Suicidal behavior is a major cause of morbidity and mortality in the United States,1 and active-duty and reserve military personnel and veterans account for nearly 18% of suicide deaths.² By one estimate, as many as 22 veterans die by suicide each day.³ These rates are thought to be due to a higher incidence of mental illness in certain veteran populations relative to the general population.^4–8 Consequently, a number of mental health services are available to veterans in a variety of clinical and community settings.

See related commentary

Chaplains and clinicians bring complementary skills and services to the problem of suicide risk among veterans. In particular, helping at-risk veterans deal with experiences of guilt is an opportunity for interdisciplinary collaboration. Available literature supports the potential utility of chaplaincy services in supporting at-risk veteran populations.^9–15

But while most healthcare facilities have chaplains on staff, there is little information to guide any such collaboration. Further, healthcare providers appear to have a limited understanding of chaplaincy services, the “language” within which chaplains operate, or the roles chaplains play in healthcare settings.¹⁶

In the following discussion, using the example of experiences of guilt, we offer our insights and suggestions on how chaplaincy services may prove useful in alleviating this complex emotion in veterans at risk of suicide.

BENEFITS OF TALKING TO A CHAPLAIN

By one estimate, as many as 22 veterans die by suicide each day

Collaboration between healthcare providers and pastoral care professionals has been suggested as a means of enhancing the treatment of patients with mental illness.^17,18 Chaplains draw from a variety of faith traditions and are usually trained to respond to the needs of people from a variety of religious and spiritual backgrounds. They provide some non-faith­based services (eg, crisis intervention, life review, bereavement counseling) resembling those also provided in formal mental healthcare settings.¹⁹ By facilitating religious and spiritual coping and religious practice and responding to religious and spiritual needs, chaplains also offer a level of support not typically offered by formal mental healthcare providers.²⁰

Veterans at risk of suicide sometimes look to pastoral care providers, particularly chaplains, for mental health support.^9,10 Research on the effects of chaplaincy services on suicidal behavior is just beginning to emerge.¹⁵ Still, the US Department of Health and Human Services has recognized pastoral care services as having a “beneficial and therapeutic effect on the medical condition of a patient.”¹¹

For example, in one study, hospital inpatients reported higher satisfaction if they had been visited by a chaplain.¹² Chaplains help align treatment plans with patient values and wishes.¹³ In another study,¹⁴ patients undergoing coronary artery bypass grafting who were randomized to receive five visits from a chaplain were found to have a higher rate of positive religious coping (eg, forgiveness, letting go of anger). Positive religious coping has been correlated with lower levels of psychological stress and better mental health outcomes.

EXPERIENCING GUILT IS LINKED TO RISK OF SUICIDE

Suicidal behavior is complex, multifaceted, and linked to genetic, neurologic, psychological, social, and cultural factors.²¹

Assessing for and addressing certain complex emotions, such as guilt and shame, is an important part of suicide prevention efforts. Guilt is defined as a “controllable psychological state that is typically linked to a specific action or behavior, and which entails regret or remorse.”²²

Close to 75% of veterans who had thought about suicide said they frequently experienced guilt

Guilt has been linked to risk of suicide in veterans.^23–25 In one study, close to 75% of veterans who had thought about suicide said they frequently experienced guilt about having violated the precepts of their faith group, family, God, life, or the military.²⁶

Such findings suggest that the sense of guilt experienced by some at-risk veterans may be grounded in a variety of contexts. For example, faith communities that place a strong emphasis on obedience to moral, ethical, and religious precepts may contribute to the experience of guilt unless balanced by a message of grace or favor from a benevolent God or deity. Without this balance, engaging in activities that are not fully sanctioned by one’s faith community may lead to guilt.

Families might also contribute to veterans’ experiences of guilt by placing unrealistic expectations on them. And the family environment may not be conducive to resolving feelings of guilt in veterans, harboring resentment and antipathies and making it very difficult to alleviate any ensuing sense of distress.

CLINICIAN’S ROLE IN ASSESSING GUILT

In addressing and assessing guilt in veterans at risk of suicide, clinicians should try to recognize the source and clinical implications of this emotion.

Recognize the source of guilt

Guilt may indicate a clinical disorder such as a mood disorder (eg, major depression).²⁷ Mood disorders significantly increase the risk of suicidal behavior.^28,29

Beyond diagnosing a clinical disorder, prescribing pharmacotherapy, and referring for mental healthcare services, recognizing the source of this emotion remains an important part of addressing a patient’s experience of guilt. Especially when associated with a clinical disorder, guilt is often irrational and excessive and does not appropriately reflect the experience or situation in question.

Case conceptualization, defined as “synthesizing the patient’s experience with relevant clinical theory and research,”³⁰ can be used to understand the context in which the guilt-inducing action or behavior occurred and the veteran’s own interpretation of his or her actions. Understanding the source of the patient’s guilt could be used to plan treatment and resolve any underlying sense of distress.

As with other negative emotions, the affective component of guilt is often the result of cognitive distortions made as the person tries to make sense of what has occurred or to reconcile beliefs of right and wrong with the guilt-inducing behavior.³¹ The common cognitive errors associated with guilt include:

• Hindsight bias (a belief that one should have known what was going to happen as a result of one’s actions)
• Responsibility distortion (a belief that one’s actions directly caused an adverse event)
• Justification distortion (a belief that one’s actions were not justified by the situation)
• Wrongdoing distortion (a belief that one violated one’s own standards of right and wrong).³¹

Cognitive therapy to counter cognitive distortions

A variety of clinical options exist to help veterans manage and resolve guilt.

Mood disorders significantly increase the risk of suicidal behavior

Cognitive therapy can counter the cognitive distortions that drive feelings of guilt. The goal is to guide patients to examine the evidence, process the event, and realize that their behavior was appropriate for the given situation. Cognitive processing therapy and prolonged exposure therapy have both been shown to decrease trauma-related guilt, though cognitive processing therapy was found to be better at decreasing guilt that arose from cognitive distortions.³²

Guilt and suicide ideation have also been associated with a belief that one’s actions constituted an unforgivable sin.³³ Responding to these inherently religious-spiritual cognitive distortions may be beyond the scope of expertise for many healthcare professionals. In such cases, it may be prudent to consider complementing clinical services with pastoral care. It follows that pastoral care services should only be provided if the veteran voices a desire and readiness for them. The clinician and chaplain can then work together to provide coordinated care to best meet the patient’s needs, to address the experience of guilt, and to alleviate the sense of distress.

A CHAPLAIN’S PERSPECTIVE ON GUILT

A prominent feature of pastoral practice is  helping people, including at-risk veterans, resolve feelings of guilt regardless of the context on which the emotion is founded (eg, religion, shame).¹⁰ For many people, guilt is an impenetrable barrier, preventing resolution of whatever experience led to a sense of inner turmoil.

Forgiveness

In the context of pastoral care, resolution of guilt is ordinarily tied to a need for forgiveness. There are multiple ways in which forgiveness can be grounded in religious and spiritual contexts.³⁴ Examples include forgiving others (ie, forswearing resentment, anger, or hatred directed toward another person), being forgiven by God or another benevolent deity, and forgiving oneself for violating perceived personal transgressions.³⁵ In some cases, divine forgiveness may be conditional on interpersonal forgiveness.³⁶ Forgiveness is also sometimes seen as a remedy for sin and a way to restore moral order.³⁷

Some people may initially think they can never be forgiven. With time and the weight of one’s experiences, the impossibility of forgiveness can become so ingrained that it becomes a core belief. These core beliefs set up a vicious circle of thoughts and feelings, in which people and places and events from the past are continuously brought forward into the present. Anger and resentment become the steady diet for the tormented self that feels forever powerless over experienced injustices. These relived experiences drive the person into a deep isolation where the self becomes less human—a thing, an object. This experience of losing oneself proves excruciating and often leads to contemplation of suicide as a way to resolve anguish.

Hope emerges

Pastoral care services provide a means to reframe one’s core beliefs, manage and resolve the burden of guilt, and uncover new motivation for living.

The practice of spiritual direction within the discipline of pastoral care listens for these inner movements and encourages the person to give voice to them in his or her own words. No longer limited by a diminished, tormented self, the real self begins to relate to another reality that changes his or her identity, relieves the burden of guilt, and gives reason, purpose, and meaning to life.

Even with this opportunity for a new life, however, cognitive distortions based on a disproportional “faith-based prism” may persist. In this case, clinicians and chaplains must work closely together to reframe old understandings of self and incorrect understandings of religion and spirituality into one that continues to reinforce this newfound sense of hope.³⁸

A VETERAN OF IRAQ WITH SUICIDE IDEATION

The following case illustrates how clinicians and chaplains may be able to work together to help facilitate the resolution of guilt.

A veteran who had served in Iraq had entered the Domiciliary Care Program at a US Department of Veterans Affairs medical center. He reported experiencing problems with guilt, forgiveness, and suicide ideation. A clinical therapeutic program was prescribed after a psychological evaluation uncovered that he was also struggling with depression and posttraumatic stress disorder.

Guilt is often irrational and excessive and does not appropriately reflect the experience or situation

His mental healthcare providers recognized the importance of incorporating a religious-spiritual component into the therapeutic plan, and so consulted with a chaplain to plan a suitable course of action. Specifically, this veteran reported feeling that he could not be forgiven for his military experiences, a feeling that was giving way to alienation and isolation from the God of his faith tradition.

The chaplain helped this veteran reflect on his military experiences, giving him the perspective he needed to view his God as one who truly loves him. He recognized instances in which he could have lost his life had it not been for others who intervened on his behalf at just the right time. This awareness caused him to think about his life differently, challenging him to reframe his relationship with God. Instead of simple coincidences, the veteran began to consider the mystery behind these times and places.

Over time and in keeping with the tenets of his faith tradition, the veteran stated that he was ultimately able to accept and receive God’s love and forgiveness. He now reports that these inner spiritual movements serve as a source of support during occasional relapses into emotional distress. These movements allow him to consider the mystery of his present life and its value based on his experience of his God’s love and forgiveness.

CARE FOR SUICIDE SURVIVORS

The experience of guilt is not limited to veterans. Those bereaved by suicide are also left to manage their own experiences of the loss and ensuing complex emotions. Friends and loved ones who survive a suicide decedent may experience guilt, feeling that they somehow contributed to or failed to prevent the suicide. Such feelings of guilt are hypothesized to lower the threshold for suicidal behavior in those bereaved.³⁹

Guilt and shame are also frequently encountered in survivors of nonfatal suicide attempts.⁴⁰ Chaplaincy services might also prove useful for these individuals.

TIME IS EVERYTHING

Patients who may have an active psychopathology should have their clinical therapeutic needs attended to first. If the clinician deems pastoral care services to be an appropriate complementary support option, care should be taken to select a pastoral care provider who is adequately prepared for this role. Different professional organizations (eg, Association of Professional Chaplains) have established board-certification procedures, minimum education requirements, and supervised practical experience required for chaplaincy certification.

Also, spiritual growth and development remain a core focus of pastoral practice. Clinicians should discontinue any collaboration with pastoral care providers who question an individual’s faith or commitment to his or her faith, or who promote thinking or actions that could be deleterious to the patient’s therapeutic trajectory.

SUMMING UP

We have here presented our perspectives on how chaplaincy services can be used to complement clinical services in support of at-risk veterans struggling with experiences of guilt. Unfortunately, the current level of collaboration between chaplains and clinicians in support of at-risk veteran populations is limited.²⁰ Our hope is that clinicians managing these at-risk patients will develop a greater awareness of how chaplaincy services might be able to help in alleviating experiences of guilt in at-risk veteran populations. A further hope is that such cases will serve as an opportunity for greater interdisciplinary collaboration, benefiting at-risk veterans most in need of support.
 

Acknowledgment: Dr. Rasmussen was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, US Department of Veterans Affairs, VISN 2 Center of Excellence for Suicide Prevention.

Suicidal behavior is a major cause of morbidity and mortality in the United States,1 and active-duty and reserve military personnel and veterans account for nearly 18% of suicide deaths.² By one estimate, as many as 22 veterans die by suicide each day.³ These rates are thought to be due to a higher incidence of mental illness in certain veteran populations relative to the general population.^4–8 Consequently, a number of mental health services are available to veterans in a variety of clinical and community settings.

See related commentary

Chaplains and clinicians bring complementary skills and services to the problem of suicide risk among veterans. In particular, helping at-risk veterans deal with experiences of guilt is an opportunity for interdisciplinary collaboration. Available literature supports the potential utility of chaplaincy services in supporting at-risk veteran populations.^9–15

But while most healthcare facilities have chaplains on staff, there is little information to guide any such collaboration. Further, healthcare providers appear to have a limited understanding of chaplaincy services, the “language” within which chaplains operate, or the roles chaplains play in healthcare settings.¹⁶

In the following discussion, using the example of experiences of guilt, we offer our insights and suggestions on how chaplaincy services may prove useful in alleviating this complex emotion in veterans at risk of suicide.

BENEFITS OF TALKING TO A CHAPLAIN

By one estimate, as many as 22 veterans die by suicide each day

Collaboration between healthcare providers and pastoral care professionals has been suggested as a means of enhancing the treatment of patients with mental illness.^17,18 Chaplains draw from a variety of faith traditions and are usually trained to respond to the needs of people from a variety of religious and spiritual backgrounds. They provide some non-faith­based services (eg, crisis intervention, life review, bereavement counseling) resembling those also provided in formal mental healthcare settings.¹⁹ By facilitating religious and spiritual coping and religious practice and responding to religious and spiritual needs, chaplains also offer a level of support not typically offered by formal mental healthcare providers.²⁰

Veterans at risk of suicide sometimes look to pastoral care providers, particularly chaplains, for mental health support.^9,10 Research on the effects of chaplaincy services on suicidal behavior is just beginning to emerge.¹⁵ Still, the US Department of Health and Human Services has recognized pastoral care services as having a “beneficial and therapeutic effect on the medical condition of a patient.”¹¹

For example, in one study, hospital inpatients reported higher satisfaction if they had been visited by a chaplain.¹² Chaplains help align treatment plans with patient values and wishes.¹³ In another study,¹⁴ patients undergoing coronary artery bypass grafting who were randomized to receive five visits from a chaplain were found to have a higher rate of positive religious coping (eg, forgiveness, letting go of anger). Positive religious coping has been correlated with lower levels of psychological stress and better mental health outcomes.

EXPERIENCING GUILT IS LINKED TO RISK OF SUICIDE

Suicidal behavior is complex, multifaceted, and linked to genetic, neurologic, psychological, social, and cultural factors.²¹

Assessing for and addressing certain complex emotions, such as guilt and shame, is an important part of suicide prevention efforts. Guilt is defined as a “controllable psychological state that is typically linked to a specific action or behavior, and which entails regret or remorse.”²²

Close to 75% of veterans who had thought about suicide said they frequently experienced guilt

Guilt has been linked to risk of suicide in veterans.^23–25 In one study, close to 75% of veterans who had thought about suicide said they frequently experienced guilt about having violated the precepts of their faith group, family, God, life, or the military.²⁶

Such findings suggest that the sense of guilt experienced by some at-risk veterans may be grounded in a variety of contexts. For example, faith communities that place a strong emphasis on obedience to moral, ethical, and religious precepts may contribute to the experience of guilt unless balanced by a message of grace or favor from a benevolent God or deity. Without this balance, engaging in activities that are not fully sanctioned by one’s faith community may lead to guilt.

Families might also contribute to veterans’ experiences of guilt by placing unrealistic expectations on them. And the family environment may not be conducive to resolving feelings of guilt in veterans, harboring resentment and antipathies and making it very difficult to alleviate any ensuing sense of distress.

CLINICIAN’S ROLE IN ASSESSING GUILT

In addressing and assessing guilt in veterans at risk of suicide, clinicians should try to recognize the source and clinical implications of this emotion.

