Ariel Modrykamien, MD, FCCP, FACP

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰

In the early stages of acute respiratory distress syndrome (ARDS), multiple areas of the lung collapse, most often in the dependent regions. A factor involved in this process is the loss of functional surfactant, creating a condition in which alveolar units are unstable and prone to collapse due to unopposed surface tension. This situation, similar to that in premature infants, results in a reduced volume of aerated lung, intrapulmonary shunting, and, therefore, poor oxygenation.

The treatment of this alveolar collapse is lung reinflation (or “recruitment,” a term first used by Lachmann).¹ Gattinoni et al² showed that the percentage of recruitable lung could range from a negligible fraction to 50% or more.

There are various means of reopening injured lungs and keeping them open. The choice of recruitment maneuver is based on the individual patient and the ventilatory mode.³

In this article, we review airway pressure release ventilation (APRV), a mode of mechanical ventilation that may be useful in situations in which, due to ARDS, the lungs need to be recruited and held open. APRV was developed as a lung-protective mode, allowing recruitment while minimizing ventilator-induced lung injury.

BASIC PRINCIPLES OF PROTECTIVE VENTILATION

This curve has two inflection points between which its slope is steep, indicating greater compliance or elasticity. Below the lower inflection point, the alveoli may collapse; above the upper inflection point, the lung loses its elastic properties and the alveoli are overdistended. To protect the lungs, the challenge in mechanical ventilation is to keep the lungs between these two points throughout the respiratory cycle.

Avoiding lung collapse by using PEEP

During mechanical ventilation, the pressure in the lungs is lowest, and thus the alveoli are most prone to collapse, at the end of expiration.

We want to prevent the alveoli from collapsing with each expiration and reopening with each inspiration, as this cycle of opening and closing damages them (causing atelectrauma, ie, cyclical atelectasis).⁴ Preventing it prevents the release of inflammatory mediators and the perpetuation of lung injury (biotrauma).⁵

The solution is to apply positive end-expiratory pressure (PEEP), taking into account the value of the lower inflection point when setting the PEEP level.

Villar et al⁶ compared outcomes in an intervention group that received a PEEP level 2 cm H₂O above the lower inflection point plus low tidal volumes, and in a control group that received higher tidal volumes and low PEEP (5 cm H₂O). The study was stopped early, after significantly more patients had died in the control group than in the intervention group (53% vs 32%, P = .04).

Avoiding overdistention by keeping the tidal volume low

Tidal volumes that exceed the upper inflection point overstretch the lung and induce volutrauma, which can manifest as pneumothorax or pneumomediastinum, or both—the lungs rupture like a balloon. Also, overdistention produces liberation of inflammatory mediators in the blood (biotrauma). High tidal volumes should therefore be avoided or limited as much as possible.

The ARDS Network,⁷ in a multicenter, randomized, controlled trial, showed that fewer patients die if they receive mechanical ventilation with low tidal volumes rather than higher, “conventional” tidal volumes. Patients were randomized to receive either a tidal volume of 6 mL/kg and a plateau pressure lower than 30 cm H₂O or a tidal volume of 12 mL/kg and a plateau pressure lower than 50 cm H₂O. They were followed for 180 days or until discharged home, breathing without assistance. A total of 861 patients were enrolled. The mortality rate was significantly lower in the low tidal volume group than in the group with conventional tidal volumes, 31% vs 40%.

Lower tidal volumes were also associated with faster attenuation of the inflammatory response.⁸

Amato et al⁹ randomized 58 patients to receive mechanical ventilation with tidal volumes of either 6 mL/kg or 12 mL/kg. The PEEP level was maintained above the lower inflection point. At 28 days, 62% of the patients in the intervention group were still alive, compared with only 29% in the control group. However, many concerns were expressed over the high mortality rate in the control group.

Based on these studies, the use of low tidal volumes with appropriate levels of PEEP to ensure lung recruitment is the current standard of care in mechanical ventilation of patients with ARDS.¹⁰

APRV: A PRESSURE-CONTROLLED MODE THAT ALLOWS SPONTANEOUS BREATHS

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

A baseline high pressure (P high) is set first. Mandatory breaths are achieved by releasing the high baseline pressure in the circuit very briefly, usually to 0 cm H₂O (P low), which allows the lungs to partially deflate, and then quickly resuming the high pressure before the unstable alveoli can collapse.

In theory, the optimal release time (the very short time in low pressure, or T low) in APRV should be determined by the time constant of the expiratory flow. The time constant (t) is the time it takes to empty 63% of the lung volume. It is calculated as:

t = C × R

where C is the combined compliance of the lung and chest wall, and R is the combined resistance of the endotracheal tube and the natural airways. In diseases that lead to lower lung compliance (such as ARDS), the time constant is shorter. A practical equilibrium time—or the time it takes for the lung volume in expiration to reach steady state (no expiratory flow)—is about 4 time constants.¹⁴

Since the release time in APRV is much shorter than the equilibrium time, a residual volume of air remains in the lung, creating intentional auto-PEEP. Ideally, this intentional auto-PEEP should be high enough to avoid derecruitment (optimally above the lower inflection point). In APRV the auto-PEEP is controlled by the settings, and this intentional restriction of the expiratory flow is critical to avoid derecruitment of unstable alveolar units.

The amount of time spent at the higher pressure (T high) is generally 80% to 95% of the cycle (ie, the lungs are “inflated” 80% to 95% of the time), and the amount of time at the lower pressure (T low) is 0.6 to 0.8 seconds.

Thus, APRV settings provide a relatively high mean airway pressure, which prevents collapse of unstable alveoli and over time recruits additional alveolar units in the injured lung. The major difference between this mode and more conventional modes is that in APRV the mean inspiratory pressure is maximized and end-expiratory pressure is due to intentional auto-PEEP. In addition, spontaneous breathing is allowed throughout the entire cycle (Figure 2).¹³

Although APRV does not approximate the physiology of spontaneous breathing with healthy lungs, it is nonetheless relatively comfortable and well tolerated. Its theoretical advantage in patients with lung injury is its ability to maximize alveoli recruitment by maintaining a higher mean inspiratory pressure, while the peak alveolar pressure remains lower than with conventional ventilation (Figure 1).

Other modes that are similar to APRV

Other modes of mechanical ventilation very similar to APRV are biphasic positive airway pressure (BiPAP) and bilevel ventilation.

BiPAP differs from APRV only in the timing of the upper and lower pressure levels. In BiPAP, T high is usually shorter than T low. Therefore, in order to avoid derecruitment, P low has to be set above zero with both a high and a low PEEP level.¹³

No studies have demonstrated one mode to be more beneficial than the other, although BiPAP might be more predictable, as both pressures are known.

Bilevel ventilation works like APRV but incorporates pressure support to spontaneous breathing. The use of pressure support may affect the positive physiologic effects (see section below) of unsupported spontaneous breathing. Nevertheless, this strategy might be useful to address severe hypercapnia in the context of APRV.

