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Delirium in the ICU: Best sedation practices lead to the best outcomes
Delirium is a frequent form of organ failure among the critically ill, impacting up to 80% of mechanically ventilated patients (Ely EW et al. JAMA. 2004;291[14]:1753-62). Its cardinal manifestations include disturbances in attention and cognition that occur acutely (e.g., hours to days) that are not better explained by another disease process (such as a toxidrome or dementia) (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 5th ed., 2013). Duration of delirium in the intensive care unit (ICU) is independently associated with poor outcomes, such as mortality and hospital length of stay, even when accounting for comorbidities, coma duration, sedative use, and severity of illness. Delirium during critical illness is an important bellwether for a patient’s clinical status, often serving as a harbinger for severe or worsening disease.
Over the last two decades, the critical care community has come to understand the importance of recognizing delirium, which is often underdiagnosed, as well as delirium prevention. In the ICU, several factors coalesce to form the perfect environment for the development of delirium. Patients often have preexisting comorbidities that predispose to delirium, such as preexisting cognitive impairment, and the severity of critical illness increases the risk of delirium further. There are also bedside factors, however, that are important for the intensivist to address, many of which are modifiable. These include routinely screening for delirium and assessing level of consciousness, implementing early mobility and rehabilitation, targeting light sedation, and avoiding deliriogenic medications such as benzodiazepines. These evidence-based care practices form the foundation of the 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (i.e., PADIS guidelines), which aim to reduce delirium and iatrogenesis from critical care (Devlin JW et al. Crit Care Med. 2018;46[9]:e825-e873). The severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) pathogen that has caused the coronavirus disease 2019 (COVID-19) pandemic, however, has brought unprecedented challenges to critical care. One unfortunate side effect has been increased use of deep sedation and, thus, a greater incidence of delirium (Pun BT et al. Lancet Respir Med. 2021;9[3]:239-50). While the impact of the pandemic is unprecedented, thoughtful and careful sedation use remains vital to providing optimal care for the critically ill patient.
The link between sedation and delirium
The advent of modern mechanical ventilation brought critical care medicine into a period of rapid growth. Practices derived from the operating room, such as deep sedation and paralysis, became commonplace. Yet, starting in the late 1990s and early 2000s, evidence started growing regarding the impact of delirium and the unique aspects of the ICU that made it so prevalent. Delirium is strongly linked to inpatient mortality in mechanically ventilated adults, and it is best understood as an additional form of organ failure, much like other organ failures commonly recognized and treated by intensivists, such as respiratory or renal failure. Certain medications and sedation practices are associated with the development and duration of delirium. Benzodiazepines, a common sedative medication, are strongly linked to the development of delirium. In a study comparing commonly used sedative and analgesic agents, the use of lorazepam was associated with a greater risk of delirium the following day among critically ill, mechanically ventilated patients (Pandhariphande PP et al. Anesthesiology. 2006;104[1]:21-6). Given how commonly benzodiazepines are used and delirium develops in the ICU, this association has striking implications for clinical care and outcomes such as mortality. It is also significant, given that benzodiazepine use has increased during the pandemic, potentially creating significant downstream consequences. Benzodiazepines should be actively avoided when at all possible, given their propensity to lead to delirium, in accordance with the most recent guidelines.
Which sedation agent to choose?
While the negative effects of benzodiazepine-based sedation are well established, the optimal sedation agent remains unclear. Several other drugs are commonly used in the ICU, including propofol, dexmedetomidine, and opioid agents such as fentanyl and morphine. Propofol and dexmedetomidine are used specifically for their sedative properties, though they have dramatically different effects on the depth of sedation and different mechanisms of action. Opioid agents are most commonly used for their analgesic effect; however, in higher doses or combined with other medications, they have the secondary effect of inducing sedation. No particular sedation agent, however, beyond the avoidance of benzodiazepines has been recommended for use in the most recent guidelines. In the PRODEX and MIDEX studies, dexmedetomidine was noninferior to both midazolam and propofol in achieving targeted light to moderate sedation, and dexmedetomidine was associated with a shorter duration of mechanical ventilation compared to midazolam (Jakob SM et al. JAMA. 2012;307[11]:1151-60). More recently, the SPICE-III trial studied dexmedetomidine vs. usual care and found no difference in 90-day mortality (Shehabi Y et al. N Engl J Med. 2019;380[26]:2506-17).