Recognize the source of guilt

Guilt may indicate a clinical disorder such as a mood disorder (eg, major depression).²⁷ Mood disorders significantly increase the risk of suicidal behavior.^28,29

Beyond diagnosing a clinical disorder, prescribing pharmacotherapy, and referring for mental healthcare services, recognizing the source of this emotion remains an important part of addressing a patient’s experience of guilt. Especially when associated with a clinical disorder, guilt is often irrational and excessive and does not appropriately reflect the experience or situation in question.

Case conceptualization, defined as “synthesizing the patient’s experience with relevant clinical theory and research,”³⁰ can be used to understand the context in which the guilt-inducing action or behavior occurred and the veteran’s own interpretation of his or her actions. Understanding the source of the patient’s guilt could be used to plan treatment and resolve any underlying sense of distress.

As with other negative emotions, the affective component of guilt is often the result of cognitive distortions made as the person tries to make sense of what has occurred or to reconcile beliefs of right and wrong with the guilt-inducing behavior.³¹ The common cognitive errors associated with guilt include:

• Hindsight bias (a belief that one should have known what was going to happen as a result of one’s actions)
• Responsibility distortion (a belief that one’s actions directly caused an adverse event)
• Justification distortion (a belief that one’s actions were not justified by the situation)
• Wrongdoing distortion (a belief that one violated one’s own standards of right and wrong).³¹

Cognitive therapy to counter cognitive distortions

A variety of clinical options exist to help veterans manage and resolve guilt.

Mood disorders significantly increase the risk of suicidal behavior

Cognitive therapy can counter the cognitive distortions that drive feelings of guilt. The goal is to guide patients to examine the evidence, process the event, and realize that their behavior was appropriate for the given situation. Cognitive processing therapy and prolonged exposure therapy have both been shown to decrease trauma-related guilt, though cognitive processing therapy was found to be better at decreasing guilt that arose from cognitive distortions.³²

Guilt and suicide ideation have also been associated with a belief that one’s actions constituted an unforgivable sin.³³ Responding to these inherently religious-spiritual cognitive distortions may be beyond the scope of expertise for many healthcare professionals. In such cases, it may be prudent to consider complementing clinical services with pastoral care. It follows that pastoral care services should only be provided if the veteran voices a desire and readiness for them. The clinician and chaplain can then work together to provide coordinated care to best meet the patient’s needs, to address the experience of guilt, and to alleviate the sense of distress.

A CHAPLAIN’S PERSPECTIVE ON GUILT

A prominent feature of pastoral practice is  helping people, including at-risk veterans, resolve feelings of guilt regardless of the context on which the emotion is founded (eg, religion, shame).¹⁰ For many people, guilt is an impenetrable barrier, preventing resolution of whatever experience led to a sense of inner turmoil.

Forgiveness

In the context of pastoral care, resolution of guilt is ordinarily tied to a need for forgiveness. There are multiple ways in which forgiveness can be grounded in religious and spiritual contexts.³⁴ Examples include forgiving others (ie, forswearing resentment, anger, or hatred directed toward another person), being forgiven by God or another benevolent deity, and forgiving oneself for violating perceived personal transgressions.³⁵ In some cases, divine forgiveness may be conditional on interpersonal forgiveness.³⁶ Forgiveness is also sometimes seen as a remedy for sin and a way to restore moral order.³⁷

Some people may initially think they can never be forgiven. With time and the weight of one’s experiences, the impossibility of forgiveness can become so ingrained that it becomes a core belief. These core beliefs set up a vicious circle of thoughts and feelings, in which people and places and events from the past are continuously brought forward into the present. Anger and resentment become the steady diet for the tormented self that feels forever powerless over experienced injustices. These relived experiences drive the person into a deep isolation where the self becomes less human—a thing, an object. This experience of losing oneself proves excruciating and often leads to contemplation of suicide as a way to resolve anguish.

Hope emerges

Pastoral care services provide a means to reframe one’s core beliefs, manage and resolve the burden of guilt, and uncover new motivation for living.

The practice of spiritual direction within the discipline of pastoral care listens for these inner movements and encourages the person to give voice to them in his or her own words. No longer limited by a diminished, tormented self, the real self begins to relate to another reality that changes his or her identity, relieves the burden of guilt, and gives reason, purpose, and meaning to life.

Even with this opportunity for a new life, however, cognitive distortions based on a disproportional “faith-based prism” may persist. In this case, clinicians and chaplains must work closely together to reframe old understandings of self and incorrect understandings of religion and spirituality into one that continues to reinforce this newfound sense of hope.³⁸

A VETERAN OF IRAQ WITH SUICIDE IDEATION

The following case illustrates how clinicians and chaplains may be able to work together to help facilitate the resolution of guilt.

A veteran who had served in Iraq had entered the Domiciliary Care Program at a US Department of Veterans Affairs medical center. He reported experiencing problems with guilt, forgiveness, and suicide ideation. A clinical therapeutic program was prescribed after a psychological evaluation uncovered that he was also struggling with depression and posttraumatic stress disorder.

Guilt is often irrational and excessive and does not appropriately reflect the experience or situation

His mental healthcare providers recognized the importance of incorporating a religious-spiritual component into the therapeutic plan, and so consulted with a chaplain to plan a suitable course of action. Specifically, this veteran reported feeling that he could not be forgiven for his military experiences, a feeling that was giving way to alienation and isolation from the God of his faith tradition.

The chaplain helped this veteran reflect on his military experiences, giving him the perspective he needed to view his God as one who truly loves him. He recognized instances in which he could have lost his life had it not been for others who intervened on his behalf at just the right time. This awareness caused him to think about his life differently, challenging him to reframe his relationship with God. Instead of simple coincidences, the veteran began to consider the mystery behind these times and places.

Over time and in keeping with the tenets of his faith tradition, the veteran stated that he was ultimately able to accept and receive God’s love and forgiveness. He now reports that these inner spiritual movements serve as a source of support during occasional relapses into emotional distress. These movements allow him to consider the mystery of his present life and its value based on his experience of his God’s love and forgiveness.

CARE FOR SUICIDE SURVIVORS

The experience of guilt is not limited to veterans. Those bereaved by suicide are also left to manage their own experiences of the loss and ensuing complex emotions. Friends and loved ones who survive a suicide decedent may experience guilt, feeling that they somehow contributed to or failed to prevent the suicide. Such feelings of guilt are hypothesized to lower the threshold for suicidal behavior in those bereaved.³⁹

Guilt and shame are also frequently encountered in survivors of nonfatal suicide attempts.⁴⁰ Chaplaincy services might also prove useful for these individuals.

TIME IS EVERYTHING

Patients who may have an active psychopathology should have their clinical therapeutic needs attended to first. If the clinician deems pastoral care services to be an appropriate complementary support option, care should be taken to select a pastoral care provider who is adequately prepared for this role. Different professional organizations (eg, Association of Professional Chaplains) have established board-certification procedures, minimum education requirements, and supervised practical experience required for chaplaincy certification.

Also, spiritual growth and development remain a core focus of pastoral practice. Clinicians should discontinue any collaboration with pastoral care providers who question an individual’s faith or commitment to his or her faith, or who promote thinking or actions that could be deleterious to the patient’s therapeutic trajectory.

SUMMING UP

We have here presented our perspectives on how chaplaincy services can be used to complement clinical services in support of at-risk veterans struggling with experiences of guilt. Unfortunately, the current level of collaboration between chaplains and clinicians in support of at-risk veteran populations is limited.²⁰ Our hope is that clinicians managing these at-risk patients will develop a greater awareness of how chaplaincy services might be able to help in alleviating experiences of guilt in at-risk veteran populations. A further hope is that such cases will serve as an opportunity for greater interdisciplinary collaboration, benefiting at-risk veterans most in need of support.
 

Acknowledgment: Dr. Rasmussen was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, US Department of Veterans Affairs, VISN 2 Center of Excellence for Suicide Prevention.

Suicidal behavior is a major cause of morbidity and mortality in the United States,1 and active-duty and reserve military personnel and veterans account for nearly 18% of suicide deaths.² By one estimate, as many as 22 veterans die by suicide each day.³ These rates are thought to be due to a higher incidence of mental illness in certain veteran populations relative to the general population.^4–8 Consequently, a number of mental health services are available to veterans in a variety of clinical and community settings.

See related commentary

Chaplains and clinicians bring complementary skills and services to the problem of suicide risk among veterans. In particular, helping at-risk veterans deal with experiences of guilt is an opportunity for interdisciplinary collaboration. Available literature supports the potential utility of chaplaincy services in supporting at-risk veteran populations.^9–15

But while most healthcare facilities have chaplains on staff, there is little information to guide any such collaboration. Further, healthcare providers appear to have a limited understanding of chaplaincy services, the “language” within which chaplains operate, or the roles chaplains play in healthcare settings.¹⁶

In the following discussion, using the example of experiences of guilt, we offer our insights and suggestions on how chaplaincy services may prove useful in alleviating this complex emotion in veterans at risk of suicide.

BENEFITS OF TALKING TO A CHAPLAIN

By one estimate, as many as 22 veterans die by suicide each day

Collaboration between healthcare providers and pastoral care professionals has been suggested as a means of enhancing the treatment of patients with mental illness.^17,18 Chaplains draw from a variety of faith traditions and are usually trained to respond to the needs of people from a variety of religious and spiritual backgrounds. They provide some non-faith­based services (eg, crisis intervention, life review, bereavement counseling) resembling those also provided in formal mental healthcare settings.¹⁹ By facilitating religious and spiritual coping and religious practice and responding to religious and spiritual needs, chaplains also offer a level of support not typically offered by formal mental healthcare providers.²⁰

Veterans at risk of suicide sometimes look to pastoral care providers, particularly chaplains, for mental health support.^9,10 Research on the effects of chaplaincy services on suicidal behavior is just beginning to emerge.¹⁵ Still, the US Department of Health and Human Services has recognized pastoral care services as having a “beneficial and therapeutic effect on the medical condition of a patient.”¹¹

For example, in one study, hospital inpatients reported higher satisfaction if they had been visited by a chaplain.¹² Chaplains help align treatment plans with patient values and wishes.¹³ In another study,¹⁴ patients undergoing coronary artery bypass grafting who were randomized to receive five visits from a chaplain were found to have a higher rate of positive religious coping (eg, forgiveness, letting go of anger). Positive religious coping has been correlated with lower levels of psychological stress and better mental health outcomes.

EXPERIENCING GUILT IS LINKED TO RISK OF SUICIDE

Suicidal behavior is complex, multifaceted, and linked to genetic, neurologic, psychological, social, and cultural factors.²¹

Assessing for and addressing certain complex emotions, such as guilt and shame, is an important part of suicide prevention efforts. Guilt is defined as a “controllable psychological state that is typically linked to a specific action or behavior, and which entails regret or remorse.”²²

Close to 75% of veterans who had thought about suicide said they frequently experienced guilt

Guilt has been linked to risk of suicide in veterans.^23–25 In one study, close to 75% of veterans who had thought about suicide said they frequently experienced guilt about having violated the precepts of their faith group, family, God, life, or the military.²⁶

Such findings suggest that the sense of guilt experienced by some at-risk veterans may be grounded in a variety of contexts. For example, faith communities that place a strong emphasis on obedience to moral, ethical, and religious precepts may contribute to the experience of guilt unless balanced by a message of grace or favor from a benevolent God or deity. Without this balance, engaging in activities that are not fully sanctioned by one’s faith community may lead to guilt.

Families might also contribute to veterans’ experiences of guilt by placing unrealistic expectations on them. And the family environment may not be conducive to resolving feelings of guilt in veterans, harboring resentment and antipathies and making it very difficult to alleviate any ensuing sense of distress.

CLINICIAN’S ROLE IN ASSESSING GUILT

In addressing and assessing guilt in veterans at risk of suicide, clinicians should try to recognize the source and clinical implications of this emotion.

Recognize the source of guilt

Guilt may indicate a clinical disorder such as a mood disorder (eg, major depression).²⁷ Mood disorders significantly increase the risk of suicidal behavior.^28,29

Beyond diagnosing a clinical disorder, prescribing pharmacotherapy, and referring for mental healthcare services, recognizing the source of this emotion remains an important part of addressing a patient’s experience of guilt. Especially when associated with a clinical disorder, guilt is often irrational and excessive and does not appropriately reflect the experience or situation in question.

Case conceptualization, defined as “synthesizing the patient’s experience with relevant clinical theory and research,”³⁰ can be used to understand the context in which the guilt-inducing action or behavior occurred and the veteran’s own interpretation of his or her actions. Understanding the source of the patient’s guilt could be used to plan treatment and resolve any underlying sense of distress.

As with other negative emotions, the affective component of guilt is often the result of cognitive distortions made as the person tries to make sense of what has occurred or to reconcile beliefs of right and wrong with the guilt-inducing behavior.³¹ The common cognitive errors associated with guilt include:

• Hindsight bias (a belief that one should have known what was going to happen as a result of one’s actions)
• Responsibility distortion (a belief that one’s actions directly caused an adverse event)
• Justification distortion (a belief that one’s actions were not justified by the situation)
• Wrongdoing distortion (a belief that one violated one’s own standards of right and wrong).³¹

Cognitive therapy to counter cognitive distortions

A variety of clinical options exist to help veterans manage and resolve guilt.

Mood disorders significantly increase the risk of suicidal behavior

Cognitive therapy can counter the cognitive distortions that drive feelings of guilt. The goal is to guide patients to examine the evidence, process the event, and realize that their behavior was appropriate for the given situation. Cognitive processing therapy and prolonged exposure therapy have both been shown to decrease trauma-related guilt, though cognitive processing therapy was found to be better at decreasing guilt that arose from cognitive distortions.³²

Guilt and suicide ideation have also been associated with a belief that one’s actions constituted an unforgivable sin.³³ Responding to these inherently religious-spiritual cognitive distortions may be beyond the scope of expertise for many healthcare professionals. In such cases, it may be prudent to consider complementing clinical services with pastoral care. It follows that pastoral care services should only be provided if the veteran voices a desire and readiness for them. The clinician and chaplain can then work together to provide coordinated care to best meet the patient’s needs, to address the experience of guilt, and to alleviate the sense of distress.

A CHAPLAIN’S PERSPECTIVE ON GUILT

A prominent feature of pastoral practice is  helping people, including at-risk veterans, resolve feelings of guilt regardless of the context on which the emotion is founded (eg, religion, shame).¹⁰ For many people, guilt is an impenetrable barrier, preventing resolution of whatever experience led to a sense of inner turmoil.

Forgiveness

In the context of pastoral care, resolution of guilt is ordinarily tied to a need for forgiveness. There are multiple ways in which forgiveness can be grounded in religious and spiritual contexts.³⁴ Examples include forgiving others (ie, forswearing resentment, anger, or hatred directed toward another person), being forgiven by God or another benevolent deity, and forgiving oneself for violating perceived personal transgressions.³⁵ In some cases, divine forgiveness may be conditional on interpersonal forgiveness.³⁶ Forgiveness is also sometimes seen as a remedy for sin and a way to restore moral order.³⁷

Some people may initially think they can never be forgiven. With time and the weight of one’s experiences, the impossibility of forgiveness can become so ingrained that it becomes a core belief. These core beliefs set up a vicious circle of thoughts and feelings, in which people and places and events from the past are continuously brought forward into the present. Anger and resentment become the steady diet for the tormented self that feels forever powerless over experienced injustices. These relived experiences drive the person into a deep isolation where the self becomes less human—a thing, an object. This experience of losing oneself proves excruciating and often leads to contemplation of suicide as a way to resolve anguish.

Hope emerges

Pastoral care services provide a means to reframe one’s core beliefs, manage and resolve the burden of guilt, and uncover new motivation for living.

The practice of spiritual direction within the discipline of pastoral care listens for these inner movements and encourages the person to give voice to them in his or her own words. No longer limited by a diminished, tormented self, the real self begins to relate to another reality that changes his or her identity, relieves the burden of guilt, and gives reason, purpose, and meaning to life.