INITIAL VENTILATOR SETTINGS IN APRV

P high. In selecting an initial P high, we measure the plateau pressure in a conventional mode using an accepted protective strategy, such as volume-control mode. If the plateau pressure is lower than 30 cm H₂O, we use this pressure as our initial P high. If the plateau pressure is higher than 30 cm H₂O, we select 30 cm H₂O as an initial P high to minimize peak alveolar pressure and reduce the risk of lung overdistention.

P low is set at 0 cm H₂O.

T high is set at 4 seconds and is then adjusted if necessary.

T low is probably the most difficult variable to set because it needs to be short enough to avoid derecruitment but still long enough to allow alveolar ventilation. We usually start with a T low of 0.6 to 0.8 seconds.

ADJUSTING THE VENTILATOR SETTINGS

For hypoxemia. Physician-controlled variables that affect oxygenation in APRV are:

• Mean airway pressure (dependent primarily on P high and T high)
• Fraction of inspired oxygen (Fio₂).

Inadequate oxygenation usually requires increasing one or both of these settings.

Physician-controlled variables that affect alveolar ventilation in the APRV mode are:

• Pressure gradient (P high minus P low)
• Airway pressure release time (T low)
• Airway pressure release frequency.¹⁴ Frequency is related to total cycle time of mandatory breaths by the following equation³:

frequency = 60/cycle time = 60/(T high + T low).

Note that if T low remains constant, adjusting T high will adjust frequency (the more time the lung remains inflated, the lower the respiratory frequency). Conversely, some ventilators allow adjustment of frequency, making T high the dependent variable. The goal of this mode is to recruit alveoli and improve oxygenation, so we usually do not modify the pressure gradient to improve ventilation.

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

For hypercapnia. A frequent and expected consequence of lung-protective ventilation strategies is hypercapnia, termed “permissive” hypercapnia because it is allowed to some extent. In APRV, some degree of CO₂ retention is not unusual. When the measured Paco₂ becomes extreme, we usually increase the frequency of releases by shortening T high, recognizing that this adjustment may affect recruitment by lowering the mean airway pressure.

Spontaneous breaths. A positive aspect of APRV that contributes to its tolerability for patients is that it allows for spontaneous respiration. In some studies of patients with ARDS ventilated with APRV, spontaneous breathing accounted for 10% to 30% of the total minute ventilation and was responsible for an improvement in ventilation-perfusion matching and oxygenation.^15,16 We titrate our patients’ sedation to a goal of spontaneous breathing of at least 10% of total minute ventilation.

WEANING FROM APRV

Weaning from APRV is done carefully to avoid derecruitment. Some authors recommend lowering P high by 2 to 3 cm H₂O at a time and lengthening T high by increments of 0.5 to 2.0 seconds.^13,17

Once P high is about 16 cm H₂O, T high is at 12 to 15 seconds, and spontaneous respiration accounts for most or all of the minute volume, the mode can be changed to continuous positive airway pressure (CPAP) and titrated downwards. Usually, when CPAP is at 5 to 10 cm H₂O, the patient is extubated, provided that mental status or concerns about airway protection or secretions are not contraindications.

PHYSIOLOGIC EFFECTS OF APRV WITH SPONTANEOUS BREATHING

Effects on the respiratory system

During spontaneous breathing, the greatest displacement of the diaphragm is in dependent regions. These regions are the best ventilated.¹⁸ Compared with spontaneously breathing patients, mechanically ventilated patients have a smaller inspiratory displacement of the dependent part of the lung.¹⁹

A study using computed tomography demonstrated that the reduction of lung volume observed in patients with acute lung injury (ALI) predominantly affects the lower lobes (dependent areas).²⁰ Causative mechanisms could be an increase in lung weight related to ALI and a passive collapse of the lower lobes associated with an upward shift of the diaphragm.

In a preliminary study, the topographic distribution of lung collapse was different in spontaneously breathing ARDS patients than in patients who were paralyzed. In particular, lung densities were not concentrated in the dependent regions in the former group.²¹

Oxygenation is better with APRV with spontaneous breathing than with mechanical ventilation alone. This effect is at least partly attributable to recruitment of collapsed lung tissue and increased aeration of the dependent areas of the lung.²²

Putensen et al¹⁵ compared ventilation-perfusion distribution in 24 patients with ARDS who were randomized to APRV with spontaneous breathing (more than 10% of the total minute ventilation), APRV without spontaneous breathing, or pressure-support ventilation. Spontaneous breathing during APRV improved ventilation-perfusion matching and increased systemic blood flow.

Neumann et al²³ recently compared the effect of APRV with spontaneous breathing vs APRV without spontaneous breathing in terms of ventilation perfusion in an animal model of lung injury. APRV with spontaneous breathing increased ventilation in juxta-diaphragmatic regions, predominantly in dependent areas. Spontaneous breathing had a significant effect on the spatial distribution of ventilation and pulmonary perfusion.

Based on these studies, we generally use APRV with no pressure support. This strategy permits recruitment and expansion of dependent lung areas.

Effects on the cardiovascular system and hemodynamics

Räsänen et al,²⁴ in an animal model, compared cardiovascular performance during APRV, spontaneous breathing, and continuous positive pressure ventilation. No significant differences in cardiovascular function were detected between APRV and spontaneous breathing. In contrast, continuous positive pressure ventilation decreased blood pressure, stroke volume, cardiac output, and oxygen delivery.

Falkenhain et al,²⁵ in a subsequent case report, found that a change in mode from intermittent mandatory ventilation with PEEP to APRV resulted in improvement in the cardiac output of a patient requiring mechanical ventilation.

The lack of deleterious effect of APRV on cardiovascular function is probably a result of its spontaneous breathing component. The reduction in mean intrathoracic pressure during spontaneous breathing (compared to paralysis) improves venous return and biventricular filling, boosting cardiac output and oxygen delivery.²⁶

Hering et al²⁷ compared APRV with spontaneous breathing (at least 30% of the total minute ventilation) vs APRV with no spontaneous breathing in 12 patients with ALI. This study showed higher renal blood flow, glomerular filtration, and osmolar clearance in the APRV-with-spontaneous-breathing group.

The same investigators evaluated the effects of spontaneous breathing with APRV on intestinal blood flow in an animal model of lung injury.²⁸ Spontaneous breathing with APRV improved arterial oxygenation, the systemic hemodynamic profile, and regional perfusion to the stomach and small bowel compared with full ventilatory support.

ANIMAL STUDIES OF APRV

Stock et al,¹¹ in their original description of APRV in 1987, reported experimental results in dogs. In that study, 10 dogs with and without ARDS were randomized to APRV with a custom-built device vs volume-control mode with a Harvard pump ventilator plus PEEP. APRV delivered adequate alveolar ventilation, had lower peak airway pressures, and promoted better arterial oxygenation (at the same tidal volume and mean airway pressure) compared with volume control.

