do?" Examples include: (i) the (non-) use d. Post-traumatic stress disorder We therefore propose the following of analgesia and sedation scales;2,12 and (ii) the non-avoidance of e. ICU-acquired weakness.
sedation drug overdosage (e.g. non- Determine whether the patient
use of daily sedations stops13).
3. Pharmacology concerns arising from requires analgesia, sedation,
Underuse of delirium scales may be the fact that the pharmacodynamic included in this category but that behaviour of drugs (and their Analgesia and sedation are important deficit may be seen as part of a pharmacokinetic profiles) in the aspects of ICU practice, relied on to larger difficulty with delirium very ill patients encountered in ICU ease the patient's experience of an among ICU patients.14,15 practice may differ significantly often unavoidably stressful Fig. 2. Proposed pre-
evaluation algorithm for
Is the patient agitated/ the identification of ICU patients who may require (Use objective/subjective scale) analgesia, sedation orboth. (‘Comfort' is adifficult concept to define.
In some studies it hasbeen evaluated usingvisual analogue scales from 1 [acceptable] to 10 [unbearable].) Comfortcriteria evaluated inclinical studies have included the time of thefirst transfer from bed tochair, first oral feedingand speech recovery (see Correctable cause of Blot et al.20 for an example of such criteria in action). A low patient:staffratio (1:1 if possible) is animportant element in theeffective monitoring ofpatient comfort.
Prescribe analgesics Prescribe sedatives environment, and to eliminate pain, as the unique or main drug for Drugs for sedation
anxiety, delirium and other forms of "sedation". Sedative effects may also The major classes of sedative drugs distress. Use of analgesics and be achieved with morphine (usually comprise the benzodiazepines, sedatives is particularly widespread when slightly overdosed) and, in propofol and the α -agonists. Opioids among patients who require general, the continuous infusion of must be considered separately, as mechanical ventilation and associated opioids has hypnotic-sparing effects discussed above. neuromuscular blockade,16 but is by that may be construed as, or confused Extensive commentary on the no means limited to that category of with, sedative effects. However, properties of individual drugs within isobolographic analyses suggest that these classes would be superfluous, the opioids are not per se sedatives.17 Emphasis on pain and pain relief though it maybe remarked that Clinical studies such as that of Strøm should be mandatory, because pain notwithstanding the penetration of et al.18 of ‘no-sedative' protocols (whether of idiopathic or iatrogenic agents such as remifentanil and the based on the sole use of low-dose origin) is for many patients a α -adrenergic agonist morphine boluses are implicitly principal source of ICU-related dexmedetomidine, there is still predicated on that view.a We therefore distress. However the phrase significant reliance on propofol, consider it important to maintain the ‘analgesia and sedation' is deceitful in benzodiazepines and opioids. Instead distinction between need for analgesia that it suggests these two objectives we offer Figure 3 (on pages 4 and 5) and need for hypnotics, and to assert are synonymous and in some way as a summary, in simple visual that fully satisfying these two needs interchangeable: they are not. Pain format, of our estimation of how well requires two distinct categories of requires the use of pain-relieving these various drugs fulfil the priorities drugs (or other relevant measures), identified in Figure 1. not the use of sedation. Failure to Hence, our first proposal is that a One notable omission from the web differentiate clearly between patients structured algorithm such as that depicted in Figures 1 and 3 is who need sedation and patients who illustrated in Figure 2 should be used delirium. This does not signify that we need analgesia is the first of the routinely for the pre-evaluation of do not regard delirium prevention and unmet needs of sedation. patients, in order to differentiate those management as priorities in ICU care who are truly candidates for sedation This issue is complicated by the – they certainly are priorities.
from those who need pain relief or evolution of analgesia-based sedation However, the spectrum of ICU some change to their environment.
(ABS), notably the use of remifentanil a Whether the extent of in-study use of supplemental sedatives in patients randomized to morphine-only medication in the study of Strøm et al.18 supports or rebuts that view is an unresolved point between us. Inter alia we add our support to the observation by Brochard19 that "a protocol of no-sedation impliesmore than simply not giving patients sedatives." We note also that the unit in which Strøm et al. conducted their research had a reported patient:nurseratio of 1:1. We consider this to be a fact with practical significance beyond the limits of that study. Intensetimes, Issue 14: October 2011 Haemodynamic stability Suitability for use after extubation Non-accumulative PK Promotion of natural sleep Preservation of ventilatory drive Metabolic stability Avoidance of PONV Fig. a.
Haemodynamic stability Suitability for use after extubation Propofol is a widely used hypnotic in anaesthesia and ICU sedation. Its maininterest, as compared to other hypnotics(such as midazolam) used for ICU sedation, Non-accumulative PK is its non-accumulative PK. Its limitationsare illustrated in the radar analysis: it has no intrinsic analgesic properties, does notpromote natural sleep and may give rise to propofol infusion syndrome (see text); in many countries, its prolonged use (forseveral days) is forbidden. Its use afterextubation is difficult because it does notpreserve, at high doses, ventilatory drive. Inpostoperative patients admitted to the ICU Promotion of natural sleep Preservation of ventilatory drive in particular, propofol decreases theincidence of PONV. Metabolic stability Avoidance of PONV Fig. b.