In choosing the best sedation agent to avoid delirium, the largest and most applicable trial to date is the “Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure,” or MENDS2 trial (Hughes CG et al. N Engl J Med. 2021;384:1424-36). This study was a double-blind, multicenter randomized controlled trial of dexmedetomidine vs propofol in critically ill patients with sepsis receiving mechanical ventilation. The primary outcome was days alive without delirium or coma over the 14-day intervention period. The study enrolled 438 patients between 13 sites, with 422 patients receiving either dexmedetomidine or propofol. Hughes and colleagues found no difference in the primary outcome of days alive without delirium or coma between the dexmedetomidine and the propofol arms. The study also found no difference in secondary outcomes, including ventilator-free days, 90-day mortality, and 6-month global cognition, as well as no difference in safety endpoints. Importantly, there was excellent compliance with guideline-recommended practices of spontaneous awakening and breathing trials and early mobility, both of which are associated with reduced sedation exposure. The study did have some notable nuances, however. The overall doses of trial drugs were relatively low, and there was a moderate use of rescue sedation. There was also a small amount of crossover use of propofol and dexmedetomidine between treatment arms (10%), although the authors note that this was lower than in prior related studies. Overall, the MENDS2 study suggests there is likely clinical equipoise between propofol and dexmedetomidine in terms of delirium outcomes when combined with best practices, such targeted light sedation, paired awakening and breathing trials, and early mobility.
How should we manage sedation to prevent delirium?
Building off of the recent MENDS2 study and earlier work in the field, along with the 2018 PADIS guidelines, the general paradigm of sedation management should be focused on using light sedation with sedation interruptions to minimize overall sedation exposure. Based on the best available evidence to date, targeting less overall sedation leads to improved outcomes in critically ill patients, including mortality and duration of mechanical ventilation. Benzodiazepines should be avoided due to their association with delirium, but currently there is no evidence to suggest one nonbenzodiazepine sedative is better than another. Intensivists can feel comfortable choosing between agents based on a patient’s individual clinical needs, especially when patients are receiving paired spontaneous awakening and breathing trials and early rehabilitation. These same principles should be applied to sedation management and delirium patients in COVID-19 patients as well. While certain circumstances will necessitate deeper sedation at times (e.g., refractory hypoxemia due to ARDS from COVID-19), clinicians should continually reassess the actual sedation needs of the patient with the goal of reducing overall sedation. Focusing effort on these evidence-based practices will help reduce the incidence of delirium and ultimately improve patient outcomes.
Dr. Mart is with the Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center; and VA Tennessee Valley Healthcare System Geriatric Research Education and Clinical Center (GRECC), Nashville, Tennessee.
Delirium is a frequent form of organ failure among the critically ill, impacting up to 80% of mechanically ventilated patients (Ely EW et al. JAMA. 2004;291[14]:1753-62). Its cardinal manifestations include disturbances in attention and cognition that occur acutely (e.g., hours to days) that are not better explained by another disease process (such as a toxidrome or dementia) (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 5th ed., 2013). Duration of delirium in the intensive care unit (ICU) is independently associated with poor outcomes, such as mortality and hospital length of stay, even when accounting for comorbidities, coma duration, sedative use, and severity of illness. Delirium during critical illness is an important bellwether for a patient’s clinical status, often serving as a harbinger for severe or worsening disease.
Over the last two decades, the critical care community has come to understand the importance of recognizing delirium, which is often underdiagnosed, as well as delirium prevention. In the ICU, several factors coalesce to form the perfect environment for the development of delirium. Patients often have preexisting comorbidities that predispose to delirium, such as preexisting cognitive impairment, and the severity of critical illness increases the risk of delirium further. There are also bedside factors, however, that are important for the intensivist to address, many of which are modifiable. These include routinely screening for delirium and assessing level of consciousness, implementing early mobility and rehabilitation, targeting light sedation, and avoiding deliriogenic medications such as benzodiazepines. These evidence-based care practices form the foundation of the 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (i.e., PADIS guidelines), which aim to reduce delirium and iatrogenesis from critical care (Devlin JW et al. Crit Care Med. 2018;46[9]:e825-e873). The severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) pathogen that has caused the coronavirus disease 2019 (COVID-19) pandemic, however, has brought unprecedented challenges to critical care. One unfortunate side effect has been increased use of deep sedation and, thus, a greater incidence of delirium (Pun BT et al. Lancet Respir Med. 2021;9[3]:239-50). While the impact of the pandemic is unprecedented, thoughtful and careful sedation use remains vital to providing optimal care for the critically ill patient.
