Intensive care sedation: the past, present and the future

Despite the universal prescription of sedative drugs in the intensive care unit (ICU), current practice is not guided by high-level evidence. Landmark sedation trials have made significant contributions to our understanding of the problems associated with ICU sedation and have promoted changes to current practice. We identified challenges and limitations of clinical trials which reduced the generalizability and the universal adoption of key interventions. We present an international perspective regarding current sedation practice and a blueprint for future research, which seeks to avoid known limitations and generate much-needed high-level evidence to better guide clinicians' management and therapeutic choices of sedative agents.

clinical situations [2,3]. Second, sedation is often undertaken by using a combination of drugs (benzodiazepines, propofol, narcotics, α 2 central receptor agonists, enteral sedatives, and antipsychotics), and each is administered dynamically in response to perceived and target sedation and analgesia. Th is additional layer of complexity makes trial design even more diffi cult and blinding of an intervention almost impossible. Th ird, the premise of many studies that achieving a given target level of sedation with one sedative versus another is not widely accepted as a means to achieve diff erent clinical outcomes. Fourth, there is signifi cant variability in the intensity of ICU nursing and medical bedside care and subsequently in sedation practices worldwide [4], making research fi ndings in one context diffi cult to interpret and generalize. Finally, there is uncertainty about how best to diagnose delirium [5,6], a major outcome in most sedation studies. In this level-I data-poor environment, strong opinions abound, creating additional obstacles to the genera tion of higher-level evidence and the implemen ta tion of new recommendations.
In this point-of-view article, we seek to provide a global perspective on sedation to address important progress in the fi eld and to highlight recent and imminent developments in high-quality evidence generation.

International sedation guidelines
In the 1980s and 1990s, sedation practice and drug selection for adult ICU patients were largely an extension of the practice of general anesthesia. Generally, the goal was deep sedation, and neuromuscular blocker use was not uncommon [7]. Because of the paucity of ICU-specifi c data regarding sedation, the fi rst ICU sedation guidelines published in 1995 contained six recommendations and were based on 13 references [8]. Nevertheless, this pioneering eff ort recognized that adequate analgesia was a primary goal, that long-term administration of lora zepam had prolonged clinical eff ects, and that the greater acquisition costs of new sedatives (then midazolam and propofol) were potentially balanced by downstream clinical benefi ts with short-term use. Th e 2002 Society of Critical Care Medicine guidelines produced 28 recommendations based on 235 references [9]. Th is guideline included an introduction to the assessment and treatment of delirium and drug-specifi c recommen da tions for various time frames and clinical situations. Both the 1992 and 2002 guidelines, however, recognized the dearth of high-quality trials. Th ough an improvement on the previous guidelines, the 2002 guidelines did not embrace new evidence outside of the US and thus had limited applicability. Hence, a number of country-specifi c guidelines appeared, refl ect ing newer information and local practices and matching individual formulary regulations [10,11].
Th e updated 2013 Society of Critical Care Medicine guidelines provide an unparalleled evaluation and review of the literature (more than 18,000 published articles) with 54 statements and recommendations [12]. Two important recommendations include an emphasis on the analgesia-fi rst concept, or 'analgesia fi rst sedation' [13], and the many benefi ts resulting from a lighter level of sedation for ICU patients. Additional aspects of the guidelines relate to an expanded understanding of the risk factors for and impact of delirium, and perhaps paradoxically, even more questions are raised about the management of this serious syndrome.