Martin et al (1991)²⁹ studied seven neonatal lambs with ALI with four ventilatory modes: pressure-support ventilation, APRV, volume control, and spontaneous breathing. APRV maintained oxygenation while augmenting alveolar ventilation compared with pressure-support ventilation. APRV also provided ventilation at a lower peak pressure in contrast to volume control. The authors concluded that APRV was an effective mode to maintain oxygenation and assist alveolar ventilation with minimal cardiovascular impact in their animal model of ALI.

HUMAN STUDIES OF APRV

Garner et al (1988)³⁰ studied 14 patients after operative coronary revascularization, giving them volume control mode (12 mL/kg) and then, when they were hemodynamically stable, APRV. While APRV and volume control supported ventilation and arterial oxygenation equally in all cases, peak airway pressure was greater with volume control.

Räsänen et al (1991)³¹ designed a prospective, multicenter, crossover trial in which 50 patients with ALI were ventilated with conventional ventilation and subsequently with APRV. Patients in both groups were adequately ventilated and oxygenated. However, as described in the aforementioned study,²⁴ the peak airway pressure was lower in the APRV group.

Davis et al (1993)³² studied 15 patients with ARDS requiring ventilatory support who received intermittent mandatory ventilation plus PEEP and then were placed on APRV. Peak airway pressure was lower, but mean airway pressure was higher with APRV. There were no statistically significant differences in gas exchange or hemodynamic variables.

Putensen et al,³³ in a study designed on the basis of prior publications,¹⁵ randomized 30 patients with multiple trauma to either APRV with spontaneous breathing (n = 15) or pressure-control ventilation (n = 15) for 72 hours. Weaning was performed with APRV in both groups. APRV was associated with increases in lung compliance and oxygenation and reduction of shunting. Interestingly, the use of APRV was associated with shorter duration of ventilatory support (15 vs 21 days), shorter length of intensive care unit stay (23 vs 30 days), and shorter duration of sedation and use of vasopressors.

An important confounder in this trial was that all patients on pressure-control ventilation were initially paralyzed, favoring the APRV group.

Varpula and colleagues³⁴ performed a prospective randomized intervention study to determine whether the response of oxygenation to the prone position differed between APRV vs pressure-controlled synchronized intermittent mandatory ventilation with pressure support. Forty-five patients with ALI were randomized within 72 hours of initiation of mechanical ventilation to receive one of these two modes; 33 ultimately received the assigned treatment. All patients were positioned on their stomachs for 6 hours once or twice a day. The response in terms of oxygenation to the first pronation was similar in both groups, whereas there was a significant improvement after the second pronation in the APRV group. The authors concluded that prone positioning and allowance of spontaneous breathing during APRV had advantageous effects on gas exchange.

In 2004, the same investigators³⁵ randomized 58 patients with ALI after stabilization to either APRV or pressure-controlled synchronized intermittent mandatory ventilation. There were no significant differences in the clinically important outcomes such as ventilator-free days, sedation days, need of hemodialysis, or intensive care unit-free days.

Dart et al,³⁶ in a retrospective study of 46 trauma patients who were ventilated with APRV for 72 hours, found an improvement in the Pao₂/Fio₂ ratio and a decrement in peak airway pressure after APRV was started.

Table 2 summarizes the randomized clinical trials of APRV.^33–35,37

CONCERNS ABOUT APRV

Overstretching. One of the major concerns when applying APRV is overstretching the lung parenchyma.^26,38 It is important to recognize that, when choosing a P high setting, this variable is not the only determinant of the tidal volume. Spontaneous breathing causes the pleural pressure to become less positive. As a result, there is an increase in the transpulmonary pressure (pressure in alveoli minus pressure in the pleura). This augmentation of transpulmonary pressure will result in a higher tidal volume and the risk of overdistention and volume-induced lung injury.

Atelectrauma. As mentioned earlier, damage may occur when airways open and close with each tidal cycle. This is particularly worrisome when the end-expiratory pressure is below the lower inflection point, as some diseased alveolar units may collapse. In APRV, the airway pressure is released to zero. Even though the intentional auto-PEEP might maintain a certain end-expiratory pressure, this parameter is truly uncontrolled.³⁹

If the patient cannot breath spontaneously. Another consideration is that many of the benefits of APRV are based on the spontaneous breathing component. Unfortunately, patients who need heavy sedation or neuromuscular paralysis with lack of spontaneous breathing efforts may lose the physiologic advantages of this mode.

Despite these limitations, APRV presents many attractive benefits as an alternative mode of mechanical ventilation in patients who do not respond to conventional modes.

Table 3 summarizes the advantages and disadvantages of each component of APRV.

In the early stages of acute respiratory distress syndrome (ARDS), multiple areas of the lung collapse, most often in the dependent regions. A factor involved in this process is the loss of functional surfactant, creating a condition in which alveolar units are unstable and prone to collapse due to unopposed surface tension. This situation, similar to that in premature infants, results in a reduced volume of aerated lung, intrapulmonary shunting, and, therefore, poor oxygenation.

The treatment of this alveolar collapse is lung reinflation (or “recruitment,” a term first used by Lachmann).¹ Gattinoni et al² showed that the percentage of recruitable lung could range from a negligible fraction to 50% or more.

There are various means of reopening injured lungs and keeping them open. The choice of recruitment maneuver is based on the individual patient and the ventilatory mode.³

In this article, we review airway pressure release ventilation (APRV), a mode of mechanical ventilation that may be useful in situations in which, due to ARDS, the lungs need to be recruited and held open. APRV was developed as a lung-protective mode, allowing recruitment while minimizing ventilator-induced lung injury.

BASIC PRINCIPLES OF PROTECTIVE VENTILATION

This curve has two inflection points between which its slope is steep, indicating greater compliance or elasticity. Below the lower inflection point, the alveoli may collapse; above the upper inflection point, the lung loses its elastic properties and the alveoli are overdistended. To protect the lungs, the challenge in mechanical ventilation is to keep the lungs between these two points throughout the respiratory cycle.

Avoiding lung collapse by using PEEP

During mechanical ventilation, the pressure in the lungs is lowest, and thus the alveoli are most prone to collapse, at the end of expiration.

We want to prevent the alveoli from collapsing with each expiration and reopening with each inspiration, as this cycle of opening and closing damages them (causing atelectrauma, ie, cyclical atelectasis).⁴ Preventing it prevents the release of inflammatory mediators and the perpetuation of lung injury (biotrauma).⁵

The solution is to apply positive end-expiratory pressure (PEEP), taking into account the value of the lower inflection point when setting the PEEP level.

Villar et al⁶ compared outcomes in an intervention group that received a PEEP level 2 cm H₂O above the lower inflection point plus low tidal volumes, and in a control group that received higher tidal volumes and low PEEP (5 cm H₂O). The study was stopped early, after significantly more patients had died in the control group than in the intervention group (53% vs 32%, P = .04).