Haemodynamic stability Suitability for use after extubation Midazolam is also widely used for ICUsedation. Its haemodynamic stability isbetter than that of propofol. It provides Non-accumulative PK amnesia and anxiolysis, but it accumulatesafter several days of administration, especially in patients with impaired renaland hepatic function and in elderly patients.
As a class, benzodiazepines promote the occurrence of delirium. Midazolam is notsuitable for sedation after extubationbecause it alters ventilatory drive. Promotion of natural sleep Preservation of ventilatory drive Metabolic stability Avoidance of PONV Fig. c.
Opioids have strong analgesic effects but Haemodynamic stability provide no amnesia or anxiolysis. From a pharmacokinetic point of view, this class of Suitability for use after extubation drug is very heterogeneous, and includes drugs that have very long contextual halflives (fentanyl and to a lesser extentsufentanil), drugs with active metabolites Non-accumulative PK (morphine) that prolong the pharmacologicaleffect, especially in patients with renal failure, and drugs with very short contextualhalf lives (e.g. remifentanil) that are consistent with very rapid elimination (minutes) even after days of administration.
Given the relatively restricted use ofremifentanil for ICU sedation, it has beenconsidered that, as a class, opioids haveaccumulative PK. They do not promote Promotion of natural sleep Preservation of ventilatory drive natural sleep. Their effect on ICU deliriumis complex. Lack of analgesia (as discussedin the text) can trigger delirium. Morphine Metabolic stability Avoidance of PONV can also trigger delirium, and in manypatients morphine withdrawal is associatedwith the disappearance of delirium. See the text for a more detailed discussion onanalgo-sedation. Fig. d.
Haemodynamic stability Suitability for use after extubation 2-agonists are mainly represented by clonidine and dexmedetomidine. Thesedrugs are strong anxiolytics and have intrinsic analgesic properties in addition to Non-accumulative PK their sedative effects. They promote endogenous sleep, preserve ventilatory driveand can be safely used after extubation, which is unique among the drugs discussedin this article. They have other interesting effects that have not been fully explored,such as organ protection. Clonidine anddexmedetomidine have very differentpharmacokinetic properties, withdexmedetomidine having non-cumulative Promotion of natural sleep Preservation of ventilatory drive PK. Because of the difference in PKbetween the two drugs, reflected by a non-cumulative PK score of 4 for Metabolic stability Avoidance of PONV dexmedetomidine and 2 for clonidine, theaverage value for the class is 3, as shown in Fig. e.
Fig. 3. Radar analysis of major ICU sedative drugs. Higher scores in any domain indicate greater
fulfilment of the desired therapeutic effect. The relative values for each item reflect the authors'
opinions based on the literature. See sub-legend to Fig. 3d for a fuller discussion of intra-class
differences in non-accumulative PK for opioids, particularly remifentanil.
Intensetimes, Issue 14: October 2011 presentations encompassed by the For many other patients, however, term ‘delirium' is so extensive and sedation must be configured to various that we consider the term preserve respiratory drive and avoid cannot helpfully be included in such respiratory muscle (especially a highly reductionist depiction of the diaphragm) dysfunction. profiles of various classes of sedative Alterations to the anticipated duration drugs. Further discussion of this of sedation in response to the clinical aspect of sedation practice follows progress of the patient may require There is an extensive repertoire of later in this review.
the initial sedative regimen to be re- robust, validated and reproducible The goals identified in Figures 1 and considered; Figure 4 outlines how pain and sedation scales suitable 3 do not, of course, present in regimens may change with the for the ICU, and we do not isolation from the patient's wider duration of sedation, but these propose to consider these in clinical circumstances. It is essential suggestions are only a framework – detailb (see references 23–31, for to address the goals of sedation in the detailed evaluation of the needs of context of a patient's course through individual patients is essential.
The more pressing issue attaching sedation, starting with induction.
Avoidance of over-sedation is a to these scales is their widespread Clinical reasoning for sedation should central consideration, and regular and non-application in routine start with a statement of the sedation repeated use must be made of practice. Procedural and goals for any given day and anticipate sedation scales to titrate and monitor administrative arrangements vary shifts of those goals in ensuing days.
the level of sedation (see Sidebar too widely between countries and The way to assure responsiveness to ‘Pain and sedation scales').
units for us to offer any single the patient's changing needs is to use The emphasis in Figure 4 on the daily recommendation for addressing scales that measure objectively the re-evaluation of pain status should be this deficit, but we consider level of analgesia and sedation, and noted: experience of pain may ensuring the systematic use of actively look for the presence/absence fluctuate during an ICU admission these scales to be a major target of delirium (see Sidebar ‘Pain and and the fact that pain may have been in the development of sedation sedation scales).
excluded as a source of discomfort practice. This could be achieved during pre-evaluation (see Figure 2) Induction of sedation
quickly if there were a does not mean that it can thereafter commitment (at the unit level and An algorithm for the induction of be disregarded. Also of note is the above) to make systematic pain sedation appears in Figure 4.