The link between sedation and delirium
The advent of modern mechanical ventilation brought critical care medicine into a period of rapid growth. Practices derived from the operating room, such as deep sedation and paralysis, became commonplace. Yet, starting in the late 1990s and early 2000s, evidence started growing regarding the impact of delirium and the unique aspects of the ICU that made it so prevalent. Delirium is strongly linked to inpatient mortality in mechanically ventilated adults, and it is best understood as an additional form of organ failure, much like other organ failures commonly recognized and treated by intensivists, such as respiratory or renal failure. Certain medications and sedation practices are associated with the development and duration of delirium. Benzodiazepines, a common sedative medication, are strongly linked to the development of delirium. In a study comparing commonly used sedative and analgesic agents, the use of lorazepam was associated with a greater risk of delirium the following day among critically ill, mechanically ventilated patients (Pandhariphande PP et al. Anesthesiology. 2006;104[1]:21-6). Given how commonly benzodiazepines are used and delirium develops in the ICU, this association has striking implications for clinical care and outcomes such as mortality. It is also significant, given that benzodiazepine use has increased during the pandemic, potentially creating significant downstream consequences. Benzodiazepines should be actively avoided when at all possible, given their propensity to lead to delirium, in accordance with the most recent guidelines.
Which sedation agent to choose?
While the negative effects of benzodiazepine-based sedation are well established, the optimal sedation agent remains unclear. Several other drugs are commonly used in the ICU, including propofol, dexmedetomidine, and opioid agents such as fentanyl and morphine. Propofol and dexmedetomidine are used specifically for their sedative properties, though they have dramatically different effects on the depth of sedation and different mechanisms of action. Opioid agents are most commonly used for their analgesic effect; however, in higher doses or combined with other medications, they have the secondary effect of inducing sedation. No particular sedation agent, however, beyond the avoidance of benzodiazepines has been recommended for use in the most recent guidelines. In the PRODEX and MIDEX studies, dexmedetomidine was noninferior to both midazolam and propofol in achieving targeted light to moderate sedation, and dexmedetomidine was associated with a shorter duration of mechanical ventilation compared to midazolam (Jakob SM et al. JAMA. 2012;307[11]:1151-60). More recently, the SPICE-III trial studied dexmedetomidine vs. usual care and found no difference in 90-day mortality (Shehabi Y et al. N Engl J Med. 2019;380[26]:2506-17).
In choosing the best sedation agent to avoid delirium, the largest and most applicable trial to date is the “Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure,” or MENDS2 trial (Hughes CG et al. N Engl J Med. 2021;384:1424-36). This study was a double-blind, multicenter randomized controlled trial of dexmedetomidine vs propofol in critically ill patients with sepsis receiving mechanical ventilation. The primary outcome was days alive without delirium or coma over the 14-day intervention period. The study enrolled 438 patients between 13 sites, with 422 patients receiving either dexmedetomidine or propofol. Hughes and colleagues found no difference in the primary outcome of days alive without delirium or coma between the dexmedetomidine and the propofol arms. The study also found no difference in secondary outcomes, including ventilator-free days, 90-day mortality, and 6-month global cognition, as well as no difference in safety endpoints. Importantly, there was excellent compliance with guideline-recommended practices of spontaneous awakening and breathing trials and early mobility, both of which are associated with reduced sedation exposure. The study did have some notable nuances, however. The overall doses of trial drugs were relatively low, and there was a moderate use of rescue sedation. There was also a small amount of crossover use of propofol and dexmedetomidine between treatment arms (10%), although the authors note that this was lower than in prior related studies. Overall, the MENDS2 study suggests there is likely clinical equipoise between propofol and dexmedetomidine in terms of delirium outcomes when combined with best practices, such targeted light sedation, paired awakening and breathing trials, and early mobility.