Sedative drugs in intensive care unit sedation
Many of the current drugs used in ICU sedation were initially introduced for general anesthesia or short-term sedation during regional anesthesia. Th is is why many of the currently used sedatives and analgesics have never been formally evaluated for safety and effi cacy for ICU sedation. Th is also may explain the poor safety record of some sedative agents and the relatively late discovery of the adverse eff ects of ICU sedation.
Opioids have been an integral part of caring for critically ill patients since the early days of intensive care. Th e analgesic and sedative characteristics of morphine have been recognized since the 19th century, when it was used to comfort dying patients. Morphine is widely used in ICUs, and its sedative eff ects, especially at higher doses, may seem attractive in combining pain relief and sedation. Th e recent claim that the use of morphine alone represents 'no sedation' is clearly misleading [14], as morphine provides analgo-sedation. Th e eff ects, however, of long-term treatment with morphine or morphinebased regimens have not been formally evaluated in ICU patients. Despite well-known adverse eff ects (histamine release, hypotension, respiratory depression, tolerance and dependence, and accumulation of active metabolites) and long duration of action, morphine is likely to keep its place in the ICU because of familiarity, availability, and cost-eff ectiveness, at least in comforting dying patients, particularly in cost-restricted settings. Fentanyl is a shorter-acting opiate with no active metabolites; however, like morphine, it has a long context-sensitive half-life and accumulates in renal failure [15]. Although fentanyl has less-sedating eff ects than morphine, it potentiates the eff ects of sedative drugs and in high doses can produce somnolence and sedation [16]. Driven by the perceived cardiovascular stability and favorable kinetics [17,18], fentanyl appears to have replaced morphine to a large extent; whether this evolution in practice is clinically benefi cial, however, remains untested.
Th e history of sedative use in the ICU has been long and complex. In the absence of long-term safety data, familiarity with short-term use and its apparent safety profi le led to the introduction of etomidate as a continuous infusion for ICU sedation, with resulting adverse events including adrenal suppression and a 19% absolute increase in mortality in trauma patients [19,20]. Benzodiazepines, however, have the longest history and remain the most commonly used ICU sedative agents around the world. Th eir unpredictable accumulation, however, with prolonged sedation as a consequence, has been recognized for a long time [21,22]. It was, therefore, natural that the short-acting anesthetic propofol would be introduced for ICU sedation with great enthusiasm and expectations. Th ough allowing rapid awakening after short-term use, propofol also appeared to unpredictably accumulate after long-term use and to cause prolonged sedation [23]. Soon after its introduction, a serious adverse eff ect, the propofol infu sion syndrome (PRIS), was recognized [24]. As originally described [24], PRIS was characterized by rhabdomyo lysis, hyperkalemia, metabolic acidosis, and renal and cardiac failure and is associated with a high mortality.
Despite many years of benzodiazepines and propofol use, few studies compared these medications [25] and only recently have they been evaluated for safety and effi cacy in large randomized controlled trials. Th is has been a direct consequence of the introduction of dexmedeto mi dine for ICU sedation. Dexmedetomidine, a sedative with high α 2 -adrenoreceptor affi nity and agonist action in the locus ceruleus, is the fi rst sedative drug introduced for long-term ICU sedation to undergo formal evaluation for safety and effi cacy according to modern drug develop ment standards. Th is has necessitated comparisons with standard care sedation, and both midazolam and propofol have been used as comparators [26,27]. Th ese trials have also provided insights into the comparative effi cacy and safety profi les of these common sedatives. Dexmedetomidine has been shown to be non-inferior to both midazolam and propofol in maintaining light to moderate sedation [26,27]. It appears to shorten time to extubation and enhance arousability and patients' ability to communicate with caregivers. Dexmedetomidine may reduce delirium after long-term sedation as compared with midazolam [26] and also reduce the overall neurocognitive adverse events of sedation, such as agitation, anxiety, and delirium, when compared with propofol [27]. Th ese trials excluded patients with severe kidney and liver disease, thus limiting the generalizability of the fi ndings. Furthermore, known side eff ects (such as bradycardia) and the acquisition cost of dexmedetomi dine remain a concern. Th e safety and effi cacy of dexmedetomidine, however, have not been evaluated in some ICU patient groups, such as patients with acute neurologic disorder (for example, stroke and head trauma).
Inhaled anesthetic agents such as sevofl urane and isofl urane have been advocated for ICU sedation [28]. To avoid repeating the etomidate story, safety assessment according to current drug development standards is mandatory before introducing new drugs for ICU sedation [29]. At the moment, even the most basic experimental safety data on the long-term eff ects of prolonged administration of inhalational anesthetics are lacking.