Even with this opportunity for a new life, however, cognitive distortions based on a disproportional “faith-based prism” may persist. In this case, clinicians and chaplains must work closely together to reframe old understandings of self and incorrect understandings of religion and spirituality into one that continues to reinforce this newfound sense of hope.³⁸

A VETERAN OF IRAQ WITH SUICIDE IDEATION

The following case illustrates how clinicians and chaplains may be able to work together to help facilitate the resolution of guilt.

A veteran who had served in Iraq had entered the Domiciliary Care Program at a US Department of Veterans Affairs medical center. He reported experiencing problems with guilt, forgiveness, and suicide ideation. A clinical therapeutic program was prescribed after a psychological evaluation uncovered that he was also struggling with depression and posttraumatic stress disorder.

Guilt is often irrational and excessive and does not appropriately reflect the experience or situation

His mental healthcare providers recognized the importance of incorporating a religious-spiritual component into the therapeutic plan, and so consulted with a chaplain to plan a suitable course of action. Specifically, this veteran reported feeling that he could not be forgiven for his military experiences, a feeling that was giving way to alienation and isolation from the God of his faith tradition.

The chaplain helped this veteran reflect on his military experiences, giving him the perspective he needed to view his God as one who truly loves him. He recognized instances in which he could have lost his life had it not been for others who intervened on his behalf at just the right time. This awareness caused him to think about his life differently, challenging him to reframe his relationship with God. Instead of simple coincidences, the veteran began to consider the mystery behind these times and places.

Over time and in keeping with the tenets of his faith tradition, the veteran stated that he was ultimately able to accept and receive God’s love and forgiveness. He now reports that these inner spiritual movements serve as a source of support during occasional relapses into emotional distress. These movements allow him to consider the mystery of his present life and its value based on his experience of his God’s love and forgiveness.

CARE FOR SUICIDE SURVIVORS

The experience of guilt is not limited to veterans. Those bereaved by suicide are also left to manage their own experiences of the loss and ensuing complex emotions. Friends and loved ones who survive a suicide decedent may experience guilt, feeling that they somehow contributed to or failed to prevent the suicide. Such feelings of guilt are hypothesized to lower the threshold for suicidal behavior in those bereaved.³⁹

Guilt and shame are also frequently encountered in survivors of nonfatal suicide attempts.⁴⁰ Chaplaincy services might also prove useful for these individuals.

TIME IS EVERYTHING

Patients who may have an active psychopathology should have their clinical therapeutic needs attended to first. If the clinician deems pastoral care services to be an appropriate complementary support option, care should be taken to select a pastoral care provider who is adequately prepared for this role. Different professional organizations (eg, Association of Professional Chaplains) have established board-certification procedures, minimum education requirements, and supervised practical experience required for chaplaincy certification.

Also, spiritual growth and development remain a core focus of pastoral practice. Clinicians should discontinue any collaboration with pastoral care providers who question an individual’s faith or commitment to his or her faith, or who promote thinking or actions that could be deleterious to the patient’s therapeutic trajectory.

SUMMING UP

We have here presented our perspectives on how chaplaincy services can be used to complement clinical services in support of at-risk veterans struggling with experiences of guilt. Unfortunately, the current level of collaboration between chaplains and clinicians in support of at-risk veteran populations is limited.²⁰ Our hope is that clinicians managing these at-risk patients will develop a greater awareness of how chaplaincy services might be able to help in alleviating experiences of guilt in at-risk veteran populations. A further hope is that such cases will serve as an opportunity for greater interdisciplinary collaboration, benefiting at-risk veterans most in need of support.
 

Acknowledgment: Dr. Rasmussen was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, US Department of Veterans Affairs, VISN 2 Center of Excellence for Suicide Prevention.

In their commentary, Kopacz et al¹ propose that collaboration with professionally trained and certified clinical chaplains provides an opportunity for interdisciplinary care with increased benefit to veterans at risk of suicide. They rightly identify the pivotal issue of guilt as one that falls squarely in the domain of spiritual (or pastoral) care.

See related commentary

As professionals involved in the training of board-certifiable chaplains (and one of us is a veteran), we find that guilt in patients with suicidal tendencies is a profoundly spiritual issue that can be addressed effectively through collaboration among chaplains, physicians, and mental health providers.

Guilt is a serious spiritual condition that can easily be undertreated, or treated under the rubric of depression, which is related but not identical. Undertreatment occurs when caregivers, eager to see the guilt-sufferer experience relief, inadvertently short-circuit the necessary process of working through, rather than around, the guilt. Allowing patients to talk about their feelings of guilt without minimizing those feelings can be helpful even if, as Kopacz et al point out, the feelings are often irrational. We believe that people have an innate need to be truly heard and understood before they can become open to a reinterpretation of their feelings. Only then can the seeds of self-forgiveness begin to take root.

Hearing the words “There is hope for you to feel forgiven” can be more helpful than hearing “You didn’t really do anything bad,” particularly if the patient is religious. Hearing these words from a chaplain is often more effective than hearing them from a lay person, just as many of us take basic health information more seriously when we hear it from a physician. Even if the veteran is not overtly religious, there may be a unique exchange between that person and a religious authority when it concerns the violation of a millennia­old, widely known teaching from the Bible, such as “Thou shalt not kill.”

Guilt in patients with suicidal tendencies is a profoundly spiritual issue

Kopacz et al also rightly suggest that unless religious prohibitions have been balanced with teachings on forgiveness and grace, the teachings can actually exacerbate feelings of guilt and elevate them to harmful proportions, especially in the potentially vulnerable psyche of a veteran who may have been traumatized. If there is no religious or spiritual guidance for balancing prohibitions with graces, the patient may be left to spiral in an unending loop of guilt with no way out.

We therefore propose the following categories for different types (or “shades”) of guilt that can be effectively addressed by chaplains in concert with other members of the healthcare team. For simplicity, we call these types real guilt, survivor guilt, mistaken guilt, and complex-compound guilt.

REAL GUILT

An important role professional chaplains can play is to allow patients (in this case, veterans) to express their remorse and regret for violations of their own moral codes. In many cases, they have in fact hurt or killed another person, and they need the chance to unburden their hearts and spirits, especially if they were taught that killing people is a sin. Veterans who have harmed or killed others, even if under orders, are often left with bona fide feelings of guilt that need to be aired and released in a safe and confidential environment. This is often most effective when done by someone who not only is trained in nonjudgmental and nondirective listening, but also is a religious authority who can assure the patient of his or her innate worthiness and of the ability to be forgiven.

As Kopacz et al note, guilt is linked to a specific action or behavior and usually entails regret or remorse. Many veterans belong to or have had exposure to faith groups with strong moral codes and prohibitions, and so may see the chaplain as having authority to act as confessor and granter of absolution.

SURVIVOR GUILT

Survivor guilt is commonly understood as the feeling of surviving a terrible event or situation while someone else did not. Those who suffer from survivor guilt judge themselves unworthy of survival and believe the deceased to have been more courageous, virtuous, or somehow a better person than they. They torture themselves with ideas of the deceased person’s virtues—imagined or real—and sometimes go on to believe that “It should have been me who was killed.”

The burden of feeling that the wrong person died can be overwhelming. If these people are not helped to see their own worth and helped to find outlets for their sense of having been spared (by God, by their own wits, or by sheer luck), they are likely to struggle more. This is related but not identical to what we  call mistaken guilt. The two types are similar because they share a sense of randomness and helplessness, but they are different for reasons we will explain below.

Chaplains can be particularly effective partners in the care of veterans with survivor guilt, helping them to make meaning out of a life-changing event, rather than find meaning inherently in that event. Meaning, purpose, and “God’s plan for my life” are common themes in the pastoral conversation that can provide a compass for the disoriented survivor.

MISTAKEN GUILT

Mistaken guilt describes when a person who is involved in the death of another but is absolutely blameless—and could not possibly have prevented that death—literally “mis-takes” the guilt upon himself or herself in spite of the facts. Because of the helplessness induced by this feeling, mistaken guilt can be more difficult to treat than other forms. These patients continue to suffer despite assurances that the death occurred through absolutely no fault of their own.²

‘There is hope to feel forgiven’ can be more helpful than ‘You didn’t do anything bad’

Hickling³ has written extensively about this phenomenon in innocent motor vehicle drivers who cause pedestrian deaths, and he considers this type of guilt one of the most difficult to recover from precisely because of the helplessness factor. He has explained that if patients can find a real reason by which they were culpable for what happened, they can change their ways. But if they were absolutely innocent (as in many incidents in training or combat), they often cannot make sense of what happened in a way that allows them to move on because there is nothing they could have done differently and therefore nothing they can change.⁴

These patients almost certainly need long-term intervention such as cognitive behavioral therapy in order to train their mind away from such destructive thoughts. However, they are also very likely to be helped by a chaplain if they find that the event triggers memories of other past infractions of which they may need to unburden themselves (ie, confess).

COMPOUND-COMPLEX GUILT

As the name implies, compound-complex guilt is a combination of the other types and may have additional layers.

Compound-complex guilt leaves sufferers literally feeling guilty for feeling guilty. Though this may border on a genuine clinical disorder, it is also to some degree normal (eg, due to cultural taboos and norms) for people to feel culpable for not being able to “move on” or “forgive themselves” as quickly as others may want them to. Buddhists call this tendency the “second arrow effect.” The first arrow is the feeling of guilt (or other painful feeling) that strikes the individual, but the second arrow is the one he or she drives in afterward by thinking it is wrong or weak to even have the feeling.

Patients who suffer from this type of guilt blame themselves for the conundrum they are in and feel even worse. This is not unlike the vortex of unresolved and complicated grief.

Those who suffer from compound-complex guilt may layer the primary guilt with additional guilt for feeling weak, for needing help, or for asking for help. Especially in the culture of the military, the fear of stigma when asking for help (especially with mental health) is still quite strong. Therefore, chaplains can serve as a less threatening entry point for the veteran needing multiple professionals involved in his or her care.

NONJUDGMENTAL LISTENING

Nonjudgmental listening is essential to get at the source or sources of guilt, regardless of the type, in order to allow the wounds to air out and begin healing. Many veterans suffering from guilt may need intensive pharmacologic and cognitive therapy to fully recover, and care from a chaplain is not a substitute for psychiatric evaluation and treatment, especially if there is a risk of suicide.

However, chaplains may be able to help with the “deep work” of spiritual healing that is part of veterans’ overall recovery. This is true not only because chaplains are especially trained to do this, but also because they are the team members most likely to have uniquely spiritual language to speak to the condition. The language of confession, absolution, repentance, redemption, atonement, and forgiveness is language of the spiritual realm.

In addition, chaplains’ freedom from hourly billing concerns and their often less formalized interactions with patients may help to build trust. Well-trained chaplains, who are often quite gifted at creating an atmosphere of reverence and safety (sanctuary) in the most unlikely situations, are well suited to help the interdisciplinary team treat this vulnerable patient population.

SUGGESTED READING

For more insights into the role of chaplains on the interdisciplinary healthcare team, we recommend the following book: Cadge W. Paging God: Religion in the Halls of Medicine. Chicago, IL: University of Chicago Press; 2012.

In their commentary, Kopacz et al¹ propose that collaboration with professionally trained and certified clinical chaplains provides an opportunity for interdisciplinary care with increased benefit to veterans at risk of suicide. They rightly identify the pivotal issue of guilt as one that falls squarely in the domain of spiritual (or pastoral) care.

See related commentary

As professionals involved in the training of board-certifiable chaplains (and one of us is a veteran), we find that guilt in patients with suicidal tendencies is a profoundly spiritual issue that can be addressed effectively through collaboration among chaplains, physicians, and mental health providers.

Guilt is a serious spiritual condition that can easily be undertreated, or treated under the rubric of depression, which is related but not identical. Undertreatment occurs when caregivers, eager to see the guilt-sufferer experience relief, inadvertently short-circuit the necessary process of working through, rather than around, the guilt. Allowing patients to talk about their feelings of guilt without minimizing those feelings can be helpful even if, as Kopacz et al point out, the feelings are often irrational. We believe that people have an innate need to be truly heard and understood before they can become open to a reinterpretation of their feelings. Only then can the seeds of self-forgiveness begin to take root.

Hearing the words “There is hope for you to feel forgiven” can be more helpful than hearing “You didn’t really do anything bad,” particularly if the patient is religious. Hearing these words from a chaplain is often more effective than hearing them from a lay person, just as many of us take basic health information more seriously when we hear it from a physician. Even if the veteran is not overtly religious, there may be a unique exchange between that person and a religious authority when it concerns the violation of a millennia­old, widely known teaching from the Bible, such as “Thou shalt not kill.”

Guilt in patients with suicidal tendencies is a profoundly spiritual issue

Kopacz et al also rightly suggest that unless religious prohibitions have been balanced with teachings on forgiveness and grace, the teachings can actually exacerbate feelings of guilt and elevate them to harmful proportions, especially in the potentially vulnerable psyche of a veteran who may have been traumatized. If there is no religious or spiritual guidance for balancing prohibitions with graces, the patient may be left to spiral in an unending loop of guilt with no way out.

We therefore propose the following categories for different types (or “shades”) of guilt that can be effectively addressed by chaplains in concert with other members of the healthcare team. For simplicity, we call these types real guilt, survivor guilt, mistaken guilt, and complex-compound guilt.

REAL GUILT

An important role professional chaplains can play is to allow patients (in this case, veterans) to express their remorse and regret for violations of their own moral codes. In many cases, they have in fact hurt or killed another person, and they need the chance to unburden their hearts and spirits, especially if they were taught that killing people is a sin. Veterans who have harmed or killed others, even if under orders, are often left with bona fide feelings of guilt that need to be aired and released in a safe and confidential environment. This is often most effective when done by someone who not only is trained in nonjudgmental and nondirective listening, but also is a religious authority who can assure the patient of his or her innate worthiness and of the ability to be forgiven.

As Kopacz et al note, guilt is linked to a specific action or behavior and usually entails regret or remorse. Many veterans belong to or have had exposure to faith groups with strong moral codes and prohibitions, and so may see the chaplain as having authority to act as confessor and granter of absolution.

SURVIVOR GUILT

Survivor guilt is commonly understood as the feeling of surviving a terrible event or situation while someone else did not. Those who suffer from survivor guilt judge themselves unworthy of survival and believe the deceased to have been more courageous, virtuous, or somehow a better person than they. They torture themselves with ideas of the deceased person’s virtues—imagined or real—and sometimes go on to believe that “It should have been me who was killed.”

The burden of feeling that the wrong person died can be overwhelming. If these people are not helped to see their own worth and helped to find outlets for their sense of having been spared (by God, by their own wits, or by sheer luck), they are likely to struggle more. This is related but not identical to what we  call mistaken guilt. The two types are similar because they share a sense of randomness and helplessness, but they are different for reasons we will explain below.

Chaplains can be particularly effective partners in the care of veterans with survivor guilt, helping them to make meaning out of a life-changing event, rather than find meaning inherently in that event. Meaning, purpose, and “God’s plan for my life” are common themes in the pastoral conversation that can provide a compass for the disoriented survivor.

MISTAKEN GUILT

Mistaken guilt describes when a person who is involved in the death of another but is absolutely blameless—and could not possibly have prevented that death—literally “mis-takes” the guilt upon himself or herself in spite of the facts. Because of the helplessness induced by this feeling, mistaken guilt can be more difficult to treat than other forms. These patients continue to suffer despite assurances that the death occurred through absolutely no fault of their own.²

‘There is hope to feel forgiven’ can be more helpful than ‘You didn’t do anything bad’

Hickling³ has written extensively about this phenomenon in innocent motor vehicle drivers who cause pedestrian deaths, and he considers this type of guilt one of the most difficult to recover from precisely because of the helplessness factor. He has explained that if patients can find a real reason by which they were culpable for what happened, they can change their ways. But if they were absolutely innocent (as in many incidents in training or combat), they often cannot make sense of what happened in a way that allows them to move on because there is nothing they could have done differently and therefore nothing they can change.⁴

These patients almost certainly need long-term intervention such as cognitive behavioral therapy in order to train their mind away from such destructive thoughts. However, they are also very likely to be helped by a chaplain if they find that the event triggers memories of other past infractions of which they may need to unburden themselves (ie, confess).