How should we manage sedation to prevent delirium?
Building off of the recent MENDS2 study and earlier work in the field, along with the 2018 PADIS guidelines, the general paradigm of sedation management should be focused on using light sedation with sedation interruptions to minimize overall sedation exposure. Based on the best available evidence to date, targeting less overall sedation leads to improved outcomes in critically ill patients, including mortality and duration of mechanical ventilation. Benzodiazepines should be avoided due to their association with delirium, but currently there is no evidence to suggest one nonbenzodiazepine sedative is better than another. Intensivists can feel comfortable choosing between agents based on a patient’s individual clinical needs, especially when patients are receiving paired spontaneous awakening and breathing trials and early rehabilitation. These same principles should be applied to sedation management and delirium patients in COVID-19 patients as well. While certain circumstances will necessitate deeper sedation at times (e.g., refractory hypoxemia due to ARDS from COVID-19), clinicians should continually reassess the actual sedation needs of the patient with the goal of reducing overall sedation. Focusing effort on these evidence-based practices will help reduce the incidence of delirium and ultimately improve patient outcomes.
Dr. Mart is with the Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center; and VA Tennessee Valley Healthcare System Geriatric Research Education and Clinical Center (GRECC), Nashville, Tennessee.
Delirium is a frequent form of organ failure among the critically ill, impacting up to 80% of mechanically ventilated patients (Ely EW et al. JAMA. 2004;291[14]:1753-62). Its cardinal manifestations include disturbances in attention and cognition that occur acutely (e.g., hours to days) that are not better explained by another disease process (such as a toxidrome or dementia) (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 5th ed., 2013). Duration of delirium in the intensive care unit (ICU) is independently associated with poor outcomes, such as mortality and hospital length of stay, even when accounting for comorbidities, coma duration, sedative use, and severity of illness. Delirium during critical illness is an important bellwether for a patient’s clinical status, often serving as a harbinger for severe or worsening disease.
Over the last two decades, the critical care community has come to understand the importance of recognizing delirium, which is often underdiagnosed, as well as delirium prevention. In the ICU, several factors coalesce to form the perfect environment for the development of delirium. Patients often have preexisting comorbidities that predispose to delirium, such as preexisting cognitive impairment, and the severity of critical illness increases the risk of delirium further. There are also bedside factors, however, that are important for the intensivist to address, many of which are modifiable. These include routinely screening for delirium and assessing level of consciousness, implementing early mobility and rehabilitation, targeting light sedation, and avoiding deliriogenic medications such as benzodiazepines. These evidence-based care practices form the foundation of the 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (i.e., PADIS guidelines), which aim to reduce delirium and iatrogenesis from critical care (Devlin JW et al. Crit Care Med. 2018;46[9]:e825-e873). The severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) pathogen that has caused the coronavirus disease 2019 (COVID-19) pandemic, however, has brought unprecedented challenges to critical care. One unfortunate side effect has been increased use of deep sedation and, thus, a greater incidence of delirium (Pun BT et al. Lancet Respir Med. 2021;9[3]:239-50). While the impact of the pandemic is unprecedented, thoughtful and careful sedation use remains vital to providing optimal care for the critically ill patient.
The link between sedation and delirium
The advent of modern mechanical ventilation brought critical care medicine into a period of rapid growth. Practices derived from the operating room, such as deep sedation and paralysis, became commonplace. Yet, starting in the late 1990s and early 2000s, evidence started growing regarding the impact of delirium and the unique aspects of the ICU that made it so prevalent. Delirium is strongly linked to inpatient mortality in mechanically ventilated adults, and it is best understood as an additional form of organ failure, much like other organ failures commonly recognized and treated by intensivists, such as respiratory or renal failure. Certain medications and sedation practices are associated with the development and duration of delirium. Benzodiazepines, a common sedative medication, are strongly linked to the development of delirium. In a study comparing commonly used sedative and analgesic agents, the use of lorazepam was associated with a greater risk of delirium the following day among critically ill, mechanically ventilated patients (Pandhariphande PP et al. Anesthesiology. 2006;104[1]:21-6). Given how commonly benzodiazepines are used and delirium develops in the ICU, this association has striking implications for clinical care and outcomes such as mortality. It is also significant, given that benzodiazepine use has increased during the pandemic, potentially creating significant downstream consequences. Benzodiazepines should be actively avoided when at all possible, given their propensity to lead to delirium, in accordance with the most recent guidelines.