advice to evaluate sedation using assessment (albeit with perhaps Titration of duration of sedation need quantitative scales in order to ensure imperfect instruments) part of not be an immediate goal, but early that dosages of sedative drugs are routine practice.
thought must be given to whether the kept to the minimum needed to patient is likely to require deep achieve the target level of sedation b Electroencephalographic-based measures/ and/or prolonged sedation. Deep (see Sidebar ‘Pain and sedation calculations such as the bispectral index, sedation will likely be necessary for spectral entropy and auditory-evokedpotential have been evaluated for this patients with intracranial Controversial possibilities purpose but remain for the moment tools of hypertension, severe ARDS and other research rather than of clinical decision In patients not requiring profound conditions – the use of the vague term making.32–40 The demonstration of limited depth of sedation several interesting correlations between the Ramsay/Richmond ‘deep sedation' acknowledges the lack (i.e. controversial) possibilities Agitation–Sedation Scale scores and blood of evidence on which to base present themselves. Among these is concentrations of sedative drugs in older definitive guidance in this area. Use ICU patients41 is an additional illustration the use of a single agent with of deep sedation (approximating to of the pitfalls that can arise from reliance analgesic properties to deliver on ‘objective' measures of sedation in the surgical anaesthesia) is certainly relatively short-term sedation.
ICU and of the importance of clinical necessary in patients who require Examples of this type of agent are indices (with their corollary, vigilance on neuromuscular blocking agents the part of staff). dexmedetomidine (or clonidine in (NMBAs). Use of similar sedation in some countries) and remifentanil; patients who require mechanical ketamine and the volatile anaesthetics ventilation varies between countries, may also be included in this partly in response to varying attitudes category.21 There is ample evidence to the use of NMBAs in this situation. for the clinical effectiveness and Patients with severe alterations in benefits of ABS in the adult ICU, cardiovascular function and limited even if not all reports are fully oxygen delivery may require a affirmative.22 It is clear that, in many reduction in oxygen consumption individual cases, sole use of (VO ) in order to avoid tissue hypoxia.
remifentanil (primarily as an Induction of sedation for a patient that is or will be under mechanical ventilation Evaluate priorities or major immediate risks: hemodynamic instability, inhalation, difficult tracheal intubation Different pharmacological regimens Anticipate requirement for deep AND for induction and maintenance prolonged sedation (severe ARDS, of sedation (e.g. etomidate, intracranial hypertension, other) opioid, succinylcholine) Anticipated sedation Anticipated sedation for >48–72 h for <48–72 h Opioid (sufentanil, fentanyl) AND hypnotic (midazolam) Attempt single agent with analgesic Consider short-acting opioid Opioid (sufentanil, (remifentanil) with midazolam • Dexmedetomidine hypnotic (propofol) Programme the following measures: • Evaluate level of sedation and Evaluate level of sedation and pain scales several times daily Programme the following measures: pain scales several times daily • Find the lowest doses/concentrations • Evaluate level of sedation and Attempt to adapt ventilation to of opioid and hypnotic compatible pain scales several times daily improve night natural sleep with the target level of sedation • Find the lowest doses/concentrations • Daily interruption of sedation to of opioid and hypnotic compatible avoid accumulation of drugs with the target level of sedation • If paralysis required, monitor If not efficient add • Daily interruption of sedation to neuro-muscular transmission Continue single agent if efficient avoid accumulation of drugs Fig. 4. Decision tree of matters to be considered in the induction of sedation.
analgesic) is associated with It might be expected that the of a short-acting agent such as demonstrable sedative effects.
pharmacokinetic qualities of drugs remifentanil to provide long-duration Nevertheless, the notion of sedation would be influential in relation to the sedation may be advantageous when based on what primarily is an analgesic planned or anticipated duration of programmed (temporary) withdrawal agent is a problematic one. Many sedation. Certainly it remains the case of sedation is required, as for example practitioners would regard this that, in patients in whom drug in the repeated evaluation of central application as unproven or at least not accumulation might be expected and nervous system function. proven to an adequate degree. We for whom it would be detrimental, Targets in ongoing sedation
entirely respect that point of view but consideration should be given to Figure 5 outlines our proposals for feel that there is just about sufficient shorter-acting drugs. However, if, as procedures to be followed during the evidence of value for this option not to shown in Figure 4 and practised in maintenance of sedation. The be automatically excluded. The clinical many centres, ICU sedation now continuing need for daily review and circumstances and presentation of includes routine daily sedation stops, systematic assessment of sedation individual patients are important in the potential for drug accumulation is level is re-emphasized. Other determining whether single-agent greatly reduced. Where sedation stops important requirements include analgo-sedation should be attempted; are practised we see no unsustainable reassessment of the goals of sedation, selected postoperative patients tension in the use of longer-acting monitoring for the development of admitted to the ICU for a relatively sedatives for patients likely to be tolerance and the avoidance of brief period of observation and sedated for relatively short periods of propofol infusion syndrome (PRIS).42,c recovery might be candidates for this time. Conversely, we consider that use Intensetimes, Issue 14: October 2011 Maintenance of sedation • Regular intra-day evaluation of pain/sedation scales• Daily interruption of sedation performed; doses/concentrations of hypnotics titrated using different scales • Institute, if level of sedation adequate, delirium scale • Adaptation of ventilation on the day/night cycle? Every morning:• What are the goals for sedation today?• Tolerance of sedation (vasoplegia, PRIS?) Delirium detected? Consider prevention of delirium in patients thought to be at risk • Consider non-pharmacological methods (promote natural sleep; adapt ventilator to the patient)• Haloperidol, α -agonist or other pharmacological agents to treat delirium Fig. 5. Proposals for the monitoring of sedation and for delirium prevention. PRIS: propofol infusion syndrome.