COMPOUND-COMPLEX GUILT

As the name implies, compound-complex guilt is a combination of the other types and may have additional layers.

Compound-complex guilt leaves sufferers literally feeling guilty for feeling guilty. Though this may border on a genuine clinical disorder, it is also to some degree normal (eg, due to cultural taboos and norms) for people to feel culpable for not being able to “move on” or “forgive themselves” as quickly as others may want them to. Buddhists call this tendency the “second arrow effect.” The first arrow is the feeling of guilt (or other painful feeling) that strikes the individual, but the second arrow is the one he or she drives in afterward by thinking it is wrong or weak to even have the feeling.

Patients who suffer from this type of guilt blame themselves for the conundrum they are in and feel even worse. This is not unlike the vortex of unresolved and complicated grief.

Those who suffer from compound-complex guilt may layer the primary guilt with additional guilt for feeling weak, for needing help, or for asking for help. Especially in the culture of the military, the fear of stigma when asking for help (especially with mental health) is still quite strong. Therefore, chaplains can serve as a less threatening entry point for the veteran needing multiple professionals involved in his or her care.

NONJUDGMENTAL LISTENING

Nonjudgmental listening is essential to get at the source or sources of guilt, regardless of the type, in order to allow the wounds to air out and begin healing. Many veterans suffering from guilt may need intensive pharmacologic and cognitive therapy to fully recover, and care from a chaplain is not a substitute for psychiatric evaluation and treatment, especially if there is a risk of suicide.

However, chaplains may be able to help with the “deep work” of spiritual healing that is part of veterans’ overall recovery. This is true not only because chaplains are especially trained to do this, but also because they are the team members most likely to have uniquely spiritual language to speak to the condition. The language of confession, absolution, repentance, redemption, atonement, and forgiveness is language of the spiritual realm.

In addition, chaplains’ freedom from hourly billing concerns and their often less formalized interactions with patients may help to build trust. Well-trained chaplains, who are often quite gifted at creating an atmosphere of reverence and safety (sanctuary) in the most unlikely situations, are well suited to help the interdisciplinary team treat this vulnerable patient population.

SUGGESTED READING

For more insights into the role of chaplains on the interdisciplinary healthcare team, we recommend the following book: Cadge W. Paging God: Religion in the Halls of Medicine. Chicago, IL: University of Chicago Press; 2012.

In their commentary, Kopacz et al¹ propose that collaboration with professionally trained and certified clinical chaplains provides an opportunity for interdisciplinary care with increased benefit to veterans at risk of suicide. They rightly identify the pivotal issue of guilt as one that falls squarely in the domain of spiritual (or pastoral) care.

See related commentary

As professionals involved in the training of board-certifiable chaplains (and one of us is a veteran), we find that guilt in patients with suicidal tendencies is a profoundly spiritual issue that can be addressed effectively through collaboration among chaplains, physicians, and mental health providers.

Guilt is a serious spiritual condition that can easily be undertreated, or treated under the rubric of depression, which is related but not identical. Undertreatment occurs when caregivers, eager to see the guilt-sufferer experience relief, inadvertently short-circuit the necessary process of working through, rather than around, the guilt. Allowing patients to talk about their feelings of guilt without minimizing those feelings can be helpful even if, as Kopacz et al point out, the feelings are often irrational. We believe that people have an innate need to be truly heard and understood before they can become open to a reinterpretation of their feelings. Only then can the seeds of self-forgiveness begin to take root.

Hearing the words “There is hope for you to feel forgiven” can be more helpful than hearing “You didn’t really do anything bad,” particularly if the patient is religious. Hearing these words from a chaplain is often more effective than hearing them from a lay person, just as many of us take basic health information more seriously when we hear it from a physician. Even if the veteran is not overtly religious, there may be a unique exchange between that person and a religious authority when it concerns the violation of a millennia­old, widely known teaching from the Bible, such as “Thou shalt not kill.”

Guilt in patients with suicidal tendencies is a profoundly spiritual issue

Kopacz et al also rightly suggest that unless religious prohibitions have been balanced with teachings on forgiveness and grace, the teachings can actually exacerbate feelings of guilt and elevate them to harmful proportions, especially in the potentially vulnerable psyche of a veteran who may have been traumatized. If there is no religious or spiritual guidance for balancing prohibitions with graces, the patient may be left to spiral in an unending loop of guilt with no way out.

We therefore propose the following categories for different types (or “shades”) of guilt that can be effectively addressed by chaplains in concert with other members of the healthcare team. For simplicity, we call these types real guilt, survivor guilt, mistaken guilt, and complex-compound guilt.

REAL GUILT

An important role professional chaplains can play is to allow patients (in this case, veterans) to express their remorse and regret for violations of their own moral codes. In many cases, they have in fact hurt or killed another person, and they need the chance to unburden their hearts and spirits, especially if they were taught that killing people is a sin. Veterans who have harmed or killed others, even if under orders, are often left with bona fide feelings of guilt that need to be aired and released in a safe and confidential environment. This is often most effective when done by someone who not only is trained in nonjudgmental and nondirective listening, but also is a religious authority who can assure the patient of his or her innate worthiness and of the ability to be forgiven.

As Kopacz et al note, guilt is linked to a specific action or behavior and usually entails regret or remorse. Many veterans belong to or have had exposure to faith groups with strong moral codes and prohibitions, and so may see the chaplain as having authority to act as confessor and granter of absolution.

SURVIVOR GUILT

Survivor guilt is commonly understood as the feeling of surviving a terrible event or situation while someone else did not. Those who suffer from survivor guilt judge themselves unworthy of survival and believe the deceased to have been more courageous, virtuous, or somehow a better person than they. They torture themselves with ideas of the deceased person’s virtues—imagined or real—and sometimes go on to believe that “It should have been me who was killed.”

The burden of feeling that the wrong person died can be overwhelming. If these people are not helped to see their own worth and helped to find outlets for their sense of having been spared (by God, by their own wits, or by sheer luck), they are likely to struggle more. This is related but not identical to what we  call mistaken guilt. The two types are similar because they share a sense of randomness and helplessness, but they are different for reasons we will explain below.

Chaplains can be particularly effective partners in the care of veterans with survivor guilt, helping them to make meaning out of a life-changing event, rather than find meaning inherently in that event. Meaning, purpose, and “God’s plan for my life” are common themes in the pastoral conversation that can provide a compass for the disoriented survivor.

MISTAKEN GUILT

Mistaken guilt describes when a person who is involved in the death of another but is absolutely blameless—and could not possibly have prevented that death—literally “mis-takes” the guilt upon himself or herself in spite of the facts. Because of the helplessness induced by this feeling, mistaken guilt can be more difficult to treat than other forms. These patients continue to suffer despite assurances that the death occurred through absolutely no fault of their own.²

‘There is hope to feel forgiven’ can be more helpful than ‘You didn’t do anything bad’

Hickling³ has written extensively about this phenomenon in innocent motor vehicle drivers who cause pedestrian deaths, and he considers this type of guilt one of the most difficult to recover from precisely because of the helplessness factor. He has explained that if patients can find a real reason by which they were culpable for what happened, they can change their ways. But if they were absolutely innocent (as in many incidents in training or combat), they often cannot make sense of what happened in a way that allows them to move on because there is nothing they could have done differently and therefore nothing they can change.⁴

These patients almost certainly need long-term intervention such as cognitive behavioral therapy in order to train their mind away from such destructive thoughts. However, they are also very likely to be helped by a chaplain if they find that the event triggers memories of other past infractions of which they may need to unburden themselves (ie, confess).

COMPOUND-COMPLEX GUILT

As the name implies, compound-complex guilt is a combination of the other types and may have additional layers.

Compound-complex guilt leaves sufferers literally feeling guilty for feeling guilty. Though this may border on a genuine clinical disorder, it is also to some degree normal (eg, due to cultural taboos and norms) for people to feel culpable for not being able to “move on” or “forgive themselves” as quickly as others may want them to. Buddhists call this tendency the “second arrow effect.” The first arrow is the feeling of guilt (or other painful feeling) that strikes the individual, but the second arrow is the one he or she drives in afterward by thinking it is wrong or weak to even have the feeling.

Patients who suffer from this type of guilt blame themselves for the conundrum they are in and feel even worse. This is not unlike the vortex of unresolved and complicated grief.

Those who suffer from compound-complex guilt may layer the primary guilt with additional guilt for feeling weak, for needing help, or for asking for help. Especially in the culture of the military, the fear of stigma when asking for help (especially with mental health) is still quite strong. Therefore, chaplains can serve as a less threatening entry point for the veteran needing multiple professionals involved in his or her care.

NONJUDGMENTAL LISTENING

Nonjudgmental listening is essential to get at the source or sources of guilt, regardless of the type, in order to allow the wounds to air out and begin healing. Many veterans suffering from guilt may need intensive pharmacologic and cognitive therapy to fully recover, and care from a chaplain is not a substitute for psychiatric evaluation and treatment, especially if there is a risk of suicide.

However, chaplains may be able to help with the “deep work” of spiritual healing that is part of veterans’ overall recovery. This is true not only because chaplains are especially trained to do this, but also because they are the team members most likely to have uniquely spiritual language to speak to the condition. The language of confession, absolution, repentance, redemption, atonement, and forgiveness is language of the spiritual realm.

In addition, chaplains’ freedom from hourly billing concerns and their often less formalized interactions with patients may help to build trust. Well-trained chaplains, who are often quite gifted at creating an atmosphere of reverence and safety (sanctuary) in the most unlikely situations, are well suited to help the interdisciplinary team treat this vulnerable patient population.

SUGGESTED READING

For more insights into the role of chaplains on the interdisciplinary healthcare team, we recommend the following book: Cadge W. Paging God: Religion in the Halls of Medicine. Chicago, IL: University of Chicago Press; 2012.

Yes. Although implantable cardioverter-defibrillators (ICDs) prevent sudden cardiac death in patients with advanced heart failure, their benefit in terminally ill patients is small.¹ Furthermore, the shocks they deliver at the end of life can cause distress. Therefore, it is reasonable to consider ICD deactivation if the patient or family wishes.

See related commentary

A DIFFICULT DECISION

End-of-life decisions place significant emotional burdens on patients, their families, and their healthcare providers and can have social and legal consequences.

Turning off an ICD is an especially difficult decision, considering that these devices protect against sudden cardiac death and fatal arrhythmias. Also, patients and their representatives may find it more difficult to withdraw from active care than to forgo further interventions (more on this below), and they may misunderstand discussions about ICD deactivation, perceiving them as the beginning of abandonment.

ICD DEACTIVATION IS OFTEN DONE HAPHAZARDLY OR NOT AT ALL

Many healthcare providers are not trained in or comfortable with discussing end-of-life issues, and many hospitals and hospice programs lack policies and protocols for managing implanted devices at the end of life. Consequently, ICD management at the end of life varies among providers and tends to be suboptimal.²

In a report of a survey in 414 hospice facilities, 97% of facilities reported that they admitted patients with ICDs, but only 10% had a policy on device deactivation.³

In a survey of 47 European medical centers, only 4% said they addressed ICD deactivation with their patients.⁴

A study of 125 patients with ICDs who had died found that 52% had do-not-resuscitate orders. Nevertheless, in 100 patients the ICD had remained active in the last 24 hours of their life, and 31 of these patients had received shocks during their last 24 hours.⁵

In a survey of next of kin of patients with ICDs who had died of any cause,⁶ in only 27 of 100 cases had the clinician discussed ICD deactivation, and about three-fourths of these discussions had occurred during the last few days of life. Twenty-seven patients had received ICD discharges in the last month of life, and 8% had received a discharge during the final minutes.

TRAINING AND PROTOCOLS ARE NEEDED

Healthcare professionals need education about device deactivation at the end of life so that they are comfortable communicating with patients and families about this critical issue. To this end, several cardiac and palliative care societies have jointly released an expert statement on managing ICDs and other implantable devices in end-of-life situations.⁷

Many providers harbor a misunderstanding of the difference between withholding a device and withdrawing (or turning off) a device that is already implanted.² Some mistakenly believe they would be committing a crime by deactivating an implanted life-sustaining device. Legally and ethically, there is no difference between withholding a device and withdrawing a device. Legally, carrying out a request to withdraw life-sustaining treatment is neither physician-assisted suicide nor euthanasia.

DISCUSSION SHOULD BEGIN EARLY AND SHOULD BE ONGOING

The discussion of ICD deactivation should begin before the device is implanted and should continue as the patient’s health status changes. In a survey, 40% of patients said they felt that ICD deactivation should be discussed before the device is implanted, and only 5% felt that this discussion should be undertaken in the last days of life.⁸

At the least, it is important to identify patients with ICDs on admission to hospice and to have policies in place that ensure adequate patient education to make an informed decision about ICD deactivation at the end of life.

The topic should be discussed when goals of care change and when do-not-resuscitate status is addressed, and also when advanced directives are being acknowledged. If the patient or his or her legal representative wishes to keep the ICD turned on, that wish should be respected. The essence of a discussion is not to impose the providers’ choice on the patient, but to help the patient make the right decision for himself or herself. Of note, patients entering hospice do not have to have do-not-resuscitate status.

We believe that device management in end-of-life circumstances should be part of the discussion of the goals of care. Accordingly, healthcare providers need to be familiar with device management and to have a higher comfort level in addressing such sensitive topics with patients facing the end of life, as well as with their families.

It is also advisable to apply protocols within hospice services to address ICD management options for the patient and the legal representative. An early decision regarding end-of-life deactivation will help patients avoid distressing ICD discharges and the related emotional distress in their last moments.

Yes. Although implantable cardioverter-defibrillators (ICDs) prevent sudden cardiac death in patients with advanced heart failure, their benefit in terminally ill patients is small.¹ Furthermore, the shocks they deliver at the end of life can cause distress. Therefore, it is reasonable to consider ICD deactivation if the patient or family wishes.

See related commentary

A DIFFICULT DECISION

End-of-life decisions place significant emotional burdens on patients, their families, and their healthcare providers and can have social and legal consequences.

Turning off an ICD is an especially difficult decision, considering that these devices protect against sudden cardiac death and fatal arrhythmias. Also, patients and their representatives may find it more difficult to withdraw from active care than to forgo further interventions (more on this below), and they may misunderstand discussions about ICD deactivation, perceiving them as the beginning of abandonment.

ICD DEACTIVATION IS OFTEN DONE HAPHAZARDLY OR NOT AT ALL

Many healthcare providers are not trained in or comfortable with discussing end-of-life issues, and many hospitals and hospice programs lack policies and protocols for managing implanted devices at the end of life. Consequently, ICD management at the end of life varies among providers and tends to be suboptimal.²

In a report of a survey in 414 hospice facilities, 97% of facilities reported that they admitted patients with ICDs, but only 10% had a policy on device deactivation.³

In a survey of 47 European medical centers, only 4% said they addressed ICD deactivation with their patients.⁴

A study of 125 patients with ICDs who had died found that 52% had do-not-resuscitate orders. Nevertheless, in 100 patients the ICD had remained active in the last 24 hours of their life, and 31 of these patients had received shocks during their last 24 hours.⁵

In a survey of next of kin of patients with ICDs who had died of any cause,⁶ in only 27 of 100 cases had the clinician discussed ICD deactivation, and about three-fourths of these discussions had occurred during the last few days of life. Twenty-seven patients had received ICD discharges in the last month of life, and 8% had received a discharge during the final minutes.