Which sedation agent to choose?
While the negative effects of benzodiazepine-based sedation are well established, the optimal sedation agent remains unclear. Several other drugs are commonly used in the ICU, including propofol, dexmedetomidine, and opioid agents such as fentanyl and morphine. Propofol and dexmedetomidine are used specifically for their sedative properties, though they have dramatically different effects on the depth of sedation and different mechanisms of action. Opioid agents are most commonly used for their analgesic effect; however, in higher doses or combined with other medications, they have the secondary effect of inducing sedation. No particular sedation agent, however, beyond the avoidance of benzodiazepines has been recommended for use in the most recent guidelines. In the PRODEX and MIDEX studies, dexmedetomidine was noninferior to both midazolam and propofol in achieving targeted light to moderate sedation, and dexmedetomidine was associated with a shorter duration of mechanical ventilation compared to midazolam (Jakob SM et al. JAMA. 2012;307[11]:1151-60). More recently, the SPICE-III trial studied dexmedetomidine vs. usual care and found no difference in 90-day mortality (Shehabi Y et al. N Engl J Med. 2019;380[26]:2506-17).
In choosing the best sedation agent to avoid delirium, the largest and most applicable trial to date is the “Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure,” or MENDS2 trial (Hughes CG et al. N Engl J Med. 2021;384:1424-36). This study was a double-blind, multicenter randomized controlled trial of dexmedetomidine vs propofol in critically ill patients with sepsis receiving mechanical ventilation. The primary outcome was days alive without delirium or coma over the 14-day intervention period. The study enrolled 438 patients between 13 sites, with 422 patients receiving either dexmedetomidine or propofol. Hughes and colleagues found no difference in the primary outcome of days alive without delirium or coma between the dexmedetomidine and the propofol arms. The study also found no difference in secondary outcomes, including ventilator-free days, 90-day mortality, and 6-month global cognition, as well as no difference in safety endpoints. Importantly, there was excellent compliance with guideline-recommended practices of spontaneous awakening and breathing trials and early mobility, both of which are associated with reduced sedation exposure. The study did have some notable nuances, however. The overall doses of trial drugs were relatively low, and there was a moderate use of rescue sedation. There was also a small amount of crossover use of propofol and dexmedetomidine between treatment arms (10%), although the authors note that this was lower than in prior related studies. Overall, the MENDS2 study suggests there is likely clinical equipoise between propofol and dexmedetomidine in terms of delirium outcomes when combined with best practices, such targeted light sedation, paired awakening and breathing trials, and early mobility.
How should we manage sedation to prevent delirium?
Building off of the recent MENDS2 study and earlier work in the field, along with the 2018 PADIS guidelines, the general paradigm of sedation management should be focused on using light sedation with sedation interruptions to minimize overall sedation exposure. Based on the best available evidence to date, targeting less overall sedation leads to improved outcomes in critically ill patients, including mortality and duration of mechanical ventilation. Benzodiazepines should be avoided due to their association with delirium, but currently there is no evidence to suggest one nonbenzodiazepine sedative is better than another. Intensivists can feel comfortable choosing between agents based on a patient’s individual clinical needs, especially when patients are receiving paired spontaneous awakening and breathing trials and early rehabilitation. These same principles should be applied to sedation management and delirium patients in COVID-19 patients as well. While certain circumstances will necessitate deeper sedation at times (e.g., refractory hypoxemia due to ARDS from COVID-19), clinicians should continually reassess the actual sedation needs of the patient with the goal of reducing overall sedation. Focusing effort on these evidence-based practices will help reduce the incidence of delirium and ultimately improve patient outcomes.
Dr. Mart is with the Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center; and VA Tennessee Valley Healthcare System Geriatric Research Education and Clinical Center (GRECC), Nashville, Tennessee.