There should be complementary appear not to be applied consistently to its successful management. The efforts to identify patients who have even when it is official policy to do principal instruments for delirium developed delirium or are at risk of recognition in the ICU are the doing so. Delirium prophylaxis is Confusion Assessment Method for the Critically ill patients are typically feasible and we strongly favour ICU (CAM-ICU)51 and the Intensive exposed to numerous factors that may prevention over treatment. The Care Delirium Screening Checklist precipitate delirium (Table 1). Many background to this emphasis on (ICDSC),52 both of which appear to of these factors are modifiable, though delirium is considered in the next work well.47,53–55 It is more important whether they each attract sufficient part of this essay.
to use one of these scales than to attention in the context of usual ICU deliberate too long over which one to practice is unclear: this may represent Delirium as a complication
use: the ability of ICU staff to identify a missed opportunity in delirium of sedation
delirium without these aids has prevention. Two factors experienced There are indications that poorly repeatedly been found to be by most ICU patients are (i) exposure configured sedation may play an alarmingly low.
to sedative and analgesic medications important role in the development of and (ii) sleep deprivation or Management of delirium delirium, which in turn is associated fragmentation. The delirium risk Non-pharmacological methods for the with worse outcomes in mechanically associated with both of these factors prevention of delirium have not been ventilated ICU patients.38,43–47 is potentially modifiable, as discussed fully evaluated in the ICU setting.56 Delirium appears to be substantially There is no a priori reason why they under-recognized in the ICU,48 not should not work, but many of them least because efforts at detection Early diagnosis of delirium is the key rely for their effectiveness on careful c PRIS may be seen as a reminder that studies on ICU sedation and sedatives have tended to concentrate on efficacy. Specific assessment of the safety of sedative drugs has been a rarity. We consider it highly desirable that future studies give greater importance to the investigation of side effects and theconsequences of complex metabolism (e.g. accumulation of metabolites for morphine). Information of this sort is especially relevant when choosing agentsfor long-term sedation. combination of haloperidol with Table 1. Delirium risk factors (from Girard et al.50).
quietapine is noteworthy. Factors of critical illness Iatrogenic factors With the exception of the work ofRubino et al.,66 peer-reviewed Immobilization (e.g. experience with clonidine in delirium catheters, restraints) management has emphasized its use in alcohol withdrawal syndrome; its wider utility is thus unclear. Evidence for a beneficial effect of clonidine inopioid withdrawal is equivocal and the Apolipoprotein E4 Fever/infection/sepsis Sleep disturbances dataset is small.67 Recent experience with dexmedetomidine is also limited,68,69 but includes an indication of an effect at least comparable to thatof haloperidol70 and superior to that of Metabolic disturbances midazolam.71,d We therefore nominate (e.g. sodium, calcium, this agent as an alternative first-line blood urea nitrogen, bilirubin) option for the prevention of delirium Respiratory disease and as preferable to a benzodiazepineas adjunct therapy for patients who High severity of illness have not had a fully adequate response to haloperidol. This wouldrepresent a pharmacologically Includes factors associated with delirium in both ICU and non-ICU studies. reasoned approach to deliriummedication in which an agent (i.e.
haloperidol) that had not produced a and systematic assessments of non- sufficient clinical response would be life-threatening factors that currently The relevance of pain to delirium augmented by an agent acting via are not an integral part of everyday needs to be recognized. Morrison et another mechanism (α -adrenoceptor practice in many ICUs. Multifactorial al.58 reported a very considerable agonism). We would not advocate protocols, as tested in postoperative (risk ratio >5) increase in the risk of dexmedetomidine as a routine non-ICU patients by Marcantonio et incident delirium in patients who alternative to haloperidol in al.,57 may be transferable to the ICU received less than 10-mg equivalents established cases of delirium until of parenteral morphine sulphate per there are data on this subject. The day in a hip fracture cohort. Risk of haemodynamic effects of such Action should be taken to promote delirium increased ninefold in combination therapy are for the natural sleep, which is subject to both cognitively functional patients moment not published. quantitative and qualitative experiencing severe pain. impairment in ICU patients (sleep is Cochrane reviewers in 2009 were able considered in detail in the next part The dataset for use of drugs in the to identify no adequately controlled of this essay). More generally, benefits prevention or treatment of delirium is trials to support the use of may be expected from parallel not extensive.59–62 Overall, the benzodiazepines in the treatment of medical efforts to treat conditions available data are compatible with delirium due to causes other than such as sepsis, hypoxia or antipsychotic agents being first- alcohol withdrawal among hospitalized hypotension, all of which can be choice therapies both for prophylaxis patients.61 We are of the view that organic causes of delirium. The and for the management of benzodiazepines should not be used success of early rehabilitation established delirium. First- and for the management of delirium not programmes in reducing the risk of second-generation agents appear to be arising from alcohol withdrawal. Even delirium is also relevant in this similarly effective and generally well in that setting, dexmedetomidine may tolerated: a presumption in favour of be a preferred option.72,73 Phasing out haloperidol thus seems pragmatic.