TRAINING AND PROTOCOLS ARE NEEDED

Healthcare professionals need education about device deactivation at the end of life so that they are comfortable communicating with patients and families about this critical issue. To this end, several cardiac and palliative care societies have jointly released an expert statement on managing ICDs and other implantable devices in end-of-life situations.⁷

Many providers harbor a misunderstanding of the difference between withholding a device and withdrawing (or turning off) a device that is already implanted.² Some mistakenly believe they would be committing a crime by deactivating an implanted life-sustaining device. Legally and ethically, there is no difference between withholding a device and withdrawing a device. Legally, carrying out a request to withdraw life-sustaining treatment is neither physician-assisted suicide nor euthanasia.

DISCUSSION SHOULD BEGIN EARLY AND SHOULD BE ONGOING

The discussion of ICD deactivation should begin before the device is implanted and should continue as the patient’s health status changes. In a survey, 40% of patients said they felt that ICD deactivation should be discussed before the device is implanted, and only 5% felt that this discussion should be undertaken in the last days of life.⁸

At the least, it is important to identify patients with ICDs on admission to hospice and to have policies in place that ensure adequate patient education to make an informed decision about ICD deactivation at the end of life.

The topic should be discussed when goals of care change and when do-not-resuscitate status is addressed, and also when advanced directives are being acknowledged. If the patient or his or her legal representative wishes to keep the ICD turned on, that wish should be respected. The essence of a discussion is not to impose the providers’ choice on the patient, but to help the patient make the right decision for himself or herself. Of note, patients entering hospice do not have to have do-not-resuscitate status.

We believe that device management in end-of-life circumstances should be part of the discussion of the goals of care. Accordingly, healthcare providers need to be familiar with device management and to have a higher comfort level in addressing such sensitive topics with patients facing the end of life, as well as with their families.

It is also advisable to apply protocols within hospice services to address ICD management options for the patient and the legal representative. An early decision regarding end-of-life deactivation will help patients avoid distressing ICD discharges and the related emotional distress in their last moments.

Yes. Although implantable cardioverter-defibrillators (ICDs) prevent sudden cardiac death in patients with advanced heart failure, their benefit in terminally ill patients is small.¹ Furthermore, the shocks they deliver at the end of life can cause distress. Therefore, it is reasonable to consider ICD deactivation if the patient or family wishes.

See related commentary

A DIFFICULT DECISION

End-of-life decisions place significant emotional burdens on patients, their families, and their healthcare providers and can have social and legal consequences.

Turning off an ICD is an especially difficult decision, considering that these devices protect against sudden cardiac death and fatal arrhythmias. Also, patients and their representatives may find it more difficult to withdraw from active care than to forgo further interventions (more on this below), and they may misunderstand discussions about ICD deactivation, perceiving them as the beginning of abandonment.

ICD DEACTIVATION IS OFTEN DONE HAPHAZARDLY OR NOT AT ALL

Many healthcare providers are not trained in or comfortable with discussing end-of-life issues, and many hospitals and hospice programs lack policies and protocols for managing implanted devices at the end of life. Consequently, ICD management at the end of life varies among providers and tends to be suboptimal.²

In a report of a survey in 414 hospice facilities, 97% of facilities reported that they admitted patients with ICDs, but only 10% had a policy on device deactivation.³

In a survey of 47 European medical centers, only 4% said they addressed ICD deactivation with their patients.⁴

A study of 125 patients with ICDs who had died found that 52% had do-not-resuscitate orders. Nevertheless, in 100 patients the ICD had remained active in the last 24 hours of their life, and 31 of these patients had received shocks during their last 24 hours.⁵

In a survey of next of kin of patients with ICDs who had died of any cause,⁶ in only 27 of 100 cases had the clinician discussed ICD deactivation, and about three-fourths of these discussions had occurred during the last few days of life. Twenty-seven patients had received ICD discharges in the last month of life, and 8% had received a discharge during the final minutes.

TRAINING AND PROTOCOLS ARE NEEDED

Healthcare professionals need education about device deactivation at the end of life so that they are comfortable communicating with patients and families about this critical issue. To this end, several cardiac and palliative care societies have jointly released an expert statement on managing ICDs and other implantable devices in end-of-life situations.⁷

Many providers harbor a misunderstanding of the difference between withholding a device and withdrawing (or turning off) a device that is already implanted.² Some mistakenly believe they would be committing a crime by deactivating an implanted life-sustaining device. Legally and ethically, there is no difference between withholding a device and withdrawing a device. Legally, carrying out a request to withdraw life-sustaining treatment is neither physician-assisted suicide nor euthanasia.

DISCUSSION SHOULD BEGIN EARLY AND SHOULD BE ONGOING

The discussion of ICD deactivation should begin before the device is implanted and should continue as the patient’s health status changes. In a survey, 40% of patients said they felt that ICD deactivation should be discussed before the device is implanted, and only 5% felt that this discussion should be undertaken in the last days of life.⁸

At the least, it is important to identify patients with ICDs on admission to hospice and to have policies in place that ensure adequate patient education to make an informed decision about ICD deactivation at the end of life.

The topic should be discussed when goals of care change and when do-not-resuscitate status is addressed, and also when advanced directives are being acknowledged. If the patient or his or her legal representative wishes to keep the ICD turned on, that wish should be respected. The essence of a discussion is not to impose the providers’ choice on the patient, but to help the patient make the right decision for himself or herself. Of note, patients entering hospice do not have to have do-not-resuscitate status.

We believe that device management in end-of-life circumstances should be part of the discussion of the goals of care. Accordingly, healthcare providers need to be familiar with device management and to have a higher comfort level in addressing such sensitive topics with patients facing the end of life, as well as with their families.

It is also advisable to apply protocols within hospice services to address ICD management options for the patient and the legal representative. An early decision regarding end-of-life deactivation will help patients avoid distressing ICD discharges and the related emotional distress in their last moments.

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Although exercise is probably less effective than diet in reducing weight, most studies show that adding it to a diet regimen will increase the weight loss.^1,2 Guidelines from the American Heart Association, American College of Cardiology, and Obesity Society recommend a comprehensive lifestyle program that includes a low-calorie diet as well as an increase in physical activity.³

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Here, we review the many benefits of exercise for obese patients, not only in terms of weight loss, but also its positive cardiovascular and metabolic effects. Then we discuss how to motivate and prescribe exercise for this challenging group. 

EXERCISE IMPROVES WEIGHT LOSS

Increasing energy expenditure by exercising can mobilize and burn stored fat and thus lead to weight loss.⁴

Typically, with no changes in caloric intake, exercising 60 minutes at low intensity most days of the week will remove up to 0.5 lb per week.⁵ Exercising harder for longer will take off more weight, up to 3 lb per week.^1,6 Some practitioners believe that the total volume of exercise (frequency multiplied by  time) is more important than the intensity in determining the amount of weight loss.^2,7,8

Ross et al⁹ randomized 101 obese men to try to lose weight by exercising at a low to moderate intensity, to try to lose weight by dieting, to exercise without the goal of losing weight, or to do nothing (the control group). About half the participants declined or dropped out, but 52 completed the trial. The weight-loss-through-exercise group had lost approximately 15 lb by 12 weeks; the diet group lost a similar amount. Total body fat, visceral fat, and abdominal obesity were all reduced with both diet- and exercise-induced weight loss.

Without a change in diet, exercising 1 hour at low intensity most days of the week will remove up to 0.5 lb per week

In a study in 130 severely obese adults, after 6 months of high-intensity physical activity for a mean duration of 71 minutes per week, those on an exercise-and-diet regimen lost an average of 24 lb, compared with 18 lb with diet alone.¹⁰

 Another trial involved obese patients who were instructed to jog the equivalent of 20 miles (32.2 km) a week, with no restriction on caloric intake.¹¹ They lost only 2.9 kg (6.5 lb) over 8 months. Increased food intake explained this minimal weight loss.

In an analysis of 20 studies, exercise-only interventions of 4 months or less resulted in a mean weekly weight loss of 0.4 lb (0.2 kg), with a total loss of about 5 lb (2.3 kg).12

A systematic review of 15 studies noted that aerobic exercise for 3 months or more resulted in a significant reduction in visceral adipose tissue in overweight men and women as measured by computed tomography.¹³

Effects that different types of exercise have on weight loss

In a study of 119 sedentary adults who were overweight or obese and who were randomized to aerobic, resistance, or combined aerobic-resistance training over 8 months, those involved in aerobic or combined aerobic and resistance training had the greatest reduction in total body and fat mass.¹⁴ Given that the combined aerobic-resistance training program required twice the time commitment of the aerobic-alone program, the authors suggested that the most efficient manner of reducing body and fat mass is aerobic training alone.¹⁴ In contrast, if the goal is to increase lean muscle mass rather than lose weight and fat, then resistance training would be preferred.¹⁴

A meta-analysis confirmed the benefit of aerobic exercise, which resulted in significantly more loss in weight (1.2 kg, 2.6 lb), waist circumference (1.57 cm), and fat mass (1.2 kg, 2.6 lb) than resistance training.¹⁵ However, combined aerobic and resistance training was even better, with significantly more weight loss (2.0 kg, 4.4 lb) and fat mass reduction (1.9 kg, 4.2 lb).¹⁵

In summary, aerobic and combined aerobic-resistance training appear to be more effective for weight management in obese people than resistance training alone.

ADDITIONAL BENEFITS OF EXERCISE

Increasing regular physical activity through structured exercise has the additional benefits of improving physical fitness, flexibility, mobility, and cardiovascular health.^16,17

Even before patients lose a significant amount of weight (eg, 10%), low-intensity exercise such as walking 30 to 60 minutes most days of the week will rapidly improve cardiorespiratory fitness and have positive effects on cardiovascular risk factors such as hypertension, elevated blood glucose, and dyslipidemia.^18,19 Aerobic exercise and resistance training also reduce chronic inflammation, which is a strong indicator of future disease, especially in obese patients who have high levels of inflammatory biomarkers.^20,21

Even if he or she does not lose much weight, an obese exercising person with good cardiorespiratory fitness has lower cardiovascular risk than a person who is not obese but is poorly conditioned.²²

Exercise lowers blood pressure

Overactivity of the sympathetic nervous system is thought to account for over 50% of all cases of hypertension.²³ Obesity in concert with diabetes is characterized by sympathetic overactivity and progressive loss of cardiac parasympathetic activity.²⁴ Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes, and physical exercise may promote restoration of cardioprotective autonomic modulation in the heart.²⁴

Fit, obese people have lower cardiovascular risk than unfit normal-weight people

Several studies have shown that aerobic endurance exercise lowers blood pressure in patients with hypertension, and reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining this effect.²³ Another mechanism is endothelium-mediated vasodilation: even a single exercise session may increase the bioavailability of nitric oxide and decrease postexercise blood pressure.²⁵

Different types of exercise have been shown to have different effects on blood pressure.

Aerobic training has been shown to reduce systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg.²⁶

The hypotensive effect of endurance aerobic training is probably mediated at least in part by a reduction in systemic vascular resistance through decreased activity of the sympathetic and renin-angiotensin systems and through improved insulin sensitivity.²⁶ Other factors that may be involved include improved endothelium-dependent vasodilation, enhanced baroreceptor sensitivity, and arterial compliance.²⁶

Dynamic resistance exercise has less of an effect than aerobic exercise, but it has been shown to reduce systolic blood pressure by 0.5 to 4.8 mm Hg and diastolic blood pressure by 0.5 to 4.1 mm Hg.²⁶

In a meta-analysis of studies of resistance training lasting more than 1 month in healthy adults age 18 and older, the authors noted that resistance training induced a significant blood pressure reduction in 28 normotensive or prehypertensive study groups (–3.9/–3.9 mm Hg), whereas the reduction was not significant for the five hypertensive study groups.²⁷

Isometric resistance exercise has been associated with small cardiovascular benefits, but has been shown to reduce systolic blood pressure by 10.5 to 16.5 mm Hg and diastolic blood pressure by 0.62 to 16.4 mm Hg.²⁶

Exercise improves type 2 diabetes

Regular physical activity improves glycemic control and can prevent or delay the onset of type 2 diabetes mellitus.²⁸ Furthermore, physical activity positively affects lipid levels, lowers blood pressure, reduces the rate of cardiovascular events, and restores quality of life in patients  with type 2 diabetes.^24,29

A meta-analysis of the effect of supervised exercise in adults with type 2 diabetes found that structured exercise achieved the following:

• Lowered systolic blood pressure by 2.42 mm Hg (95% confidence interval 0.45–4.39)
• Lowered diastolic blood pressure by 2.23 mm Hg (1.25–3.21)
• Raised the level of high-density lipoprotein cholesterol by 0.04 mmol/L (0.02–0.07)
• Lowered the level of low-density lipoprotein cholesterol by 0.16 mmol/L (0.01–0.30).³⁰

The metabolic stress from physical exercise can increase oxidation of carbohydrates during exercise, increase postexercise consumption of oxygen (which can increase the rate of fat oxidation during recovery periods after exercise), improve glucose tolerance and insulin sensitivity, and reduce glycemia for 2 to 72 hours depending on the intensity and duration of the exercise.²⁵

Exercise lowers the Framingham risk score

Exercise improves several of the risk factors for coronary artery disease used in calculating the Framingham risk score—ie, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol—and thus can significantly lower this number. (It is important to remember that the Framingham score is a surrogate end point of cardiovascular risk that may correlate with a real clinical end point but does not necessarily have a guaranteed relationship.)

Aerobic training lowers systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg

In a study of a 12-week exercise program in middle-aged women (ages 40–55), treadmill running for 30 minutes a day 3 days a week significantly reduced 10-year cardiovascular risk scores: 10-year risk 2.2% vs 4.3% in the nonexercising group.³¹ Others have also shown that enhanced levels of fitness are associated with lower 10-year Framingham risk estimates.³²

A study of 31 healthy sedentary adults ages 50 to 65 who were randomized to an unsupervised but pedometer-monitored home-based walking program of 30 minutes of brisk walking 5 days a week noted significant reductions in systolic and diastolic blood pressure and stroke risk, and increased functional capacity in the walking group at 12 weeks.³³ Thus, the Framingham risk scores were significantly lower in the exercising group than in with the control group.³³

Given that overweight and obese patients who are starting to exercise may find jogging or running daunting, it should also be noted that three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk in reducing cardiovascular risk in previously sedentary people.³⁴

SETTING ‘SMART’ GOALS

Because obese adults typically do not comply well with prescriptions for exercise, it is important to educate them about its benefits and to provide tools such as perceived exertion scales so they can monitor their exercise, document their performance, and chart their progress; smartphone apps can also be helpful.³⁵ Supervised exercise may improve compliance and results.³⁶ Initially, personal trainers are excellent for starting a habit change, but they are expensive. Virtual trainers are now available and cost far less.³⁷

People do not become obese overnight.They gain weight over a long time. Likewise, weight reduction takes time if done in a sustainable and healthy manner. Thus, SMART goals—specific, measurable, attainable, realistic, timely—should be set to sustain the self-discipline required.

EXERCISE RECOMMENDATIONS

Any exercise program should target 30 to 60 minutes of effort per day, most days of the week, ie, 150 to 300 minutes per week or more.³⁸ But beginners should start low and go slow to avoid dropout, musculoskeletal strain, and joint injury.