Avoiding overdistention by keeping the tidal volume low

Tidal volumes that exceed the upper inflection point overstretch the lung and induce volutrauma, which can manifest as pneumothorax or pneumomediastinum, or both—the lungs rupture like a balloon. Also, overdistention produces liberation of inflammatory mediators in the blood (biotrauma). High tidal volumes should therefore be avoided or limited as much as possible.

The ARDS Network,⁷ in a multicenter, randomized, controlled trial, showed that fewer patients die if they receive mechanical ventilation with low tidal volumes rather than higher, “conventional” tidal volumes. Patients were randomized to receive either a tidal volume of 6 mL/kg and a plateau pressure lower than 30 cm H₂O or a tidal volume of 12 mL/kg and a plateau pressure lower than 50 cm H₂O. They were followed for 180 days or until discharged home, breathing without assistance. A total of 861 patients were enrolled. The mortality rate was significantly lower in the low tidal volume group than in the group with conventional tidal volumes, 31% vs 40%.

Lower tidal volumes were also associated with faster attenuation of the inflammatory response.⁸

Amato et al⁹ randomized 58 patients to receive mechanical ventilation with tidal volumes of either 6 mL/kg or 12 mL/kg. The PEEP level was maintained above the lower inflection point. At 28 days, 62% of the patients in the intervention group were still alive, compared with only 29% in the control group. However, many concerns were expressed over the high mortality rate in the control group.

Based on these studies, the use of low tidal volumes with appropriate levels of PEEP to ensure lung recruitment is the current standard of care in mechanical ventilation of patients with ARDS.¹⁰

APRV: A PRESSURE-CONTROLLED MODE THAT ALLOWS SPONTANEOUS BREATHS

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

A baseline high pressure (P high) is set first. Mandatory breaths are achieved by releasing the high baseline pressure in the circuit very briefly, usually to 0 cm H₂O (P low), which allows the lungs to partially deflate, and then quickly resuming the high pressure before the unstable alveoli can collapse.

In theory, the optimal release time (the very short time in low pressure, or T low) in APRV should be determined by the time constant of the expiratory flow. The time constant (t) is the time it takes to empty 63% of the lung volume. It is calculated as:

t = C × R

where C is the combined compliance of the lung and chest wall, and R is the combined resistance of the endotracheal tube and the natural airways. In diseases that lead to lower lung compliance (such as ARDS), the time constant is shorter. A practical equilibrium time—or the time it takes for the lung volume in expiration to reach steady state (no expiratory flow)—is about 4 time constants.¹⁴

Since the release time in APRV is much shorter than the equilibrium time, a residual volume of air remains in the lung, creating intentional auto-PEEP. Ideally, this intentional auto-PEEP should be high enough to avoid derecruitment (optimally above the lower inflection point). In APRV the auto-PEEP is controlled by the settings, and this intentional restriction of the expiratory flow is critical to avoid derecruitment of unstable alveolar units.

The amount of time spent at the higher pressure (T high) is generally 80% to 95% of the cycle (ie, the lungs are “inflated” 80% to 95% of the time), and the amount of time at the lower pressure (T low) is 0.6 to 0.8 seconds.

Thus, APRV settings provide a relatively high mean airway pressure, which prevents collapse of unstable alveoli and over time recruits additional alveolar units in the injured lung. The major difference between this mode and more conventional modes is that in APRV the mean inspiratory pressure is maximized and end-expiratory pressure is due to intentional auto-PEEP. In addition, spontaneous breathing is allowed throughout the entire cycle (Figure 2).¹³

Although APRV does not approximate the physiology of spontaneous breathing with healthy lungs, it is nonetheless relatively comfortable and well tolerated. Its theoretical advantage in patients with lung injury is its ability to maximize alveoli recruitment by maintaining a higher mean inspiratory pressure, while the peak alveolar pressure remains lower than with conventional ventilation (Figure 1).

Other modes that are similar to APRV

Other modes of mechanical ventilation very similar to APRV are biphasic positive airway pressure (BiPAP) and bilevel ventilation.

BiPAP differs from APRV only in the timing of the upper and lower pressure levels. In BiPAP, T high is usually shorter than T low. Therefore, in order to avoid derecruitment, P low has to be set above zero with both a high and a low PEEP level.¹³

No studies have demonstrated one mode to be more beneficial than the other, although BiPAP might be more predictable, as both pressures are known.

Bilevel ventilation works like APRV but incorporates pressure support to spontaneous breathing. The use of pressure support may affect the positive physiologic effects (see section below) of unsupported spontaneous breathing. Nevertheless, this strategy might be useful to address severe hypercapnia in the context of APRV.

INITIAL VENTILATOR SETTINGS IN APRV

P high. In selecting an initial P high, we measure the plateau pressure in a conventional mode using an accepted protective strategy, such as volume-control mode. If the plateau pressure is lower than 30 cm H₂O, we use this pressure as our initial P high. If the plateau pressure is higher than 30 cm H₂O, we select 30 cm H₂O as an initial P high to minimize peak alveolar pressure and reduce the risk of lung overdistention.

P low is set at 0 cm H₂O.

T high is set at 4 seconds and is then adjusted if necessary.

T low is probably the most difficult variable to set because it needs to be short enough to avoid derecruitment but still long enough to allow alveolar ventilation. We usually start with a T low of 0.6 to 0.8 seconds.

ADJUSTING THE VENTILATOR SETTINGS

For hypoxemia. Physician-controlled variables that affect oxygenation in APRV are:

• Mean airway pressure (dependent primarily on P high and T high)
• Fraction of inspired oxygen (Fio₂).

Inadequate oxygenation usually requires increasing one or both of these settings.

Physician-controlled variables that affect alveolar ventilation in the APRV mode are:

• Pressure gradient (P high minus P low)
• Airway pressure release time (T low)
• Airway pressure release frequency.¹⁴ Frequency is related to total cycle time of mandatory breaths by the following equation³:

frequency = 60/cycle time = 60/(T high + T low).

Note that if T low remains constant, adjusting T high will adjust frequency (the more time the lung remains inflated, the lower the respiratory frequency). Conversely, some ventilators allow adjustment of frequency, making T high the dependent variable. The goal of this mode is to recruit alveoli and improve oxygenation, so we usually do not modify the pressure gradient to improve ventilation.

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

For hypercapnia. A frequent and expected consequence of lung-protective ventilation strategies is hypercapnia, termed “permissive” hypercapnia because it is allowed to some extent. In APRV, some degree of CO₂ retention is not unusual. When the measured Paco₂ becomes extreme, we usually increase the frequency of releases by shortening T high, recognizing that this adjustment may affect recruitment by lowering the mean airway pressure.

Spontaneous breaths. A positive aspect of APRV that contributes to its tolerability for patients is that it allows for spontaneous respiration. In some studies of patients with ARDS ventilated with APRV, spontaneous breathing accounted for 10% to 30% of the total minute ventilation and was responsible for an improvement in ventilation-perfusion matching and oxygenation.^15,16 We titrate our patients’ sedation to a goal of spontaneous breathing of at least 10% of total minute ventilation.