the use of benzodiazepines for There are no formally evaluated non- Atypical antipsychotics may be delirium would represent a pharmacological means of treating considered when haloperidol is considerable shift in current practice established delirium, but some of the inappropriate63,64 and the recent report (see, e.g., Salluh et al.74), but is a methods employed in prevention by Devlin et al.65 of the use of a development that we believe would might be useful adjuncts to other improve standards of sedation.
d It is worth noting that for the most part the studies identified by Campbell et al.62 used haloperidol doses below the expert-endorsed range and, with the exception of the study by Reade et al.,70 none evaluated the effects of haloperidol infusion. Intensetimes, Issue 14: October 2011 Finally, it may be noted that the Observations in preclinical and incidence of delirium in the human studies indicate that intervention group (the ‘no sedation' endogenous sleep pathways arm) of the study by Strøm et al.18 was (specifically pathways involved in the Amnesia is another aspect of the higher than that in the control group.
promotion of non-random eye ICU experience that requires This study was in effect restricted to a movement sleep) may also mediate attention. Links between ICU- specific subpopulation of medical and α -mediated sedation, providing a related stressor events,11 delirium, surgical ICU patients (namely those physiological basis for reports that sleep disturbance and amnesia are with respiratory failure and a long widely accepted but hard to median duration of ventilation) and demonstrate in any conclusive this finding from a ‘no sedation' (EEG) sleep spindles that way. Moreover, even though up to protocol based on low-dose morphine qualitatively and quantitatively about one-third of ICU may not be applicable to other patient resemble stage 2 normal sleep.84,85 patients11,91 may report no recall types. This observation is a reminder, These influences may underpin the of their time in ICU, robust however, that avoidance of sedation is ‘conscious sedation' observed during correlations between later not a guarantee of avoidance of use of dexmedetomidine. This outcomes and amnesia, delirium, delirium. The role of morphine in this property – in our experience unique wakefulness and sedative experience of delirium is unclear but among mainstream sedative agents – exposure can be highly elusive if cannot be discounted.
makes dexmedetomidine an not contrary-seeming;91 some of interesting resource for the the most persistent predictors of Sleep deprivation and disruption
management of sleep disturbance in post-ICU psychological difficulties Disruption of sleep and the the ICU and the putative are age, baseline health and the consequences of sleep disruption are consequences of an ICU stay on long- severity of the index ICU event,11 not confined to ICU patients, or even term cognitive functions.g with apparently limited relation to to hospitalized patients75–77 (sleep sedative use (except as a proxy disruption may also affect staff78).
Separately, there are experimental for severity of illness).
and limited clinical data (in patients Sleep and the effects of sleep Furthermore, the proposition that undergoing opioid detoxification) to deprivation and/or fragmentation in amnesia arising from sedation is a suggest that low-dose propofol is the ICU patient have been the subject good thing (because it expunges capable of modulating hypothalamic of several recent reviews and the recall of stressful and sleep pathways and of evoking EEG commentaries (see, e.g., references distressing experiences) is not spindle oscillations that resemble 79–82), and have been associated universally supported. In those seen during normal sleep.87,88 with a range of physiological and particular, Jones and colleagues10 These data identify propofol as psychological effects, including have articulated the idea that another resource for the promotion delirium, which may adversely affect amnesia during an ICU stay – of‘natural' sleep. The doses used for the course of recovery.f which these authors suggest may this purpose are well inside the have its origins in (among other Sleep interruption/deprivation in the usually acknowledged safe limits for things) exposure to sedative drugs ICU has both quantitative and avoidance of PRIS (though see Merz and sleep deprivation – may lead qualitative dimensions (Table 2), and et al.89 for a reminder that PRIS may to worse outcomes because the there is no single conclusive remedy occur even at low doses in lack of recalled real events allows to this challenge. However, careful delusional memory to dominate selection of sedative(s) might play a Melatonin therapy may also have the patient's recollection. This, in part in minimizing the effects of sleep promise in the correction of sleep turn, may dispose to a variety of deprivation, and this makes the patterns in ICU patients (Current unwanted psychological sequelae, effects of different drugs on the Controlled Trials including post-traumatic stress quality of sleep a consideration in the disorder (PTSD).e In this model, development of a sedative regimen. profiling of amnesia as a positivefeature of sedative therapy (see, f Observations on the deleterious effects of sleep deprivation are based substantially on studies in e.g., references 92 and 93) may be healthy volunteers. Systematic