The American College of Sports Medicine (ACSM)^38,39 recommends combining aerobic and progressive resistance exercise as the core components of an exercise program. The aerobic component can include anaerobic high-intensity interval training (see discussion below). In addition, we recommend flexibility and balance exercises for obese patients.⁴⁰

Three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk

Combining aerobic and resistance exercises likely results in greater decreases in abdominal adiposity in the obese.⁴¹ In addition, the aerobic portion of a combined exercise regimen can improve functional capacity, and the resistance portion may prevent injury by strengthening the muscles, bones, and joint support systems.⁴² Adding exercises that promote flexibility and balance helps with range of motion and prevents injuries while exercising.⁴³ These exercises not only expend calories during the exercise itself, but also increase resting energy expenditure for the remainder of the day, as the effects of the raised metabolism persist for hours.⁴⁴

Aerobic exercise is the foundation

Aerobic exercises that involve large muscle groups, especially walking, should be the foundation of cardiopulmonary exercise for obese persons.⁴⁵ Many patients can tolerate weight-bearing exercises such as walking or bike riding, but for some, exercises with limited or no weight-bearing such as swimming or aqua-aerobics are better.⁴⁶

Tips for prescribing. Patients should exercise:

• On 5 or 6 days each week
• At low to moderate intensity (30%–60% of maximum oxygen consumption [Vo₂ max])
• For at least 150 minutes per week, with a long-term goal of 300 minutes per week
• By walking, riding a stationary bicycle, or swimming.^38,47

To mobilize and use free fatty acids as an energy source, lower-intensity longer-duration aerobic exercise is preferred.⁵ Thus, frequent, low-intensity or moderate-intensity training (30%–60% of Vo₂ max) of longer duration (at least 60 minutes) may be the best approach to losing body fat in obese persons.^5,48 Early on in the exercise program, keep the intensity low, as high-intensity training will preferentially use stored glycogen or carbohydrate as an energy substrate rather than free fatty acids or fat.⁵

With light-moderate exercise, the heart rate will increase and patients will perspire, but they still should be able to carry on a conversation.

Measure (or have patients measure) the heart rate using the radial artery in their wrist after 6 minutes of walking. A pulse of 100 beats per minute or more is associated with an exercise intensity of approximately 50% (or more) of Vo₂ max.⁵

A study of 136 obese men and women who exercised for 6 months found that those doing aerobic exercise only and those doing a combination of aerobic and resistance exercise had greater cardiopulmonary fitness, greater reductions in abdominal and visceral fat, and more improved insulin sensitivity than those doing resistance exercise only.⁴¹ Although the aerobic­only group lost more weight (6 lb) than the aerobic-plus-resistance group (5.1 lb) and the resistance-only group (1.4 lb), combining aerobic and resistance exercise is considered optimal.

'SMART' goals: specific, measurable, attainable, realistic, timelyAll physical activity is beneficial, but activities that have less impact on the joints are less likely to cause injuries and joint pain. Aerobic activities that are especially useful in obese adults include walking at a speed of at least 2.5 miles per hour, bicycling, jogging, treadmill walking, swimming, aqua-aerobics, rowing, and low-impact aerobics classes.

Walking is the easiest way for most people to start their program, as it is safe, accessible, and relatively cheap with respect to equipment.³⁵ Adding a simple pedometer or smartphone app to measure the amount of exercise, together with physician counseling, may improve compliance and thus weight loss.^49,50

Obese patients may have been inactive for quite a while. Therefore, the sessions should be short and low-intensity at first, then steadily progress.⁵¹ To minimize dropout, avoid hard exercise too soon for people with a low exercise capacity or high body mass index at baseline, and give positive feedback and encouragement at each visit.⁵²

It is reasonable to introduce other aerobic exercises to vary the routine, use other muscle groups, and reduce the chance of injury from overuse of one muscle or joint group. Then, as cardiorespiratory fitness improves, the patient will be more confident about trying activities  that are more challenging, such as jogging and aerobics classes. An aerobic exercise program consisting only of swimming is less efficacious for weight loss in this population.⁵³

High-intensity interval training

High-intensity interval training involves relatively brief bursts of vigorous exercise separated by periods of recovery and is a time-efficient, novel alternative to continuous exercise.⁵⁴ The exercise component is anaerobic, meaning muscle movement that does not require oxygen. Anaerobic exercise uses fast-twitch muscle fibers, and thus helps that musculature to become stronger, larger, and more toned. Evidence suggests that high-intensity interval training induces health-enhancing adaptations similar to those of continuous exercise, despite a substantially lower time commitment.⁴¹

The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for at least 30 minutes a day on at least 5 days a week for a total of at least 150 minutes per week, or high-intensity cardiorespiratory exercise training for at least 20 minutes a day on at least 3 days a week for a goal of 75 minutes a week.³⁸ Thus, high-intensity interval training may be attractive for obese patients because it entails a shorter time commitment to achieve similar weight loss and improved insulin sensitivity than low-intensity or moderate-intensity continuous exercise.

High-intensity exercise has been shown to be effective for obese patients if they can do it.^54–56 In one study,⁵⁷ 134 obese patients, mean age 53, underwent supervised high-intensity interval training with resistance training two or three times a week, were encouraged to perform one or two additional exercise sessions a week (unsupervised), and were counseled to follow a Mediterranean diet. At 9 months, investigators noted a significant reduction in body mass, waist circumference, and fat mass.

Exercise targets: 30 to 60 minutes a day, most days of the weekA study of 12 weeks of high-intensity interval training, moderate-intensity interval training, or no exercise in 34 obese adolescent girls noted that body mass and percentage body fat were significantly decreased with both interval training regimens. However, the high-intensity group had greater reductions in waist circumference and more significant improvements in blood lipid levels, adiponectin levels, and insulin sensitivity.⁵⁸

Of 62 overweight and obese patients (mean age 53.3, mean body mass index 35.8 kg/m²), 97% adhered to a program of high-intensity interval training over 9 months, which resulted in an average weekly energy expenditure of 1,582 kcal.⁵⁵ Clinically and statistically significant improvements occurred in body mass (–5.3 kg), body mass index (–1.9 kg/m²), and waist circumference (–5.8 cm) (P < .0001 for all variables). Total fat mass, trunk fat mass, and lipid levels also significantly improved (P < .0001), and the prevalence of metabolic syndrome was reduced by 32.5% (P < .05).

In a meta-analysis of the effect of exercise on overweight adults, training of moderate or high intensity was noted to have the highest potential to reduce visceral adipose tissue in overweight men and women.¹³ Another meta-analysis noted that high-intensity interval training appeared to promote more improvement in fitness and similar improvements in some cardiometabolic risk factors than moderate exercise performed for at least 8 to 12 weeks in overweight patients.⁵⁶

A typical progressive exercise program for obese adults is shown in Table 1.

Progressive resistance exercise

Progressive resistance exercises are generally easier for obese patients, as they are not aerobically challenging, allow patients to exercise around physically active people who thus motivate them, and encourage positive feelings about completing their exercise sets.⁵⁹ The result is improved muscular fitness, socialization, and increased confidence in their abilities (self-efficacy).⁵⁹

Progressive resistance exercises also promote favorable energy balance and reduced visceral fat deposition through enhanced basal metabolism and activity levels while counteracting age- and disease-related muscle wasting.⁵⁹ They have been shown to improve cognitive ability, self-esteem, movement control, muscle mass, strength, glucose control, insulin sensitivity, resting blood pressure, lipid profile, and bone mineral density and to reduce fat weight, low back pain, arthritic discomfort, insomnia, anxiety, and depression.⁶⁰

Gym neophytes should spend a few sessions with a personal trainer to learn how to use the equipment.

While the primary goal of resistance training is more muscle strength, it can reduce fat and weight, burning up to 170 kcal in a 20-minute intense exercise session.⁶¹ It reduces both total body fat and visceral adipose tissue, thus benefiting obese persons by reducing insulin resistance.⁶² All exercise, and especially resistance exercise, can help to strengthen the musculoskeletal system, reduce muscle atrophy, and improve bone mineral density.⁶³

The ACSM guidelines³⁸ recommend progressive resistance exercise on 2 or 3 nonconsecutive days a week. It should involve:

• Exercises that work 8 to 10 muscle groups per session
• Two to four sets of 8 to 12 repetitions for each muscle group.

Exercising on nonconsecutive days allows time for the complete cycle of muscle tissue remodeling.⁶⁴ Such self-regulated intensity reduces the likelihood of excessive delayed-onset muscle soreness, which can discourage new participants.⁶⁵

To prevent muscle injury, obese people should begin with low-intensity workouts using lower resistance, one set of 8 to 12 repetitions 2 days a week. Then, they should gradually but progressively increase the intensity, volume, and frequency of the training.⁴⁷ This will obviate a plateau in training and will maximize musculoskeletal adaptation. The prescription should include exercises for the upper body (eg, biceps curls), lower body (eg, leg presses), and the midsection (eg, abdominal curl-ups, which give better abdominal muscle engagement and less risk to the back than crunches) and focus on the correct exercise form and function rather than the amount of resistance or weight lifted.

A typical progressive resistance exercise program for obese adults is shown in Table 2.

Flexibility exercise

Flexibility exercise involves stretching to improve the movement of muscles, joints, and ligaments.⁴⁵ While not specifically used in an energy-expenditure strategy, flexibility (or mobility) exercises help to increase or maintain joint range of motion and can reduce muscle and joint pain associated with obesity and exercise.⁶⁶

The ACSM recommends that stretching exercises be done when the muscles are warm after a brief warm-up or exercise session.³⁸ Typically, muscles should be stretched for at least 15 seconds, and stretching is recommended at a frequency of 2 to 4 days per week.³⁸

A good way to incorporate flexibility exercise is to join a yoga class, as yoga has been shown to improve strength and flexibility and may help control physiologic variables such as blood pressure, lipids, respiration, heart rate, and metabolic rate to improve overall exercise capacity in obese patients.⁶⁷

Balance exercise

Balance exercises help obese patients improve their stability. Poor balance is associated with injuries, accidents, and falls during activities of daily living.⁶⁸

Balance, the ability to maintain the body’s center of gravity within its base of support, can be categorized as static (sustaining the body in static equilibrium or within its base of support) or dynamic (maintaining equilibrium during a transition from a dynamic to a static state), which is more challenging.⁶⁹ Doing both static and dynamic balance training maximizes balance and stability.⁶⁹ While most activities that involve moving the body or body parts (such as walking) will improve balance, some additional balance exercises can be beneficial.

Balance exercises can be done without any equipment. Examples are balancing on one foot for 15 seconds and standing up and sitting down without using the hands. However, specific equipment can help, including physioballs, stability balls, cut-in-half stability balls, balance discs, balance wedges, wobble boards, rocker boards, and Indo boards.⁷⁰ In fact, balance boards and stability balls engage more muscle fibers in other areas of the body (lower back, lower abs, quads, hamstrings, and calves) than exercises done without those balancing devices.⁷¹

Balance training for at least 10 minutes a day, 3 days a week, for 4 weeks that incorporates various methods of balance training appears to improve balance.⁵⁶ Obese patients commencing a program should start with static balance exercises and then progress to dynamic ones. In addition, as balance training progresses, obese patients can integrate balance and stability training exercises with other pieces of equipment, such as performing squats on a balance board, and then gradually add weights (eg, dumbbells) to the exercise.

An example of a weekly comprehensive exercise program for an obese patient that incorporates all major exercise types is provided  in Table 3. In addition, some smartphone apps that are especially helpful in overweight newcomers to exercise include Couch-to-5K, GymGoal 2, Moves, Fitbit, Workout Trainer, Endomondo, MapMyFitness, Fitocracy, and Fitness Buddy.

BARIATRIC SURGERY AND LIFESTYLE MANAGEMENT FOR OBESITY

Bariatric surgery is a safe and effective treatment for severe obesity and comorbidities including type 2 diabetes mellitus, but weight loss and health outcomes vary considerably among individuals.^72,73 Of importance, postoperative weight loss after bariatric surgery and long-term weight loss largely depend on the extent to which patients can make and sustain changes to their lifestyle, including diet, exercise, and behavior modification.^72,74

Exercise, especially supervised, is associated with more weight loss after bariatric surgery.⁶¹ In a meta-analysis of bariatric patients, exercise participants involved in moderate or greater levels of exercise lost a mean of 3.6 kg more than the minimal exercise groups.⁷⁵ Another meta-analysis noted the beneficial effects of exercise incorporating more than 30 minutes a day of moderate physical activity following bariatric surgery and was associated with a greater weight loss of over 4% of body mass index.⁷⁶ These findings were consistent with those of yet another meta-analysis.⁷⁷

In summary, exercise appears to significantly increase weight loss after bariatric surgery.

TREATMENT CONSIDERATIONS IN MORBID OBESITY

Challenges faced by severely obese or morbidly obese patients affect their exercise options. The types of exercise they are able to perform are limited in most cases to very-low-impact, low-intensity exercises, which may not be as efficient in weight loss or weight maintenance.⁴⁸ Therefore, it may be prudent to set more conservative weight-loss goals for them, especially early in the program. Compliance and success rates may be better with low-impact activities such as walking, water aerobics, stationary cycling, and resistance training in the severely obese population.

The more severe the obesity, the more comorbidities such as diabetes, hypertension, hyperlipidemia, arthritis, sleep apnea, gastroesophageal reflux disease, and the greater the risk of metabolic syndrome—and conversely, the greater the potential benefit from bariatric surgery followed by exercise.⁷⁴

A LONG-TERM ENDEAVOR

For obese patients, a comprehensive exercise program will improve functional status, favorably influence cardiovascular risk factors, and help with weight loss or weight maintenance.

Managing obesity is a long-term endeavor.⁷⁸ For it to succeed, both the patient and the physician need to keep up their efforts. To keep the patient from becoming discouraged, the clinician should focus not just on weight, but also on improvements in metabolic profile and cardiorespiratory fitness. In addition, a careful evaluation, a clear exercise prescription, defined goals, ongoing monitoring (by the patient and the provider), frequent feedback, and charting of progress will improve daily performance and the chance of long-term success.

Although exercise is probably less effective than diet in reducing weight, most studies show that adding it to a diet regimen will increase the weight loss.^1,2 Guidelines from the American Heart Association, American College of Cardiology, and Obesity Society recommend a comprehensive lifestyle program that includes a low-calorie diet as well as an increase in physical activity.³

See patient information

Here, we review the many benefits of exercise for obese patients, not only in terms of weight loss, but also its positive cardiovascular and metabolic effects. Then we discuss how to motivate and prescribe exercise for this challenging group. 

EXERCISE IMPROVES WEIGHT LOSS

Increasing energy expenditure by exercising can mobilize and burn stored fat and thus lead to weight loss.⁴

Typically, with no changes in caloric intake, exercising 60 minutes at low intensity most days of the week will remove up to 0.5 lb per week.⁵ Exercising harder for longer will take off more weight, up to 3 lb per week.^1,6 Some practitioners believe that the total volume of exercise (frequency multiplied by  time) is more important than the intensity in determining the amount of weight loss.^2,7,8

Ross et al⁹ randomized 101 obese men to try to lose weight by exercising at a low to moderate intensity, to try to lose weight by dieting, to exercise without the goal of losing weight, or to do nothing (the control group). About half the participants declined or dropped out, but 52 completed the trial. The weight-loss-through-exercise group had lost approximately 15 lb by 12 weeks; the diet group lost a similar amount. Total body fat, visceral fat, and abdominal obesity were all reduced with both diet- and exercise-induced weight loss.

Without a change in diet, exercising 1 hour at low intensity most days of the week will remove up to 0.5 lb per week

In a study in 130 severely obese adults, after 6 months of high-intensity physical activity for a mean duration of 71 minutes per week, those on an exercise-and-diet regimen lost an average of 24 lb, compared with 18 lb with diet alone.¹⁰

 Another trial involved obese patients who were instructed to jog the equivalent of 20 miles (32.2 km) a week, with no restriction on caloric intake.¹¹ They lost only 2.9 kg (6.5 lb) over 8 months. Increased food intake explained this minimal weight loss.