WEANING FROM APRV

Weaning from APRV is done carefully to avoid derecruitment. Some authors recommend lowering P high by 2 to 3 cm H₂O at a time and lengthening T high by increments of 0.5 to 2.0 seconds.^13,17

Once P high is about 16 cm H₂O, T high is at 12 to 15 seconds, and spontaneous respiration accounts for most or all of the minute volume, the mode can be changed to continuous positive airway pressure (CPAP) and titrated downwards. Usually, when CPAP is at 5 to 10 cm H₂O, the patient is extubated, provided that mental status or concerns about airway protection or secretions are not contraindications.

PHYSIOLOGIC EFFECTS OF APRV WITH SPONTANEOUS BREATHING

Effects on the respiratory system

During spontaneous breathing, the greatest displacement of the diaphragm is in dependent regions. These regions are the best ventilated.¹⁸ Compared with spontaneously breathing patients, mechanically ventilated patients have a smaller inspiratory displacement of the dependent part of the lung.¹⁹

A study using computed tomography demonstrated that the reduction of lung volume observed in patients with acute lung injury (ALI) predominantly affects the lower lobes (dependent areas).²⁰ Causative mechanisms could be an increase in lung weight related to ALI and a passive collapse of the lower lobes associated with an upward shift of the diaphragm.

In a preliminary study, the topographic distribution of lung collapse was different in spontaneously breathing ARDS patients than in patients who were paralyzed. In particular, lung densities were not concentrated in the dependent regions in the former group.²¹

Oxygenation is better with APRV with spontaneous breathing than with mechanical ventilation alone. This effect is at least partly attributable to recruitment of collapsed lung tissue and increased aeration of the dependent areas of the lung.²²

Putensen et al¹⁵ compared ventilation-perfusion distribution in 24 patients with ARDS who were randomized to APRV with spontaneous breathing (more than 10% of the total minute ventilation), APRV without spontaneous breathing, or pressure-support ventilation. Spontaneous breathing during APRV improved ventilation-perfusion matching and increased systemic blood flow.

Neumann et al²³ recently compared the effect of APRV with spontaneous breathing vs APRV without spontaneous breathing in terms of ventilation perfusion in an animal model of lung injury. APRV with spontaneous breathing increased ventilation in juxta-diaphragmatic regions, predominantly in dependent areas. Spontaneous breathing had a significant effect on the spatial distribution of ventilation and pulmonary perfusion.

Based on these studies, we generally use APRV with no pressure support. This strategy permits recruitment and expansion of dependent lung areas.

Effects on the cardiovascular system and hemodynamics

Räsänen et al,²⁴ in an animal model, compared cardiovascular performance during APRV, spontaneous breathing, and continuous positive pressure ventilation. No significant differences in cardiovascular function were detected between APRV and spontaneous breathing. In contrast, continuous positive pressure ventilation decreased blood pressure, stroke volume, cardiac output, and oxygen delivery.

Falkenhain et al,²⁵ in a subsequent case report, found that a change in mode from intermittent mandatory ventilation with PEEP to APRV resulted in improvement in the cardiac output of a patient requiring mechanical ventilation.

The lack of deleterious effect of APRV on cardiovascular function is probably a result of its spontaneous breathing component. The reduction in mean intrathoracic pressure during spontaneous breathing (compared to paralysis) improves venous return and biventricular filling, boosting cardiac output and oxygen delivery.²⁶

Hering et al²⁷ compared APRV with spontaneous breathing (at least 30% of the total minute ventilation) vs APRV with no spontaneous breathing in 12 patients with ALI. This study showed higher renal blood flow, glomerular filtration, and osmolar clearance in the APRV-with-spontaneous-breathing group.

The same investigators evaluated the effects of spontaneous breathing with APRV on intestinal blood flow in an animal model of lung injury.²⁸ Spontaneous breathing with APRV improved arterial oxygenation, the systemic hemodynamic profile, and regional perfusion to the stomach and small bowel compared with full ventilatory support.

ANIMAL STUDIES OF APRV

Stock et al,¹¹ in their original description of APRV in 1987, reported experimental results in dogs. In that study, 10 dogs with and without ARDS were randomized to APRV with a custom-built device vs volume-control mode with a Harvard pump ventilator plus PEEP. APRV delivered adequate alveolar ventilation, had lower peak airway pressures, and promoted better arterial oxygenation (at the same tidal volume and mean airway pressure) compared with volume control.

Martin et al (1991)²⁹ studied seven neonatal lambs with ALI with four ventilatory modes: pressure-support ventilation, APRV, volume control, and spontaneous breathing. APRV maintained oxygenation while augmenting alveolar ventilation compared with pressure-support ventilation. APRV also provided ventilation at a lower peak pressure in contrast to volume control. The authors concluded that APRV was an effective mode to maintain oxygenation and assist alveolar ventilation with minimal cardiovascular impact in their animal model of ALI.

HUMAN STUDIES OF APRV

Garner et al (1988)³⁰ studied 14 patients after operative coronary revascularization, giving them volume control mode (12 mL/kg) and then, when they were hemodynamically stable, APRV. While APRV and volume control supported ventilation and arterial oxygenation equally in all cases, peak airway pressure was greater with volume control.

Räsänen et al (1991)³¹ designed a prospective, multicenter, crossover trial in which 50 patients with ALI were ventilated with conventional ventilation and subsequently with APRV. Patients in both groups were adequately ventilated and oxygenated. However, as described in the aforementioned study,²⁴ the peak airway pressure was lower in the APRV group.

Davis et al (1993)³² studied 15 patients with ARDS requiring ventilatory support who received intermittent mandatory ventilation plus PEEP and then were placed on APRV. Peak airway pressure was lower, but mean airway pressure was higher with APRV. There were no statistically significant differences in gas exchange or hemodynamic variables.

Putensen et al,³³ in a study designed on the basis of prior publications,¹⁵ randomized 30 patients with multiple trauma to either APRV with spontaneous breathing (n = 15) or pressure-control ventilation (n = 15) for 72 hours. Weaning was performed with APRV in both groups. APRV was associated with increases in lung compliance and oxygenation and reduction of shunting. Interestingly, the use of APRV was associated with shorter duration of ventilatory support (15 vs 21 days), shorter length of intensive care unit stay (23 vs 30 days), and shorter duration of sedation and use of vasopressors.

An important confounder in this trial was that all patients on pressure-control ventilation were initially paralyzed, favoring the APRV group.

Varpula and colleagues³⁴ performed a prospective randomized intervention study to determine whether the response of oxygenation to the prone position differed between APRV vs pressure-controlled synchronized intermittent mandatory ventilation with pressure support. Forty-five patients with ALI were randomized within 72 hours of initiation of mechanical ventilation to receive one of these two modes; 33 ultimately received the assigned treatment. All patients were positioned on their stomachs for 6 hours once or twice a day. The response in terms of oxygenation to the first pronation was similar in both groups, whereas there was a significant improvement after the second pronation in the APRV group. The authors concluded that prone positioning and allowance of spontaneous breathing during APRV had advantageous effects on gas exchange.

