Good morning, everybody, and thank you to the SSCM Programming Committee for giving me the opportunity to speak. I'm going to be talking about management of sedation in the ICU before and after the COVID-19 pandemic. I do not have any relevant disclosures. I do receive funding from the U.S. Department of Defense for a project which is unrelated to the topic that I'm going to be discussing. Here's an outline of my talk. I'm going to start off by talking about our sedation practices in the pre-COVID-19 era. Then I'm going to shift gears and spend a fair amount of time talking about how these practices underwent a sea change during the pandemic. And finally, I'm going to finish off by laying somewhat of a framework for our sedation practices moving forward. So in order to understand what our sedation practices were before the pandemic, it is very important to review the 2018 PADIS guidelines. So I'm not going to go to greater details of these guidelines, which will be highlighted later in the seminar, but I'm going to focus on a couple of important aspects. So these guidelines were an update of the 2013 guidelines, and the couple of important updates included the focus on a reduction of immobility and sleep disruption. And for the first time, patients were also included as collaborators in the establishment of these guidelines. These guidelines were extremely comprehensive, but I'd like to focus on a couple of guiding principles that have emerged from these guidelines. First is the focus on assessment-driven, protocol-based approach to pain and sedation. Second is the use of adjuncts to pain medications. Third is an overwhelming emphasis on the use of light levels of sedation over deep sedation. Fourth, an emphasis on avoidance of benzodiazepines over propofol and or dexmedetomidine-based sedation. And a renewed emphasis on family engagements as a means to reduce isoutelerium. So naturally, the question that arises is, does implementation of A2F bundles improve outcomes? And the answer is an overwhelming yes. This is data from about 68 ICUs, including about 15,000 adults who had at least one ICU, one day stay in the ICU. And the results showed that complete adherence to the bundle was associated with meaningful patient-centered outcomes. And these went from days in delirium, coma, ICU length of stay, and so on and so forth. And there was a very clear dose dependence with an adjusted odds ratio of 0.28 to 0.64, which suggested that higher compliance was associated with better outcomes. So we've seen that compliance with A2F bundle was associated with better outcomes. Then COVID hit, and we entered into this dark phase of the pandemic. We can all agree that intensive care units across the world faced unprecedented challenges during the pandemic, but what was most striking was that the ICUs came to be known as delirium factories for COVID-19 patients. And it was not uncommon to see headlines such as these. The situation was possibly best summarized by Dr. Eli, who called this a horrendous experiment which had been unleashed to exacerbate ICU delirium. So if we were to delve deeper into why ICUs became delirium factories, aside from distinct pathophysiological mechanisms, so why COVID-19 may have led to delirium, we should also focus on the disruptors of best practices which possibly led to exacerbation of this problem. These disruptors could be placed into three categories, social, heterogenic, and psychological. The social factors, the primary social factors were social distancing, quarantine regulations, and the lack of family visitations which were implemented early on in the pandemic. And the psychological factors, the sense of fear, anxiety, not only from the nature of the disease, but from the ambient atmosphere would have certainly contributed to delirium. Now I'm going to be focusing more on the heterogenic aspects which represented a departure from established guidelines and which may have clearly worsened this problem. The list of heterogenic factors reads as a complete departure from all the gains that had been accumulated up until the COVID pandemic. So as the pandemic unfolded, we saw the use of deep levels of sedation, rolling drug shortages meant the use of non-standard sedatives. For example, benzodiazepine, the use of which skyrocketed during the pandemic. The use of, liberal use of neuromuscular blocking agents and proning meant that the sedation levels, deeper levels of sedation had to be used. Prolonged immobilization again led to higher rates of delirium, and these were intimately tied to staffing challenges, capacity constraints. And staffing challenges also meant that this protocolized assessment of sedation and delirium were also disrupted to a great extent. The most comprehensive snapshot of the sedation and delirium management practices across the world was provided by Dr. Pahn's publication in the Lancet Respiratory Medicine. And we are very fortunate to have her as one of our co-speakers. So they recruited over 2,000 patients across 14 countries, and the results were quite astounding. The median RAS score was minus four in the entire cohort. More than 80% of patients were comatose for a median of 10 days, and about 55% of patients were delirious for a median of three days. Moving on to the use of continuous sedative infusions, I'd like you to focus on the use of benzodiazepines in this cohort. About 64% of patients were on a benzodiazepine infusion for a median of seven days. And this stands contrary to the guidelines which specifically recommended avoidance of these agents. Moving on to the performance of the A2F bundles during this COVID-19 pandemic, what we see is a very, very striking drop-off in the implementation of these bundle elements. And I'd like you to focus specifically on the early mobility and the family engagement components which were extremely low in the range of 16% and 8% respectively. These results clearly demonstrate that the prevalence of delirium and coma was extremely high in this population. Polypharmacy was common. Use of benzodiazepine infusions was unacceptably high at around 65%, and the A2F bundle compliance experienced a sharp drop-off. Looking into the modifiable factors, avoidance of benzodiazepines and visitations, even if they were virtual, were protective against delirium. Similar results were seen in other observational cohorts. This is a dual-center study including about 390-odd patients, wherein they found about 72% of patients experienced deep sedation, which was defined as a RAS of minus three to minus five. And this persisted for about a week, which meant that the majority of patients were very deeply sedated. Benzodiazepine use was about 30% to 40% in both subgroups, whether it was light or deep sedation. And the deeper levels of sedations were strongly associated with worse outcomes. Now, you could argue about confounding by indication, nonetheless, what the results demonstrate is that vast majority of patients remain deeply sedated. And then that the benzodiazepine use