Sedative minimization and sedation depth
About 15 years ago, Kollef and colleagues [21] reported the association of continuous intravenous sedation with prolonged mechanical ventilation. Soon after, Brook and colleagues [30] demonstrated a signifi cantly shorter ventilation time and ICU and hospital stays with the use of a sedative-analgesic protocol compared with usual sedation care in medical ICU patients. Over the last decade, sedation minimization strategies, including protocolized sedation (PS), have become the focus of strong research interest.
PS, which appears to be a promising approach, depends on the bedside clinicians titrating the individual patient's sedation needs to match identifi ed specifi c goals using routine structured assessments. In a pre-post study, protocolized analgesia and sedation resulted in reduced sedative and opioid doses and reduced ventilation and ICU times [31]. Th e success of PS, however, depends on local practices, nurse-to-patient ratios, and the intensity of nurse train ing and expertise. Th is may explain why PS was not associated with benefi ts in an Australian ICU environ ment where usual care was already oriented toward sedative minimization [32]. By means of a modifi ed sedation scale with a defi ned sedation protocol, 129 post-operative patients were randomly assigned to either light or heavy sedation [33]. Th e light sedation group received lower midazolam and morphine doses associated with 1-day and 1.5-day mean reductions in ventilation time and ICU days, respectively.
Another way to minimize sedation may be the use of programmed sedation interruptions. Daily sedation interruption (DSI) recommended in the 2002 guidelines became a key strategy after Kress and colleagues [34] reported signifi cant reductions in ventilation time and ICU stay in a single-center 128-patient randomized trial.
However, evaluation of DSI in subsequent randomized trials has produced inconsistent results. One trial was terminated early for safety concerns because the DSI group had a longer ventilation time and longer ICU and hospital lengths of stay compared with the sedation protocol group [35].
Girard and colleagues [36] combined DSI with daily spontaneous breathing trials (SBTs) in an open-label randomized trial and reported more days breathing without assistance and fewer days in the ICU and hospital and, although unexplained, suggested reduced mortality in the DSI/SBT group compared with the usual sedation care and SBT group. A limitation of this trial relates to a potential bias against the control group, given that sedatives were continued but not seemingly titrated to light sedation during the SBT, potentially leading to a longer ventilation time compared with the DSI group. Furthermore, unblinded research personnel were present during DSI in the trials by Kress and colleagues [34] and Girard and colleagues [36], creating serious potential for bias. In the trial by Girard and colleagues, the external validity of the experimental arm has also been questioned, given that the coordination of sedative titration with ventilator weaning is considered routine care in many ICUs outside the US and in many ICUs in North America.
Although DSI has many potential advantages (including the opportunity to cease infusions completely or to reduce dosage, perform a comprehensive neurological and delirium assessment, and assess for extubation readiness), it is not clear whether DSI off ers any advantages when sedation is managed with a sedation protocol that targets light sedation. To address this question, Mehta and colleagues [37] conducted a multicenter randomized trial comparing PS with combined PS plus DSI in 423 critically ill mechanically ventilated medical and surgical patients. Th e authors found no diff erence in the primary outcome of duration of mechanical ventilation and no diff erence in ICU and hospital lengths of stay between the groups. Furthermore, the DSI group received higher daily opioid and benzodiazepines doses, and nurses reported higher workload with DSI. Th e enrolled patients, however, were primarily medical and were given benzodiazepines and this may reduce the generalizability of the fi ndings. At present, although DSI appears to be safe, its eff ectiveness likely depends on the existing institutional sedation practice. If patients are kept lightly sedated, daily interruption does not appear to add further benefi t and may increase nurse workload and drug use.

Limitations of current sedation research
Th e 2013 guidelines, albeit a comprehensive review of the evidence, un covered a signifi cant gap in our knowledge. Most clinical trials of sedation practice have been inadequately powered and have not accounted for intensity of bedside care and thus lack external validity [14,33,34,38]. In addition, most shared signifi cant limitations (Table 1). First, control groups did not reliably match current best practice, leading to misalignment with current practice. As such, these studies are seen to lack both relevance and validity. Second, clinical trials evaluating sedative agents have focused on comparisons of drug A and B, although patients are often sedated with a combination of drugs [26,27]. Th ird, the use of sedation monitoring and delirium assessment were not reliably applied. Fourth, random assignment did not occur until up to 96 hours after initiation of mechanical ventilation, leading to signifi cant pre-enrolment sedative prescription, reduced duration of protocolized intervention, and reduced treatment separation between the experimental and control groups [26,27,34]. Fifth, few studies have assessed long-term patient-centered outcomes [36]. Sixth, the intervention was sometimes administered by research staff rather than clinical staff , thus limiting generali zability [33,34,36]. Finally, sedation strategy may have an impact on mortality [19,31,36]; however, there have not been any large phase III trials using mortality as the primary outcome. All of these aspects have resulted in a lack of conclusive evidence to guide clinicians in their daily practice and, thus, in variable adoption of many of the above interventions outside participating research centers. Th ese problems are of particular relevance to delirium, and there is ongoing uncertainty regarding best preventive measures and management [12].
Delirium received signifi cant attention in the 2013 Pain, Agitation, and Delirium (PAD) guidelines. Th e guidelines emphasized the value of light sedation, whenever clinically appropriate, as a possible way of preventing or attenuating delirium. None of the randomized trials comparing lighter and deeper sedation, however, led to a reduction in delirium with light sedation [14,36,37]. Recent data have also questioned the presumed link between drug-induced coma, deep sedation, and delirium [2,3,39].