In 2004, the same investigators³⁵ randomized 58 patients with ALI after stabilization to either APRV or pressure-controlled synchronized intermittent mandatory ventilation. There were no significant differences in the clinically important outcomes such as ventilator-free days, sedation days, need of hemodialysis, or intensive care unit-free days.

Dart et al,³⁶ in a retrospective study of 46 trauma patients who were ventilated with APRV for 72 hours, found an improvement in the Pao₂/Fio₂ ratio and a decrement in peak airway pressure after APRV was started.

Table 2 summarizes the randomized clinical trials of APRV.^33–35,37

CONCERNS ABOUT APRV

Overstretching. One of the major concerns when applying APRV is overstretching the lung parenchyma.^26,38 It is important to recognize that, when choosing a P high setting, this variable is not the only determinant of the tidal volume. Spontaneous breathing causes the pleural pressure to become less positive. As a result, there is an increase in the transpulmonary pressure (pressure in alveoli minus pressure in the pleura). This augmentation of transpulmonary pressure will result in a higher tidal volume and the risk of overdistention and volume-induced lung injury.

Atelectrauma. As mentioned earlier, damage may occur when airways open and close with each tidal cycle. This is particularly worrisome when the end-expiratory pressure is below the lower inflection point, as some diseased alveolar units may collapse. In APRV, the airway pressure is released to zero. Even though the intentional auto-PEEP might maintain a certain end-expiratory pressure, this parameter is truly uncontrolled.³⁹

If the patient cannot breath spontaneously. Another consideration is that many of the benefits of APRV are based on the spontaneous breathing component. Unfortunately, patients who need heavy sedation or neuromuscular paralysis with lack of spontaneous breathing efforts may lose the physiologic advantages of this mode.

Despite these limitations, APRV presents many attractive benefits as an alternative mode of mechanical ventilation in patients who do not respond to conventional modes.

Table 3 summarizes the advantages and disadvantages of each component of APRV.

In the early stages of acute respiratory distress syndrome (ARDS), multiple areas of the lung collapse, most often in the dependent regions. A factor involved in this process is the loss of functional surfactant, creating a condition in which alveolar units are unstable and prone to collapse due to unopposed surface tension. This situation, similar to that in premature infants, results in a reduced volume of aerated lung, intrapulmonary shunting, and, therefore, poor oxygenation.

The treatment of this alveolar collapse is lung reinflation (or “recruitment,” a term first used by Lachmann).¹ Gattinoni et al² showed that the percentage of recruitable lung could range from a negligible fraction to 50% or more.

There are various means of reopening injured lungs and keeping them open. The choice of recruitment maneuver is based on the individual patient and the ventilatory mode.³

In this article, we review airway pressure release ventilation (APRV), a mode of mechanical ventilation that may be useful in situations in which, due to ARDS, the lungs need to be recruited and held open. APRV was developed as a lung-protective mode, allowing recruitment while minimizing ventilator-induced lung injury.

BASIC PRINCIPLES OF PROTECTIVE VENTILATION

This curve has two inflection points between which its slope is steep, indicating greater compliance or elasticity. Below the lower inflection point, the alveoli may collapse; above the upper inflection point, the lung loses its elastic properties and the alveoli are overdistended. To protect the lungs, the challenge in mechanical ventilation is to keep the lungs between these two points throughout the respiratory cycle.

Avoiding lung collapse by using PEEP

During mechanical ventilation, the pressure in the lungs is lowest, and thus the alveoli are most prone to collapse, at the end of expiration.

We want to prevent the alveoli from collapsing with each expiration and reopening with each inspiration, as this cycle of opening and closing damages them (causing atelectrauma, ie, cyclical atelectasis).⁴ Preventing it prevents the release of inflammatory mediators and the perpetuation of lung injury (biotrauma).⁵

The solution is to apply positive end-expiratory pressure (PEEP), taking into account the value of the lower inflection point when setting the PEEP level.

Villar et al⁶ compared outcomes in an intervention group that received a PEEP level 2 cm H₂O above the lower inflection point plus low tidal volumes, and in a control group that received higher tidal volumes and low PEEP (5 cm H₂O). The study was stopped early, after significantly more patients had died in the control group than in the intervention group (53% vs 32%, P = .04).

Avoiding overdistention by keeping the tidal volume low

Tidal volumes that exceed the upper inflection point overstretch the lung and induce volutrauma, which can manifest as pneumothorax or pneumomediastinum, or both—the lungs rupture like a balloon. Also, overdistention produces liberation of inflammatory mediators in the blood (biotrauma). High tidal volumes should therefore be avoided or limited as much as possible.

The ARDS Network,⁷ in a multicenter, randomized, controlled trial, showed that fewer patients die if they receive mechanical ventilation with low tidal volumes rather than higher, “conventional” tidal volumes. Patients were randomized to receive either a tidal volume of 6 mL/kg and a plateau pressure lower than 30 cm H₂O or a tidal volume of 12 mL/kg and a plateau pressure lower than 50 cm H₂O. They were followed for 180 days or until discharged home, breathing without assistance. A total of 861 patients were enrolled. The mortality rate was significantly lower in the low tidal volume group than in the group with conventional tidal volumes, 31% vs 40%.

Lower tidal volumes were also associated with faster attenuation of the inflammatory response.⁸

Amato et al⁹ randomized 58 patients to receive mechanical ventilation with tidal volumes of either 6 mL/kg or 12 mL/kg. The PEEP level was maintained above the lower inflection point. At 28 days, 62% of the patients in the intervention group were still alive, compared with only 29% in the control group. However, many concerns were expressed over the high mortality rate in the control group.

Based on these studies, the use of low tidal volumes with appropriate levels of PEEP to ensure lung recruitment is the current standard of care in mechanical ventilation of patients with ARDS.¹⁰

APRV: A PRESSURE-CONTROLLED MODE THAT ALLOWS SPONTANEOUS BREATHS

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

A baseline high pressure (P high) is set first. Mandatory breaths are achieved by releasing the high baseline pressure in the circuit very briefly, usually to 0 cm H₂O (P low), which allows the lungs to partially deflate, and then quickly resuming the high pressure before the unstable alveoli can collapse.

In theory, the optimal release time (the very short time in low pressure, or T low) in APRV should be determined by the time constant of the expiratory flow. The time constant (t) is the time it takes to empty 63% of the lung volume. It is calculated as:

t = C × R

where C is the combined compliance of the lung and chest wall, and R is the combined resistance of the endotracheal tube and the natural airways. In diseases that lead to lower lung compliance (such as ARDS), the time constant is shorter. A practical equilibrium time—or the time it takes for the lung volume in expiration to reach steady state (no expiratory flow)—is about 4 time constants.¹⁴

Since the release time in APRV is much shorter than the equilibrium time, a residual volume of air remains in the lung, creating intentional auto-PEEP. Ideally, this intentional auto-PEEP should be high enough to avoid derecruitment (optimally above the lower inflection point). In APRV the auto-PEEP is controlled by the settings, and this intentional restriction of the expiratory flow is critical to avoid derecruitment of unstable alveolar units.