In an analysis of 20 studies, exercise-only interventions of 4 months or less resulted in a mean weekly weight loss of 0.4 lb (0.2 kg), with a total loss of about 5 lb (2.3 kg).12

A systematic review of 15 studies noted that aerobic exercise for 3 months or more resulted in a significant reduction in visceral adipose tissue in overweight men and women as measured by computed tomography.¹³

Effects that different types of exercise have on weight loss

In a study of 119 sedentary adults who were overweight or obese and who were randomized to aerobic, resistance, or combined aerobic-resistance training over 8 months, those involved in aerobic or combined aerobic and resistance training had the greatest reduction in total body and fat mass.¹⁴ Given that the combined aerobic-resistance training program required twice the time commitment of the aerobic-alone program, the authors suggested that the most efficient manner of reducing body and fat mass is aerobic training alone.¹⁴ In contrast, if the goal is to increase lean muscle mass rather than lose weight and fat, then resistance training would be preferred.¹⁴

A meta-analysis confirmed the benefit of aerobic exercise, which resulted in significantly more loss in weight (1.2 kg, 2.6 lb), waist circumference (1.57 cm), and fat mass (1.2 kg, 2.6 lb) than resistance training.¹⁵ However, combined aerobic and resistance training was even better, with significantly more weight loss (2.0 kg, 4.4 lb) and fat mass reduction (1.9 kg, 4.2 lb).¹⁵

In summary, aerobic and combined aerobic-resistance training appear to be more effective for weight management in obese people than resistance training alone.

ADDITIONAL BENEFITS OF EXERCISE

Increasing regular physical activity through structured exercise has the additional benefits of improving physical fitness, flexibility, mobility, and cardiovascular health.^16,17

Even before patients lose a significant amount of weight (eg, 10%), low-intensity exercise such as walking 30 to 60 minutes most days of the week will rapidly improve cardiorespiratory fitness and have positive effects on cardiovascular risk factors such as hypertension, elevated blood glucose, and dyslipidemia.^18,19 Aerobic exercise and resistance training also reduce chronic inflammation, which is a strong indicator of future disease, especially in obese patients who have high levels of inflammatory biomarkers.^20,21

Even if he or she does not lose much weight, an obese exercising person with good cardiorespiratory fitness has lower cardiovascular risk than a person who is not obese but is poorly conditioned.²²

Exercise lowers blood pressure

Overactivity of the sympathetic nervous system is thought to account for over 50% of all cases of hypertension.²³ Obesity in concert with diabetes is characterized by sympathetic overactivity and progressive loss of cardiac parasympathetic activity.²⁴ Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes, and physical exercise may promote restoration of cardioprotective autonomic modulation in the heart.²⁴

Fit, obese people have lower cardiovascular risk than unfit normal-weight people

Several studies have shown that aerobic endurance exercise lowers blood pressure in patients with hypertension, and reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining this effect.²³ Another mechanism is endothelium-mediated vasodilation: even a single exercise session may increase the bioavailability of nitric oxide and decrease postexercise blood pressure.²⁵

Different types of exercise have been shown to have different effects on blood pressure.

Aerobic training has been shown to reduce systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg.²⁶

The hypotensive effect of endurance aerobic training is probably mediated at least in part by a reduction in systemic vascular resistance through decreased activity of the sympathetic and renin-angiotensin systems and through improved insulin sensitivity.²⁶ Other factors that may be involved include improved endothelium-dependent vasodilation, enhanced baroreceptor sensitivity, and arterial compliance.²⁶

Dynamic resistance exercise has less of an effect than aerobic exercise, but it has been shown to reduce systolic blood pressure by 0.5 to 4.8 mm Hg and diastolic blood pressure by 0.5 to 4.1 mm Hg.²⁶

In a meta-analysis of studies of resistance training lasting more than 1 month in healthy adults age 18 and older, the authors noted that resistance training induced a significant blood pressure reduction in 28 normotensive or prehypertensive study groups (–3.9/–3.9 mm Hg), whereas the reduction was not significant for the five hypertensive study groups.²⁷

Isometric resistance exercise has been associated with small cardiovascular benefits, but has been shown to reduce systolic blood pressure by 10.5 to 16.5 mm Hg and diastolic blood pressure by 0.62 to 16.4 mm Hg.²⁶

Exercise improves type 2 diabetes

Regular physical activity improves glycemic control and can prevent or delay the onset of type 2 diabetes mellitus.²⁸ Furthermore, physical activity positively affects lipid levels, lowers blood pressure, reduces the rate of cardiovascular events, and restores quality of life in patients  with type 2 diabetes.^24,29

A meta-analysis of the effect of supervised exercise in adults with type 2 diabetes found that structured exercise achieved the following:

• Lowered systolic blood pressure by 2.42 mm Hg (95% confidence interval 0.45–4.39)
• Lowered diastolic blood pressure by 2.23 mm Hg (1.25–3.21)
• Raised the level of high-density lipoprotein cholesterol by 0.04 mmol/L (0.02–0.07)
• Lowered the level of low-density lipoprotein cholesterol by 0.16 mmol/L (0.01–0.30).³⁰

The metabolic stress from physical exercise can increase oxidation of carbohydrates during exercise, increase postexercise consumption of oxygen (which can increase the rate of fat oxidation during recovery periods after exercise), improve glucose tolerance and insulin sensitivity, and reduce glycemia for 2 to 72 hours depending on the intensity and duration of the exercise.²⁵

Exercise lowers the Framingham risk score

Exercise improves several of the risk factors for coronary artery disease used in calculating the Framingham risk score—ie, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol—and thus can significantly lower this number. (It is important to remember that the Framingham score is a surrogate end point of cardiovascular risk that may correlate with a real clinical end point but does not necessarily have a guaranteed relationship.)

Aerobic training lowers systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg

In a study of a 12-week exercise program in middle-aged women (ages 40–55), treadmill running for 30 minutes a day 3 days a week significantly reduced 10-year cardiovascular risk scores: 10-year risk 2.2% vs 4.3% in the nonexercising group.³¹ Others have also shown that enhanced levels of fitness are associated with lower 10-year Framingham risk estimates.³²

A study of 31 healthy sedentary adults ages 50 to 65 who were randomized to an unsupervised but pedometer-monitored home-based walking program of 30 minutes of brisk walking 5 days a week noted significant reductions in systolic and diastolic blood pressure and stroke risk, and increased functional capacity in the walking group at 12 weeks.³³ Thus, the Framingham risk scores were significantly lower in the exercising group than in with the control group.³³

Given that overweight and obese patients who are starting to exercise may find jogging or running daunting, it should also be noted that three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk in reducing cardiovascular risk in previously sedentary people.³⁴

SETTING ‘SMART’ GOALS

Because obese adults typically do not comply well with prescriptions for exercise, it is important to educate them about its benefits and to provide tools such as perceived exertion scales so they can monitor their exercise, document their performance, and chart their progress; smartphone apps can also be helpful.³⁵ Supervised exercise may improve compliance and results.³⁶ Initially, personal trainers are excellent for starting a habit change, but they are expensive. Virtual trainers are now available and cost far less.³⁷

People do not become obese overnight.They gain weight over a long time. Likewise, weight reduction takes time if done in a sustainable and healthy manner. Thus, SMART goals—specific, measurable, attainable, realistic, timely—should be set to sustain the self-discipline required.

EXERCISE RECOMMENDATIONS

Any exercise program should target 30 to 60 minutes of effort per day, most days of the week, ie, 150 to 300 minutes per week or more.³⁸ But beginners should start low and go slow to avoid dropout, musculoskeletal strain, and joint injury.

The American College of Sports Medicine (ACSM)^38,39 recommends combining aerobic and progressive resistance exercise as the core components of an exercise program. The aerobic component can include anaerobic high-intensity interval training (see discussion below). In addition, we recommend flexibility and balance exercises for obese patients.⁴⁰

Three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk

Combining aerobic and resistance exercises likely results in greater decreases in abdominal adiposity in the obese.⁴¹ In addition, the aerobic portion of a combined exercise regimen can improve functional capacity, and the resistance portion may prevent injury by strengthening the muscles, bones, and joint support systems.⁴² Adding exercises that promote flexibility and balance helps with range of motion and prevents injuries while exercising.⁴³ These exercises not only expend calories during the exercise itself, but also increase resting energy expenditure for the remainder of the day, as the effects of the raised metabolism persist for hours.⁴⁴

Aerobic exercise is the foundation

Aerobic exercises that involve large muscle groups, especially walking, should be the foundation of cardiopulmonary exercise for obese persons.⁴⁵ Many patients can tolerate weight-bearing exercises such as walking or bike riding, but for some, exercises with limited or no weight-bearing such as swimming or aqua-aerobics are better.⁴⁶

Tips for prescribing. Patients should exercise:

• On 5 or 6 days each week
• At low to moderate intensity (30%–60% of maximum oxygen consumption [Vo₂ max])
• For at least 150 minutes per week, with a long-term goal of 300 minutes per week
• By walking, riding a stationary bicycle, or swimming.^38,47

To mobilize and use free fatty acids as an energy source, lower-intensity longer-duration aerobic exercise is preferred.⁵ Thus, frequent, low-intensity or moderate-intensity training (30%–60% of Vo₂ max) of longer duration (at least 60 minutes) may be the best approach to losing body fat in obese persons.^5,48 Early on in the exercise program, keep the intensity low, as high-intensity training will preferentially use stored glycogen or carbohydrate as an energy substrate rather than free fatty acids or fat.⁵

With light-moderate exercise, the heart rate will increase and patients will perspire, but they still should be able to carry on a conversation.

Measure (or have patients measure) the heart rate using the radial artery in their wrist after 6 minutes of walking. A pulse of 100 beats per minute or more is associated with an exercise intensity of approximately 50% (or more) of Vo₂ max.⁵

A study of 136 obese men and women who exercised for 6 months found that those doing aerobic exercise only and those doing a combination of aerobic and resistance exercise had greater cardiopulmonary fitness, greater reductions in abdominal and visceral fat, and more improved insulin sensitivity than those doing resistance exercise only.⁴¹ Although the aerobic­only group lost more weight (6 lb) than the aerobic-plus-resistance group (5.1 lb) and the resistance-only group (1.4 lb), combining aerobic and resistance exercise is considered optimal.

'SMART' goals: specific, measurable, attainable, realistic, timelyAll physical activity is beneficial, but activities that have less impact on the joints are less likely to cause injuries and joint pain. Aerobic activities that are especially useful in obese adults include walking at a speed of at least 2.5 miles per hour, bicycling, jogging, treadmill walking, swimming, aqua-aerobics, rowing, and low-impact aerobics classes.

Walking is the easiest way for most people to start their program, as it is safe, accessible, and relatively cheap with respect to equipment.³⁵ Adding a simple pedometer or smartphone app to measure the amount of exercise, together with physician counseling, may improve compliance and thus weight loss.^49,50

Obese patients may have been inactive for quite a while. Therefore, the sessions should be short and low-intensity at first, then steadily progress.⁵¹ To minimize dropout, avoid hard exercise too soon for people with a low exercise capacity or high body mass index at baseline, and give positive feedback and encouragement at each visit.⁵²

It is reasonable to introduce other aerobic exercises to vary the routine, use other muscle groups, and reduce the chance of injury from overuse of one muscle or joint group. Then, as cardiorespiratory fitness improves, the patient will be more confident about trying activities  that are more challenging, such as jogging and aerobics classes. An aerobic exercise program consisting only of swimming is less efficacious for weight loss in this population.⁵³

High-intensity interval training

High-intensity interval training involves relatively brief bursts of vigorous exercise separated by periods of recovery and is a time-efficient, novel alternative to continuous exercise.⁵⁴ The exercise component is anaerobic, meaning muscle movement that does not require oxygen. Anaerobic exercise uses fast-twitch muscle fibers, and thus helps that musculature to become stronger, larger, and more toned. Evidence suggests that high-intensity interval training induces health-enhancing adaptations similar to those of continuous exercise, despite a substantially lower time commitment.⁴¹

The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for at least 30 minutes a day on at least 5 days a week for a total of at least 150 minutes per week, or high-intensity cardiorespiratory exercise training for at least 20 minutes a day on at least 3 days a week for a goal of 75 minutes a week.³⁸ Thus, high-intensity interval training may be attractive for obese patients because it entails a shorter time commitment to achieve similar weight loss and improved insulin sensitivity than low-intensity or moderate-intensity continuous exercise.

High-intensity exercise has been shown to be effective for obese patients if they can do it.^54–56 In one study,⁵⁷ 134 obese patients, mean age 53, underwent supervised high-intensity interval training with resistance training two or three times a week, were encouraged to perform one or two additional exercise sessions a week (unsupervised), and were counseled to follow a Mediterranean diet. At 9 months, investigators noted a significant reduction in body mass, waist circumference, and fat mass.

Exercise targets: 30 to 60 minutes a day, most days of the weekA study of 12 weeks of high-intensity interval training, moderate-intensity interval training, or no exercise in 34 obese adolescent girls noted that body mass and percentage body fat were significantly decreased with both interval training regimens. However, the high-intensity group had greater reductions in waist circumference and more significant improvements in blood lipid levels, adiponectin levels, and insulin sensitivity.⁵⁸

Of 62 overweight and obese patients (mean age 53.3, mean body mass index 35.8 kg/m²), 97% adhered to a program of high-intensity interval training over 9 months, which resulted in an average weekly energy expenditure of 1,582 kcal.⁵⁵ Clinically and statistically significant improvements occurred in body mass (–5.3 kg), body mass index (–1.9 kg/m²), and waist circumference (–5.8 cm) (P < .0001 for all variables). Total fat mass, trunk fat mass, and lipid levels also significantly improved (P < .0001), and the prevalence of metabolic syndrome was reduced by 32.5% (P < .05).

In a meta-analysis of the effect of exercise on overweight adults, training of moderate or high intensity was noted to have the highest potential to reduce visceral adipose tissue in overweight men and women.¹³ Another meta-analysis noted that high-intensity interval training appeared to promote more improvement in fitness and similar improvements in some cardiometabolic risk factors than moderate exercise performed for at least 8 to 12 weeks in overweight patients.⁵⁶

A typical progressive exercise program for obese adults is shown in Table 1.

Progressive resistance exercise

Progressive resistance exercises are generally easier for obese patients, as they are not aerobically challenging, allow patients to exercise around physically active people who thus motivate them, and encourage positive feelings about completing their exercise sets.⁵⁹ The result is improved muscular fitness, socialization, and increased confidence in their abilities (self-efficacy).⁵⁹

Progressive resistance exercises also promote favorable energy balance and reduced visceral fat deposition through enhanced basal metabolism and activity levels while counteracting age- and disease-related muscle wasting.⁵⁹ They have been shown to improve cognitive ability, self-esteem, movement control, muscle mass, strength, glucose control, insulin sensitivity, resting blood pressure, lipid profile, and bone mineral density and to reduce fat weight, low back pain, arthritic discomfort, insomnia, anxiety, and depression.⁶⁰

Gym neophytes should spend a few sessions with a personal trainer to learn how to use the equipment.

While the primary goal of resistance training is more muscle strength, it can reduce fat and weight, burning up to 170 kcal in a 20-minute intense exercise session.⁶¹ It reduces both total body fat and visceral adipose tissue, thus benefiting obese persons by reducing insulin resistance.⁶² All exercise, and especially resistance exercise, can help to strengthen the musculoskeletal system, reduce muscle atrophy, and improve bone mineral density.⁶³

The ACSM guidelines³⁸ recommend progressive resistance exercise on 2 or 3 nonconsecutive days a week. It should involve:

• Exercises that work 8 to 10 muscle groups per session
• Two to four sets of 8 to 12 repetitions for each muscle group.

Exercising on nonconsecutive days allows time for the complete cycle of muscle tissue remodeling.⁶⁴ Such self-regulated intensity reduces the likelihood of excessive delayed-onset muscle soreness, which can discourage new participants.⁶⁵

To prevent muscle injury, obese people should begin with low-intensity workouts using lower resistance, one set of 8 to 12 repetitions 2 days a week. Then, they should gradually but progressively increase the intensity, volume, and frequency of the training.⁴⁷ This will obviate a plateau in training and will maximize musculoskeletal adaptation. The prescription should include exercises for the upper body (eg, biceps curls), lower body (eg, leg presses), and the midsection (eg, abdominal curl-ups, which give better abdominal muscle engagement and less risk to the back than crunches) and focus on the correct exercise form and function rather than the amount of resistance or weight lifted.