The future of intensive care unit sedation research
To bridge the evidence gap, an evolutionary approach to sedation research is needed. A structured research program that describes current practice in detail and identifi es possible modifi able risk factors is an important fi rst step. Such multinational multicenter longitudinal cohort assessments of sedation practice have revealed a high prevalence of deep sedation early after initiation of mechanical ventilation; early deep sedation was strongly and independently associated with delayed extubation and long-term mortality (but not delirium) [2,3]. It is, therefore, imperative that any future intervention have specifi c key characteristics. First, it should be given early within minutes to hours of commencing sedation or mechanical ventilation. Second, the control group should align with best practice for the purpose of achieving relevance and external validity. Th ird, an integrated process of care (rather than specifi c drug A versus B) targeting light sedation should be investigated. Finally, investigators should use sedative agents shown to promote arousability, reduce ventilation duration, and attenuate delirium [26,27,40]. An innovative sedation strategy has been termed early goal-directed sedation and was recently tested for feasibility and safety in a pilot randomized trial [41]. Th is study suggested that early deep sedation, which was not addressed in any previous randomized trials, may be harmful and largely unjustifi ed. Th e early goal-directed sedation concept will now be tested in an adequately powered, multinational multicenter randomized trial with a patient-centered outcome [42]. Th is trial will seek to address several of the key limitations and uncertainties of prior sedation research and current practice.
We acknowledge the comprehensive nature of the 2013 PAD guidelines; we believe they do provide a framework to adapt sedation practices to suit local and institutional needs. Th e guidelines have been appropriately nonprescriptive, and considering the limitations of many studies supporting PAD recommendations, we should be cautious about implementing strategies that are designed to force untested intervention bundles (that are based on a small number of randomized trials) into general practice. Th e second decade of the 21st century should be the decade of establishing high-level evidence for ICU sedation practice. Th e need is great, the time is right, the time is now.

Competing interests
YS has received unrestricted grant-in-aid research grants from Hospira Inc. (Lake Forest, IL, USA) and research grants from Roche Diagnostics (Melbourne, Australia) and Thermo Fisher Scientifi c Inc. (Melbourne, Australia). Speakers' honoraria from Hospira Inc. and Roche Diagnostics were paid to YS's research fund. JT's department, the Department of Intensive Care Medicine of University Hospital Bern, has, or has had in the past, research contracts with Abbott Nutrition International (Abbott AG) (Baar, Switzerland), B. Braun Medical AG (Sempach, Switzerland), CSEM SA (Neuchâtel, Switzerland), Edwards Lifesciences Corporation (Irvine, CA, USA), Kenta Biotech Ltd (Zürich-Schlieren, Switzerland), Maquet Critical Care AB (Solna, Sweden), Omnicare Clinical Research AG (Oberwil, Switzerland), and Orion Corporation (Espoo, Finland) and research and development/consulting contracts with Edwards Lifesciences Corporation, Maquet Critical Care AB, Baxter Healthcare SA (Glattpark (Opfi kon), Switzerland), and Nestlé (Vevey, Switzerland). The money is or was paid into a departmental fund. JT has received no personal fi nancial gain. The department has received unrestricted educational grants from the following organizations for organizing a quarterly postgraduate educational symposium, the Berner Forum for Intensive Care: Fresenius Kabi (Schweiz) AG (Oberdorf, Switzerland), GlaxoSmithKline AG (Münchenbuchsee, Switzerland),