investigation of the clinical effects of inadequate and/or insufficientsleep in ICU patients is highly desirable. It should be noted also that methods for the objective investigation of sleep are still evolving and that even polysomnography, generally regarded as thebenchmark for sleep investigation, has limitations (practical restrictions) in the ICU setting. e The role of stress hormone effects in recall Bourne et al.83 have reviewed the available methods. of traumatic memory and the possible significance of such effects in the In the ANIST trial (Acute Neurological ICU Sedation Trial; ClinialTrials.org identifier 00390871) suppression of PTSD symptoms by use of dexmedetomidine (vs propofol, on a background of fentanyl administered for analgo- therapeutic means is beyond the scope of this sedation) has been reported in a small (n=35) mixed ICU population, including patents with or paper but perhaps an area of promise for without brain injury, to preserve or enhance cognitive function, as measured in the Adapted future research (see Schelling94). Cognitive Exam (ACE), after patients had been brought to a state of calm, awake sedation (Mirski et al.86). considered to exert relatively minor Table 2. Some factors with potential to disrupt normal sleep in depressant effects on respiration and haemodynamics, both importantconsiderations.107 • Frequent nursing and care Use of volatile anaesthetics is an area • Permanent exposure to light of sedation practice very much • Permanent exposure to noise influenced by developments in (andthe economics of) delivery systems Forced loss of physical activity (see, e.g., references 108–111], but Severity of disease shows promise as a viable alternativeto parenterally administered sedation for mechanically ventilated adult Mechanical ventilation (pressure support ventilator mode) patients in the ICU and for peri-procedural sedation. Concerns that Sedative and analgesics (propofol, benzodiazepines, opioids) sevoflurane (and, by implication, Antiepileptics, adrenergic agents other fluoride-containing agents)might have an adverse impact onrenal function have been at leastpartly allayed by Röhm et al.;107 the Weaning and post-weaning
be reached or recommendations fact that the drug was used at low Weaning from the ventilator and offered (see also Okabe et al.102 for a dose and for ≤24 h in this study may programmed interruption of sedation cautionary note on the use of have been relevant to the findings.
leading ultimately to its cessation are Cumulative dose-exposure is one accepted goals for all patients. In aspect of the use of volatile Our algorithm of clinical reasoning for some cases, however, sedation needs anaesthetics that requires further this phase of sedation appears in to be continued after weaning. investigation. In general the absence of a safety database for prolonged A priority during weaning is to The goals of analgesia/sedation after exposure to these agents is (and anticipate and avert delirium.
withdrawal of mechanical ventilation seems likely to remain) the biggest Evidence already examined in this are similar but not identical to those single obstacle to their general use in review identifies haloperidol and the with mechanical ventilation. Although sedation (Dr PV Sackey, oral α -adrenoceptor agonists clonidine analgesia and patient comfort are still communication at ESICM 2011).
(which is used extensively in the main goals, avoidance of Germany) and dexmedetomidine as respiratory depression becomes a the drugs of choice for this purpose, major goal. Among sedatives that are with the α -adrenoceptor agonists presented in the web of priorities having additional properties that may shown in Figure 1, only α -agonists favour them, including: do not substantially depress the • ‘awake sedation' respiratory drive. A second major goalis promotion of natural sleep, as has • lack of depressant effects on been already been discussed.
• re-synchronization of sleep.
Alpha -adrenergic agonists have been shown to be useful for the prevention Use of volatile anaesthetics for of withdrawal syndrome in ventilated postoperative and ICU sedation in patients who have received prolonged adults has been reported to compare courses of opioids and/or favourably with the use of midazolam or propofol, being in particular application may be especially characterized by rapid relevant for ARDS patients, in whom emergence,102–105 more rapid prolonged ventilation is often extubation and shorter total hospital necessary. First reports of the use of stay.102 Not every report of this dexmedetomidine in weaning patients modality affirms these findings106 but from non-invasive ventilation are also there is enough positive experience to encouraging,101 but further experience justify further use and evaluation.
is needed before any conclusions may Sevoflurane in particular is Intensetimes, Issue 14: October 2011 Patient weaned from mechanical ventilation Is the patient at risk of developing delirium? Introduce delirium-preventative medication Evaluate daily on delirium scale Treat if necessary Avoid medication that could trigger delirium Evaluation daily on delirium scale Need for a change in analgesia strategy to Need for a hypnotic that promotes natural recover ventilatory drive? Consider α -agonists Fig. 6. Decision tree for management of analgesia, sedation and delirium in patients weaned from mechanical ventilation.