was, again, extremely, extremely high in this population. So the obvious question then arises is whether patients with COVID-19 were the only ones who were adversely affected by these departures from established practice guidelines. So this is an interesting study, which is a one-day point prevalence study, looking at the implementation of ABCDEF bundles during the pandemic. So questionnaires were sent in January of 2021 to ICUs across 54 countries and included data from over 1,200 patients. And the results were quite astounding. The authors found that the ABCDEF implementation was extremely low across all bundle components and it was irrespective of whether a patient was COVID-positive or not. So this suggests that these departures happened across the board for all patients, irrespective of their COVID-19 status. So moving on, an obvious question that arises is that how does the sedative requirement of patients with COVID ARDS differ from those without COVID? So this is a propensity-matched cohort study, which is a single-center study, and it's data from Beth Israel and Boston, wherein the authors matched patients with or without COVID-19 ARDS. And what they found was that patients with COVID ARDS had a significantly higher use of sedatives and hypnotics while they were on mechanical ventilation. The days spent in coma were, again, significantly higher in the COVID cohort, as was in-patient mortality. And they performed a mediation analysis, wherein the results suggested that coma mediated about 59% of in-patient mortality. The take-home message from this are two. Number one is that patients with COVID-19 ARDS received significantly higher amount of sedatives when compared to patients without COVID. And two, that maybe avoidance of this excessive sedatives could have led to reduction in in-patient mortality. Consistent results were seen in this single-center observational cohort of mechanically ventilated COVID-19 patients. The authors found that the sedative use in the first 10 days of mechanical ventilation often exceeded the upper limits of recommended doses. They found that this upper limit was violated in about 48% of patients on propofol, 29% patients receiving death penalty from adenine, and about 32% of patients on ketamine. So far, we've seen that patients with COVID-19 were exposed to extremely high doses of sedatives, which often exceeded recommended limits, and polypharmacy, that is the use of multiple agents, was extremely common in this population. So we tested the hypothesis that polypharmacy was a mediator in the pathway between mechanical ventilation and delirium. And we found that polypharmacy, as defined by the use of more than three agents, mediated about 39% of the effect of mechanical ventilation on development of IC delirium. So although it does not imply causality, it suggests that polypharmacy may have led to the higher rates of delirium to a certain extent in this population. So in summary, we can say that the pandemic represented a dark period wherein the ICU community experienced major setbacks in the management of sedation and delirium. Deep sedation made a comeback, so did the rampant use of benzodiazepines and nonjudicious use of polypharmacy. A2F bundle compliance dropped off significantly, and all these potentially culminated into an extraordinarily high rate of delirium, and possibly also contributing to excess inpatient mortality. It is also perceivable that these departures from existing best practices have led to an increased burden of PICS, PICS family, and higher rates of post-traumatic stress disorder among survivors. So as we come out of the clutches of the pandemic, we have to look into the future with some optimism. So where do we go from here? The first step is to identify the mistakes of the pandemic and to learn and recalibrate from them so that we do not repeat them in the future. Second is to just get back on track. We have good data to suggest that the guidelines are A2F and A2F bundles are associated with better outcomes. Let's go back and make a conscious effort to reduce practice variability and go back to the best practices that have been established on the basis of evidence. Third is to give greater recognition to the importance of sedation and delirium management practices to identify and realize that management of sedation and delirium management is not just a cog in the wheel in ICU care, but it has wide-reaching implications which go well beyond the ICU stay. As we gradually make up for lost ground, there are a number of exciting personalized sedation strategies that are on the horizon. The first one is lung protective sedation strategy, which extends titration of sedation to just scales of cognition to those which are aimed at minimizing the synchrony and ventilator-induced lung injury. Second is patient-controlled sedation, which empowers patients themselves to optimize their sedation and analgesia. I shall not go into the role of inhaled anesthetic, which is the topic of the next talk, but the other important paradigms include the appropriate application of multimodal sedation and the use of non-pharmacological adjuncts for sedation and anxiolysis. This includes examination of music, cognitive aids, and augmented communication devices as adjuncts for sedation and delirium management. So how does the future of ICU sedation and delirium management look like? It's become abundantly clear by now that sedation and delirium management cannot be optimized if the ICU environment is not taken into consideration. So in addition to the validated tools and therapies that form part of the A2F bundle, Dr. Eli and colleagues have shared a vision for the future, and this includes three additional elements, which are aimed at creating a healing environment to optimize the management of sedation and delirium. So what does the future look like? So we can probably broaden our horizons and think of the bundle as not just A2F, but an expanded one, which includes the elements G, H, and I. So G refers to getting to know about our patients and their preferences, getting to know what our patients were when they were not critically ill so that we can tailor therapies based on their preferences. H refers to customizing the immediate ICU environment to resemble somewhat of a home-like environment, and I, which is probably the most challenging aspect of this expanded definition, lays emphasis on creating a safe, patient-centered environment, which has a low alarm burden and minimally disruptive monitoring, to name just a few. Now, if these are implemented in conjunction, not only delirium and sedation management will be simplified and effective, we can anticipate that these would go a long way in humanizing the ICU experience, and perhaps our dream of reducing delirium to near zero will not remain a dream anymore. So with that, I'd like to conclude, and thank you again for your attention. I'm more than happy to take any questions that you might have.

ICU management

sedation

COVID-19 pandemic

PADIS guidelines

patient outcomes