The amount of time spent at the higher pressure (T high) is generally 80% to 95% of the cycle (ie, the lungs are “inflated” 80% to 95% of the time), and the amount of time at the lower pressure (T low) is 0.6 to 0.8 seconds.

Thus, APRV settings provide a relatively high mean airway pressure, which prevents collapse of unstable alveoli and over time recruits additional alveolar units in the injured lung. The major difference between this mode and more conventional modes is that in APRV the mean inspiratory pressure is maximized and end-expiratory pressure is due to intentional auto-PEEP. In addition, spontaneous breathing is allowed throughout the entire cycle (Figure 2).¹³

Although APRV does not approximate the physiology of spontaneous breathing with healthy lungs, it is nonetheless relatively comfortable and well tolerated. Its theoretical advantage in patients with lung injury is its ability to maximize alveoli recruitment by maintaining a higher mean inspiratory pressure, while the peak alveolar pressure remains lower than with conventional ventilation (Figure 1).

Other modes that are similar to APRV

Other modes of mechanical ventilation very similar to APRV are biphasic positive airway pressure (BiPAP) and bilevel ventilation.

BiPAP differs from APRV only in the timing of the upper and lower pressure levels. In BiPAP, T high is usually shorter than T low. Therefore, in order to avoid derecruitment, P low has to be set above zero with both a high and a low PEEP level.¹³

No studies have demonstrated one mode to be more beneficial than the other, although BiPAP might be more predictable, as both pressures are known.

Bilevel ventilation works like APRV but incorporates pressure support to spontaneous breathing. The use of pressure support may affect the positive physiologic effects (see section below) of unsupported spontaneous breathing. Nevertheless, this strategy might be useful to address severe hypercapnia in the context of APRV.

INITIAL VENTILATOR SETTINGS IN APRV

P high. In selecting an initial P high, we measure the plateau pressure in a conventional mode using an accepted protective strategy, such as volume-control mode. If the plateau pressure is lower than 30 cm H₂O, we use this pressure as our initial P high. If the plateau pressure is higher than 30 cm H₂O, we select 30 cm H₂O as an initial P high to minimize peak alveolar pressure and reduce the risk of lung overdistention.

P low is set at 0 cm H₂O.

T high is set at 4 seconds and is then adjusted if necessary.

T low is probably the most difficult variable to set because it needs to be short enough to avoid derecruitment but still long enough to allow alveolar ventilation. We usually start with a T low of 0.6 to 0.8 seconds.

ADJUSTING THE VENTILATOR SETTINGS

For hypoxemia. Physician-controlled variables that affect oxygenation in APRV are:

• Mean airway pressure (dependent primarily on P high and T high)
• Fraction of inspired oxygen (Fio₂).

Inadequate oxygenation usually requires increasing one or both of these settings.

Physician-controlled variables that affect alveolar ventilation in the APRV mode are:

• Pressure gradient (P high minus P low)
• Airway pressure release time (T low)
• Airway pressure release frequency.¹⁴ Frequency is related to total cycle time of mandatory breaths by the following equation³:

frequency = 60/cycle time = 60/(T high + T low).

Note that if T low remains constant, adjusting T high will adjust frequency (the more time the lung remains inflated, the lower the respiratory frequency). Conversely, some ventilators allow adjustment of frequency, making T high the dependent variable. The goal of this mode is to recruit alveoli and improve oxygenation, so we usually do not modify the pressure gradient to improve ventilation.

Reprinted from Frawley PM, Habashi NM. Airway pressure release ventilation: theory and practice. AACN Clinical Issues 2001; 12:234–246, with permission from Wolters Kluwer Health/Lippincott, Williams &amp; Wilkins.

For hypercapnia. A frequent and expected consequence of lung-protective ventilation strategies is hypercapnia, termed “permissive” hypercapnia because it is allowed to some extent. In APRV, some degree of CO₂ retention is not unusual. When the measured Paco₂ becomes extreme, we usually increase the frequency of releases by shortening T high, recognizing that this adjustment may affect recruitment by lowering the mean airway pressure.

Spontaneous breaths. A positive aspect of APRV that contributes to its tolerability for patients is that it allows for spontaneous respiration. In some studies of patients with ARDS ventilated with APRV, spontaneous breathing accounted for 10% to 30% of the total minute ventilation and was responsible for an improvement in ventilation-perfusion matching and oxygenation.^15,16 We titrate our patients’ sedation to a goal of spontaneous breathing of at least 10% of total minute ventilation.

WEANING FROM APRV

Weaning from APRV is done carefully to avoid derecruitment. Some authors recommend lowering P high by 2 to 3 cm H₂O at a time and lengthening T high by increments of 0.5 to 2.0 seconds.^13,17

Once P high is about 16 cm H₂O, T high is at 12 to 15 seconds, and spontaneous respiration accounts for most or all of the minute volume, the mode can be changed to continuous positive airway pressure (CPAP) and titrated downwards. Usually, when CPAP is at 5 to 10 cm H₂O, the patient is extubated, provided that mental status or concerns about airway protection or secretions are not contraindications.

PHYSIOLOGIC EFFECTS OF APRV WITH SPONTANEOUS BREATHING

Effects on the respiratory system

During spontaneous breathing, the greatest displacement of the diaphragm is in dependent regions. These regions are the best ventilated.¹⁸ Compared with spontaneously breathing patients, mechanically ventilated patients have a smaller inspiratory displacement of the dependent part of the lung.¹⁹

A study using computed tomography demonstrated that the reduction of lung volume observed in patients with acute lung injury (ALI) predominantly affects the lower lobes (dependent areas).²⁰ Causative mechanisms could be an increase in lung weight related to ALI and a passive collapse of the lower lobes associated with an upward shift of the diaphragm.

In a preliminary study, the topographic distribution of lung collapse was different in spontaneously breathing ARDS patients than in patients who were paralyzed. In particular, lung densities were not concentrated in the dependent regions in the former group.²¹

Oxygenation is better with APRV with spontaneous breathing than with mechanical ventilation alone. This effect is at least partly attributable to recruitment of collapsed lung tissue and increased aeration of the dependent areas of the lung.²²

Putensen et al¹⁵ compared ventilation-perfusion distribution in 24 patients with ARDS who were randomized to APRV with spontaneous breathing (more than 10% of the total minute ventilation), APRV without spontaneous breathing, or pressure-support ventilation. Spontaneous breathing during APRV improved ventilation-perfusion matching and increased systemic blood flow.