Excessive sedation has confirmed techniques such as daily sedation adverse clinical consequences and we breaks,112 and that is a perspective We agree with the proposition that the consider that its widespread routine that deserves to be respected. The ‘ideal' ICU sedative regimen should use should be avoided. Use of sedation significant principle is that sedation deliver good analgesia while to compensate for resource or staff requirements are dynamic and maintaining the patient in a condition shortages is to be deplored, and is a therefore need frequent re- of mental and psychological tranquility strong signal of a need for a major assessment. A summary of measures but also clarity.112 This objective review of systems and procedures (and required for the systematic and remains elusive: however, reference to perhaps also attitudes). This is not to responsive monitoring of patient Figure 3 indicates some of the say that deep sedation may not retain a requirements in the ICU appear in possibilities for combination therapy to place in the ICU, notably in patients Table 3. Among these we would approach this ideal, both through who require non-standard forms of highlight the use of accepted scales reducing the dose of individual agents ventilatory support and/or by staff trained in their application required to achieve a specific degree of neuromuscular blockade. Experts in (emphasis added) to quantify pain effect and by using combinations to ICU care have expressed reservations sedation and the emergence of compensate for the limitations or about ‘indiscriminate' use of deficiencies of particular agents. Table 3. Principles for the systematic monitoring of patient requirements in the ICU. (From Sessler & Pedram,113 with some amendments and additions.) 1. Develop an interdisciplinary, structured approach for managing sedation and analgesia 2. Perform patient assessment and optimize the ICU environment a. Identify predisposing and precipitating factors; manage treatable factors b. Identify outpatient medications (medication reconciliation), particularly psychiatric and pain medications; restart medications as appropriate c. Optimize patient comfort and tolerance of the ICU environment: avoid noise; preserve day/night cycles d. Optimize mechanical ventilation settings for patient/ventilator synchrony 3. Regularly perform and document structured patient evaluation and monitoring a. Establish and communicate treatment goals b. Assess presence and severity of pain, as well as response to therapy c. Assess level of sedation using a validated sedation scale, as well as response to therapy d. Assess presence and severity of agitation using a validated agitation scale e. Identify delirium, and consider regular assessment of delirium, using a validated delirium assessment 4. Implement a structured patient-focused management strategy a. Select analgesic and sedative drugs based on patient needs, drug allergies, organ dysfunction (particularly renal or hepatic dysfunction), need for rapid onset and/or offset of action, anticipated duration of therapy andprior response to therapy b. Focus first on analgesia, then sedation c. Titrate analgesic and sedative drugs to a defined target, using the lowest effective dose d. Implement a structured strategy to avoid accumulation of medications/metabolites: utilize scheduled interruption or intermittent dosing of analgesic and sedative drugs e. Evaluate and manage severe agitation, including a search for causative factors, and perform rapid f. Identify delirium, correct precipitating factors and treat with haloperidol or other neuroleptic drugs g. Avoid potential adverse effects of analgesic and sedative drugs; quickly identify and manage adverse effects 5. Anticipate weaning from mechanical ventilation 6. Develop analgesia/sedation plan for after weaning from mechanical ventilation. Major goals here are: • provide comfort (analgesia, anxiolysis) • promote natural sleep • treat withdrawal syndrome from long term sedation before tracheal extubation • treat withdrawal syndrome from chronic tobacco or alcohol or psychotrope consumption • preserve ventilator drive • avoid cough impairment • prevent, diagnose and treat delirium Intensetimes, Issue 14: October 2011 Ketamine HCl is probably encountered (Green SM et al. Ann Emerg Med or cardiogenic shock when its direct negative more in paediatric ICU than in the inotropic effect may be unmasked to the treatment of adults and as such falls detriment of the patient and should be used Ketamine relaxes bronchiolar smooth outside the scope of this article. However, with caution (and only in the absence of muscle and has neutral or even possibly this is undoubtedly a useful drug and its familiar alternatives) in patients with advantageous effects on respiratory combination of analgo-sedative properties pulmonary hypertension. Use of ketamine function that have led to its being favoured plus its very low cost have contributed to should be avoided in patients with seizure by some commentators for patients with its inclusion on the WHO list of essential disorders but its generally favourable effects asthma and similar reactive airways medicines. This prominence warrants a on cerebral blood flow and the absence of diseases (Burburan SM et al. Minerva brief survey of its place in sedation any increases in intracranial pressure suggest Anestesiol 2007;73:357–65). (The that it may have value in the sedation of TBI continuous infusion of intravenous Ketamine (the S-isomer is often preferred, ketamine has been linked to reduction of for its greater potency) is a rapidly acting bronchodilator requirements in patients Clearly ketamine has much to commend it as general anaesthetic; acting primarily via with refractory bronchospasm [Miller AC et an analgo-sedative, in theory. However, as antagonism of N-methyl-D-aspartate al. Minerva Anestesiol 2011;77:812–20].) noted in a recent review (Miller AC et al.
receptors in the CNS. It has both analgesic More generally, ketamine has been idem), the quality of the clinical evidence and sedative effects. It may also be used to associated, in various human studies, with base for adult use is not as good as might be augment the effects of other analgesics reduction of airways resistance, and wished. Additional trials of greater size and and hence for an opioid-sparing effect preservation of residual capacity, minute rigour are probably needed to establish (Kapfer B et al. Anesth Analg ventilation and tidal volume (Mankikian B et ketamine as a first-line resource for the adult 2005;100:169–74; Nesher N et al. Chest al. Anesthesiology 1986;65:492–9).
Protective pharyngeal and laryngeal Also to be considered is that use of higher reflexes are preserved in ketamine-treated Ketamine's pharmacokinetic profile makes doses of ketamine can produce a patients (Green SM et al. idem; Green SM, it suitable for administration to ‘dissociative state' in which patients may be Krauss B. Ann Emerg Med 2000;36:480–2).
mechanically ventilated patients as a unable to speak or respond purposefully to continuous i.v. infusion. Its wider Ketamine does not routinely cause verbal commands, whereas lower doses may pharmacokinetic/dynamic profile as a fast- significant perturbations in cardiovascular be associated with psychomimetic effects on/fast-off agent, which offers procedural indices such as blood pressure, heart rate such as hallucinations (usually short-lasting sedation with short-term postoperative or vascular resistance (Miller AC et al.