Neumann et al²³ recently compared the effect of APRV with spontaneous breathing vs APRV without spontaneous breathing in terms of ventilation perfusion in an animal model of lung injury. APRV with spontaneous breathing increased ventilation in juxta-diaphragmatic regions, predominantly in dependent areas. Spontaneous breathing had a significant effect on the spatial distribution of ventilation and pulmonary perfusion.

Based on these studies, we generally use APRV with no pressure support. This strategy permits recruitment and expansion of dependent lung areas.

Effects on the cardiovascular system and hemodynamics

Räsänen et al,²⁴ in an animal model, compared cardiovascular performance during APRV, spontaneous breathing, and continuous positive pressure ventilation. No significant differences in cardiovascular function were detected between APRV and spontaneous breathing. In contrast, continuous positive pressure ventilation decreased blood pressure, stroke volume, cardiac output, and oxygen delivery.

Falkenhain et al,²⁵ in a subsequent case report, found that a change in mode from intermittent mandatory ventilation with PEEP to APRV resulted in improvement in the cardiac output of a patient requiring mechanical ventilation.

The lack of deleterious effect of APRV on cardiovascular function is probably a result of its spontaneous breathing component. The reduction in mean intrathoracic pressure during spontaneous breathing (compared to paralysis) improves venous return and biventricular filling, boosting cardiac output and oxygen delivery.²⁶

Hering et al²⁷ compared APRV with spontaneous breathing (at least 30% of the total minute ventilation) vs APRV with no spontaneous breathing in 12 patients with ALI. This study showed higher renal blood flow, glomerular filtration, and osmolar clearance in the APRV-with-spontaneous-breathing group.

The same investigators evaluated the effects of spontaneous breathing with APRV on intestinal blood flow in an animal model of lung injury.²⁸ Spontaneous breathing with APRV improved arterial oxygenation, the systemic hemodynamic profile, and regional perfusion to the stomach and small bowel compared with full ventilatory support.

ANIMAL STUDIES OF APRV

Stock et al,¹¹ in their original description of APRV in 1987, reported experimental results in dogs. In that study, 10 dogs with and without ARDS were randomized to APRV with a custom-built device vs volume-control mode with a Harvard pump ventilator plus PEEP. APRV delivered adequate alveolar ventilation, had lower peak airway pressures, and promoted better arterial oxygenation (at the same tidal volume and mean airway pressure) compared with volume control.

Martin et al (1991)²⁹ studied seven neonatal lambs with ALI with four ventilatory modes: pressure-support ventilation, APRV, volume control, and spontaneous breathing. APRV maintained oxygenation while augmenting alveolar ventilation compared with pressure-support ventilation. APRV also provided ventilation at a lower peak pressure in contrast to volume control. The authors concluded that APRV was an effective mode to maintain oxygenation and assist alveolar ventilation with minimal cardiovascular impact in their animal model of ALI.

HUMAN STUDIES OF APRV

Garner et al (1988)³⁰ studied 14 patients after operative coronary revascularization, giving them volume control mode (12 mL/kg) and then, when they were hemodynamically stable, APRV. While APRV and volume control supported ventilation and arterial oxygenation equally in all cases, peak airway pressure was greater with volume control.

Räsänen et al (1991)³¹ designed a prospective, multicenter, crossover trial in which 50 patients with ALI were ventilated with conventional ventilation and subsequently with APRV. Patients in both groups were adequately ventilated and oxygenated. However, as described in the aforementioned study,²⁴ the peak airway pressure was lower in the APRV group.

Davis et al (1993)³² studied 15 patients with ARDS requiring ventilatory support who received intermittent mandatory ventilation plus PEEP and then were placed on APRV. Peak airway pressure was lower, but mean airway pressure was higher with APRV. There were no statistically significant differences in gas exchange or hemodynamic variables.

Putensen et al,³³ in a study designed on the basis of prior publications,¹⁵ randomized 30 patients with multiple trauma to either APRV with spontaneous breathing (n = 15) or pressure-control ventilation (n = 15) for 72 hours. Weaning was performed with APRV in both groups. APRV was associated with increases in lung compliance and oxygenation and reduction of shunting. Interestingly, the use of APRV was associated with shorter duration of ventilatory support (15 vs 21 days), shorter length of intensive care unit stay (23 vs 30 days), and shorter duration of sedation and use of vasopressors.

An important confounder in this trial was that all patients on pressure-control ventilation were initially paralyzed, favoring the APRV group.

Varpula and colleagues³⁴ performed a prospective randomized intervention study to determine whether the response of oxygenation to the prone position differed between APRV vs pressure-controlled synchronized intermittent mandatory ventilation with pressure support. Forty-five patients with ALI were randomized within 72 hours of initiation of mechanical ventilation to receive one of these two modes; 33 ultimately received the assigned treatment. All patients were positioned on their stomachs for 6 hours once or twice a day. The response in terms of oxygenation to the first pronation was similar in both groups, whereas there was a significant improvement after the second pronation in the APRV group. The authors concluded that prone positioning and allowance of spontaneous breathing during APRV had advantageous effects on gas exchange.

In 2004, the same investigators³⁵ randomized 58 patients with ALI after stabilization to either APRV or pressure-controlled synchronized intermittent mandatory ventilation. There were no significant differences in the clinically important outcomes such as ventilator-free days, sedation days, need of hemodialysis, or intensive care unit-free days.

Dart et al,³⁶ in a retrospective study of 46 trauma patients who were ventilated with APRV for 72 hours, found an improvement in the Pao₂/Fio₂ ratio and a decrement in peak airway pressure after APRV was started.

Table 2 summarizes the randomized clinical trials of APRV.^33–35,37

CONCERNS ABOUT APRV

Overstretching. One of the major concerns when applying APRV is overstretching the lung parenchyma.^26,38 It is important to recognize that, when choosing a P high setting, this variable is not the only determinant of the tidal volume. Spontaneous breathing causes the pleural pressure to become less positive. As a result, there is an increase in the transpulmonary pressure (pressure in alveoli minus pressure in the pleura). This augmentation of transpulmonary pressure will result in a higher tidal volume and the risk of overdistention and volume-induced lung injury.

Atelectrauma. As mentioned earlier, damage may occur when airways open and close with each tidal cycle. This is particularly worrisome when the end-expiratory pressure is below the lower inflection point, as some diseased alveolar units may collapse. In APRV, the airway pressure is released to zero. Even though the intentional auto-PEEP might maintain a certain end-expiratory pressure, this parameter is truly uncontrolled.³⁹

If the patient cannot breath spontaneously. Another consideration is that many of the benefits of APRV are based on the spontaneous breathing component. Unfortunately, patients who need heavy sedation or neuromuscular paralysis with lack of spontaneous breathing efforts may lose the physiologic advantages of this mode.

Despite these limitations, APRV presents many attractive benefits as an alternative mode of mechanical ventilation in patients who do not respond to conventional modes.

Table 3 summarizes the advantages and disadvantages of each component of APRV.