[<60 min]), and that its use as a sedative in analgesia has obvious appeal, albeit one at idem). However, it is not suitable for adults can lead to emergence delirium present exploited mostly in paediatrics patients with decompensated heart failure (Giannini AJ et al. Am J Ther 2000;7:389–91).
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Riku Aantaa is associated Professor of Anesthesiology and the Chief Administrative
Physician in the Department of Anesthesiology, Intensive Care, Emergency Medicine and
Pain Therapy at the University of Turku, Turku, Finland. He finished his training in
anaesthesiology in 1992. He has a special competence in pediatric anesthesia and intensive
care. His research work has focused on clinical anaesthesiological pharmacology, mainly on
autonomous nervous system pharmacology and α -agonists. Lately his interest has expanded
to mechanisms of anaesthetic action and he has been involved in studies using such researchtools as quantitative EEG and positron emission tomography (PET) to study the effects ofanaesthesia-related drugs, such as ketamine, propofol, sevoflurane, dexmedetomidine andxenon. Riku Aantaa chaired the Finnish Society of Anesthesiologists 2006–2009 and was a Riku Aantaa
board member of the Scandinavian Society of Anesthesiology and Intensive Care during thesame period.
Dan Longrois is a Professor of Anaesthesia and Intensive Care at Bichat-Claude Bernard
Hospital (Assistance Publique-Hôpitaux de Paris), Paris, France. He trained in
anaesthesiology and intensive care and obtained a PhD in cardiovascular pharmacology at
the Paris VI University. He was a postdoctoral fellow at the Cardiovascular Division of the
Brigham and Women's Hospital at Harvard Medical School in Boston, MA, USA. He chaired
the Departments of Anaesthesia and Intensive Care in Nancy, France, from 2004 to 2008.
His clinical and experimental research is focused on the cellular and molecular mechanisms
of inflammation in cardiovascular diseases. Dan Longrois was a member of the Scientific
Committee of the French Society of Anaesthesia and Intensive Care and is a member of the
Cardiovascular Sub-Committee of the European Society of Anaesthesia. He is also the
Dan Longrois
outgoing President of the French Society of Perfusion.
Jean Mantz is Professor of Anesthesia and Critical Care Medicine at Beaujon University
Hospital, University of Paris, France. He is Chairman of the Department of Anesthesia,
Critical Care and Prehospital Emergency Medicine, which covers a large panel of
multidisciplinary surgical activities including polytrauma, neurosurgery and neurosurgical
critical care, liver transplantation and obstetrics. His clinical fields of expertise are sedation
and analgesia in the ICU, depth of anaesthesia and intraabdominal sepsis. He is also leader
of a basic research group at the Institut National de la Santé et de la Recherche Médicale
(INSERM U 676) involved in the mechanisms of action of anaesthetics on the brain and
pharmacological neuroprotection. Professor Mantz has been actively involved in clinical and
basic research, with more than 100 original articles published in peer-reviewed international
Jean Mantz
journals. He is Editor-in-chief of the French Anesthesia Journal (Annales Françaisesd'Anesthésie et de Réanimation) and associate Editor of Anesthesiology. He is also memberof the American (ASA), French (SFAR) and European (ESA) Society of Anesthesiologists,and Member of the Pharmacology Subcommittee of the ESA. He has been or still is amember of many Advisory Boards of industrial partners.
Peter H Tonner received his medical degrees at the University Hospital Eppendorf,
Hamburg, Germany, in 1987. From 1990 to 1992, he accepted a 2-year postdoctoral
fellowship at the Department of Anesthesia of the Massachusetts General Hospital/Harvard
Medical School in Boston, MA, USA. During this fellowship, he worked with Keith W Miller,
D Phil, Edward J Mallinkrodt, Professor of Anesthesia, on molecular mechanisms of
anaesthesia. In 2000, Professor Tonner changed to the University Hospital Schleswig-
Holstein, Campus Kiel, Kiel, Germany, were he was rewarded a full Professor of
Anaesthesiology in 2002. Since 2006, Professor Tonner has been Chairman of the
Department of Anaesthesia, Surgical and General Intensive Care Medicine at the Bremen
Heart Center, Klinikum Links der Weser in Bremen and, since 2010, also of the Department
Peter H Tonner
of Anaesthesia and Intensive Care Medicine at the Klinikum Bremen Nord, Germany.
Professor Tonner has authored more than 100 publications in peer-reviewed journals, alongwith several book chapters. He has edited several books on clinical and basic scienceaspects of anaesthesiology. Due to his experience in anaesthesiology and intensive caremedicine, Professor Tonner serves as a reviewer for numerous national and internationalmedical journals. Intensetimes, Issue 14: October 2011 Intensetimes, Issue 14: October 2011 intensetimes is produced by Hughes associates, Oxford, UK and is intended to provide accurate scientific and medical
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