A typical progressive resistance exercise program for obese adults is shown in Table 2.

Flexibility exercise

Flexibility exercise involves stretching to improve the movement of muscles, joints, and ligaments.⁴⁵ While not specifically used in an energy-expenditure strategy, flexibility (or mobility) exercises help to increase or maintain joint range of motion and can reduce muscle and joint pain associated with obesity and exercise.⁶⁶

The ACSM recommends that stretching exercises be done when the muscles are warm after a brief warm-up or exercise session.³⁸ Typically, muscles should be stretched for at least 15 seconds, and stretching is recommended at a frequency of 2 to 4 days per week.³⁸

A good way to incorporate flexibility exercise is to join a yoga class, as yoga has been shown to improve strength and flexibility and may help control physiologic variables such as blood pressure, lipids, respiration, heart rate, and metabolic rate to improve overall exercise capacity in obese patients.⁶⁷

Balance exercise

Balance exercises help obese patients improve their stability. Poor balance is associated with injuries, accidents, and falls during activities of daily living.⁶⁸

Balance, the ability to maintain the body’s center of gravity within its base of support, can be categorized as static (sustaining the body in static equilibrium or within its base of support) or dynamic (maintaining equilibrium during a transition from a dynamic to a static state), which is more challenging.⁶⁹ Doing both static and dynamic balance training maximizes balance and stability.⁶⁹ While most activities that involve moving the body or body parts (such as walking) will improve balance, some additional balance exercises can be beneficial.

Balance exercises can be done without any equipment. Examples are balancing on one foot for 15 seconds and standing up and sitting down without using the hands. However, specific equipment can help, including physioballs, stability balls, cut-in-half stability balls, balance discs, balance wedges, wobble boards, rocker boards, and Indo boards.⁷⁰ In fact, balance boards and stability balls engage more muscle fibers in other areas of the body (lower back, lower abs, quads, hamstrings, and calves) than exercises done without those balancing devices.⁷¹

Balance training for at least 10 minutes a day, 3 days a week, for 4 weeks that incorporates various methods of balance training appears to improve balance.⁵⁶ Obese patients commencing a program should start with static balance exercises and then progress to dynamic ones. In addition, as balance training progresses, obese patients can integrate balance and stability training exercises with other pieces of equipment, such as performing squats on a balance board, and then gradually add weights (eg, dumbbells) to the exercise.

An example of a weekly comprehensive exercise program for an obese patient that incorporates all major exercise types is provided  in Table 3. In addition, some smartphone apps that are especially helpful in overweight newcomers to exercise include Couch-to-5K, GymGoal 2, Moves, Fitbit, Workout Trainer, Endomondo, MapMyFitness, Fitocracy, and Fitness Buddy.

BARIATRIC SURGERY AND LIFESTYLE MANAGEMENT FOR OBESITY

Bariatric surgery is a safe and effective treatment for severe obesity and comorbidities including type 2 diabetes mellitus, but weight loss and health outcomes vary considerably among individuals.^72,73 Of importance, postoperative weight loss after bariatric surgery and long-term weight loss largely depend on the extent to which patients can make and sustain changes to their lifestyle, including diet, exercise, and behavior modification.^72,74

Exercise, especially supervised, is associated with more weight loss after bariatric surgery.⁶¹ In a meta-analysis of bariatric patients, exercise participants involved in moderate or greater levels of exercise lost a mean of 3.6 kg more than the minimal exercise groups.⁷⁵ Another meta-analysis noted the beneficial effects of exercise incorporating more than 30 minutes a day of moderate physical activity following bariatric surgery and was associated with a greater weight loss of over 4% of body mass index.⁷⁶ These findings were consistent with those of yet another meta-analysis.⁷⁷

In summary, exercise appears to significantly increase weight loss after bariatric surgery.

TREATMENT CONSIDERATIONS IN MORBID OBESITY

Challenges faced by severely obese or morbidly obese patients affect their exercise options. The types of exercise they are able to perform are limited in most cases to very-low-impact, low-intensity exercises, which may not be as efficient in weight loss or weight maintenance.⁴⁸ Therefore, it may be prudent to set more conservative weight-loss goals for them, especially early in the program. Compliance and success rates may be better with low-impact activities such as walking, water aerobics, stationary cycling, and resistance training in the severely obese population.

The more severe the obesity, the more comorbidities such as diabetes, hypertension, hyperlipidemia, arthritis, sleep apnea, gastroesophageal reflux disease, and the greater the risk of metabolic syndrome—and conversely, the greater the potential benefit from bariatric surgery followed by exercise.⁷⁴

A LONG-TERM ENDEAVOR

For obese patients, a comprehensive exercise program will improve functional status, favorably influence cardiovascular risk factors, and help with weight loss or weight maintenance.

Managing obesity is a long-term endeavor.⁷⁸ For it to succeed, both the patient and the physician need to keep up their efforts. To keep the patient from becoming discouraged, the clinician should focus not just on weight, but also on improvements in metabolic profile and cardiorespiratory fitness. In addition, a careful evaluation, a clear exercise prescription, defined goals, ongoing monitoring (by the patient and the provider), frequent feedback, and charting of progress will improve daily performance and the chance of long-term success.

Although exercise is probably less effective than diet in reducing weight, most studies show that adding it to a diet regimen will increase the weight loss.^1,2 Guidelines from the American Heart Association, American College of Cardiology, and Obesity Society recommend a comprehensive lifestyle program that includes a low-calorie diet as well as an increase in physical activity.³

See patient information

Here, we review the many benefits of exercise for obese patients, not only in terms of weight loss, but also its positive cardiovascular and metabolic effects. Then we discuss how to motivate and prescribe exercise for this challenging group. 

EXERCISE IMPROVES WEIGHT LOSS

Increasing energy expenditure by exercising can mobilize and burn stored fat and thus lead to weight loss.⁴

Typically, with no changes in caloric intake, exercising 60 minutes at low intensity most days of the week will remove up to 0.5 lb per week.⁵ Exercising harder for longer will take off more weight, up to 3 lb per week.^1,6 Some practitioners believe that the total volume of exercise (frequency multiplied by  time) is more important than the intensity in determining the amount of weight loss.^2,7,8

Ross et al⁹ randomized 101 obese men to try to lose weight by exercising at a low to moderate intensity, to try to lose weight by dieting, to exercise without the goal of losing weight, or to do nothing (the control group). About half the participants declined or dropped out, but 52 completed the trial. The weight-loss-through-exercise group had lost approximately 15 lb by 12 weeks; the diet group lost a similar amount. Total body fat, visceral fat, and abdominal obesity were all reduced with both diet- and exercise-induced weight loss.

Without a change in diet, exercising 1 hour at low intensity most days of the week will remove up to 0.5 lb per week

In a study in 130 severely obese adults, after 6 months of high-intensity physical activity for a mean duration of 71 minutes per week, those on an exercise-and-diet regimen lost an average of 24 lb, compared with 18 lb with diet alone.¹⁰

 Another trial involved obese patients who were instructed to jog the equivalent of 20 miles (32.2 km) a week, with no restriction on caloric intake.¹¹ They lost only 2.9 kg (6.5 lb) over 8 months. Increased food intake explained this minimal weight loss.

In an analysis of 20 studies, exercise-only interventions of 4 months or less resulted in a mean weekly weight loss of 0.4 lb (0.2 kg), with a total loss of about 5 lb (2.3 kg).12

A systematic review of 15 studies noted that aerobic exercise for 3 months or more resulted in a significant reduction in visceral adipose tissue in overweight men and women as measured by computed tomography.¹³

Effects that different types of exercise have on weight loss

In a study of 119 sedentary adults who were overweight or obese and who were randomized to aerobic, resistance, or combined aerobic-resistance training over 8 months, those involved in aerobic or combined aerobic and resistance training had the greatest reduction in total body and fat mass.¹⁴ Given that the combined aerobic-resistance training program required twice the time commitment of the aerobic-alone program, the authors suggested that the most efficient manner of reducing body and fat mass is aerobic training alone.¹⁴ In contrast, if the goal is to increase lean muscle mass rather than lose weight and fat, then resistance training would be preferred.¹⁴

A meta-analysis confirmed the benefit of aerobic exercise, which resulted in significantly more loss in weight (1.2 kg, 2.6 lb), waist circumference (1.57 cm), and fat mass (1.2 kg, 2.6 lb) than resistance training.¹⁵ However, combined aerobic and resistance training was even better, with significantly more weight loss (2.0 kg, 4.4 lb) and fat mass reduction (1.9 kg, 4.2 lb).¹⁵

In summary, aerobic and combined aerobic-resistance training appear to be more effective for weight management in obese people than resistance training alone.

ADDITIONAL BENEFITS OF EXERCISE

Increasing regular physical activity through structured exercise has the additional benefits of improving physical fitness, flexibility, mobility, and cardiovascular health.^16,17

Even before patients lose a significant amount of weight (eg, 10%), low-intensity exercise such as walking 30 to 60 minutes most days of the week will rapidly improve cardiorespiratory fitness and have positive effects on cardiovascular risk factors such as hypertension, elevated blood glucose, and dyslipidemia.^18,19 Aerobic exercise and resistance training also reduce chronic inflammation, which is a strong indicator of future disease, especially in obese patients who have high levels of inflammatory biomarkers.^20,21

Even if he or she does not lose much weight, an obese exercising person with good cardiorespiratory fitness has lower cardiovascular risk than a person who is not obese but is poorly conditioned.²²

Exercise lowers blood pressure

Overactivity of the sympathetic nervous system is thought to account for over 50% of all cases of hypertension.²³ Obesity in concert with diabetes is characterized by sympathetic overactivity and progressive loss of cardiac parasympathetic activity.²⁴ Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes, and physical exercise may promote restoration of cardioprotective autonomic modulation in the heart.²⁴

Fit, obese people have lower cardiovascular risk than unfit normal-weight people

Several studies have shown that aerobic endurance exercise lowers blood pressure in patients with hypertension, and reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining this effect.²³ Another mechanism is endothelium-mediated vasodilation: even a single exercise session may increase the bioavailability of nitric oxide and decrease postexercise blood pressure.²⁵

Different types of exercise have been shown to have different effects on blood pressure.

Aerobic training has been shown to reduce systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg.²⁶

The hypotensive effect of endurance aerobic training is probably mediated at least in part by a reduction in systemic vascular resistance through decreased activity of the sympathetic and renin-angiotensin systems and through improved insulin sensitivity.²⁶ Other factors that may be involved include improved endothelium-dependent vasodilation, enhanced baroreceptor sensitivity, and arterial compliance.²⁶

Dynamic resistance exercise has less of an effect than aerobic exercise, but it has been shown to reduce systolic blood pressure by 0.5 to 4.8 mm Hg and diastolic blood pressure by 0.5 to 4.1 mm Hg.²⁶

In a meta-analysis of studies of resistance training lasting more than 1 month in healthy adults age 18 and older, the authors noted that resistance training induced a significant blood pressure reduction in 28 normotensive or prehypertensive study groups (–3.9/–3.9 mm Hg), whereas the reduction was not significant for the five hypertensive study groups.²⁷

Isometric resistance exercise has been associated with small cardiovascular benefits, but has been shown to reduce systolic blood pressure by 10.5 to 16.5 mm Hg and diastolic blood pressure by 0.62 to 16.4 mm Hg.²⁶

Exercise improves type 2 diabetes

Regular physical activity improves glycemic control and can prevent or delay the onset of type 2 diabetes mellitus.²⁸ Furthermore, physical activity positively affects lipid levels, lowers blood pressure, reduces the rate of cardiovascular events, and restores quality of life in patients  with type 2 diabetes.^24,29

A meta-analysis of the effect of supervised exercise in adults with type 2 diabetes found that structured exercise achieved the following:

• Lowered systolic blood pressure by 2.42 mm Hg (95% confidence interval 0.45–4.39)
• Lowered diastolic blood pressure by 2.23 mm Hg (1.25–3.21)
• Raised the level of high-density lipoprotein cholesterol by 0.04 mmol/L (0.02–0.07)
• Lowered the level of low-density lipoprotein cholesterol by 0.16 mmol/L (0.01–0.30).³⁰

The metabolic stress from physical exercise can increase oxidation of carbohydrates during exercise, increase postexercise consumption of oxygen (which can increase the rate of fat oxidation during recovery periods after exercise), improve glucose tolerance and insulin sensitivity, and reduce glycemia for 2 to 72 hours depending on the intensity and duration of the exercise.²⁵

Exercise lowers the Framingham risk score

Exercise improves several of the risk factors for coronary artery disease used in calculating the Framingham risk score—ie, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol—and thus can significantly lower this number. (It is important to remember that the Framingham score is a surrogate end point of cardiovascular risk that may correlate with a real clinical end point but does not necessarily have a guaranteed relationship.)

Aerobic training lowers systolic blood pressure by 5.2 to 11.0 mm Hg and diastolic blood pressure by 3.0 to 7.7 mm Hg

In a study of a 12-week exercise program in middle-aged women (ages 40–55), treadmill running for 30 minutes a day 3 days a week significantly reduced 10-year cardiovascular risk scores: 10-year risk 2.2% vs 4.3% in the nonexercising group.³¹ Others have also shown that enhanced levels of fitness are associated with lower 10-year Framingham risk estimates.³²

A study of 31 healthy sedentary adults ages 50 to 65 who were randomized to an unsupervised but pedometer-monitored home-based walking program of 30 minutes of brisk walking 5 days a week noted significant reductions in systolic and diastolic blood pressure and stroke risk, and increased functional capacity in the walking group at 12 weeks.³³ Thus, the Framingham risk scores were significantly lower in the exercising group than in with the control group.³³

Given that overweight and obese patients who are starting to exercise may find jogging or running daunting, it should also be noted that three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk in reducing cardiovascular risk in previously sedentary people.³⁴

SETTING ‘SMART’ GOALS

Because obese adults typically do not comply well with prescriptions for exercise, it is important to educate them about its benefits and to provide tools such as perceived exertion scales so they can monitor their exercise, document their performance, and chart their progress; smartphone apps can also be helpful.³⁵ Supervised exercise may improve compliance and results.³⁶ Initially, personal trainers are excellent for starting a habit change, but they are expensive. Virtual trainers are now available and cost far less.³⁷

People do not become obese overnight.They gain weight over a long time. Likewise, weight reduction takes time if done in a sustainable and healthy manner. Thus, SMART goals—specific, measurable, attainable, realistic, timely—should be set to sustain the self-discipline required.

EXERCISE RECOMMENDATIONS

Any exercise program should target 30 to 60 minutes of effort per day, most days of the week, ie, 150 to 300 minutes per week or more.³⁸ But beginners should start low and go slow to avoid dropout, musculoskeletal strain, and joint injury.

The American College of Sports Medicine (ACSM)^38,39 recommends combining aerobic and progressive resistance exercise as the core components of an exercise program. The aerobic component can include anaerobic high-intensity interval training (see discussion below). In addition, we recommend flexibility and balance exercises for obese patients.⁴⁰

Three brisk 10-minute walks a day are at least as effective as one continuous 30-minute walk

Combining aerobic and resistance exercises likely results in greater decreases in abdominal adiposity in the obese.⁴¹ In addition, the aerobic portion of a combined exercise regimen can improve functional capacity, and the resistance portion may prevent injury by strengthening the muscles, bones, and joint support systems.⁴² Adding exercises that promote flexibility and balance helps with range of motion and prevents injuries while exercising.⁴³ These exercises not only expend calories during the exercise itself, but also increase resting energy expenditure for the remainder of the day, as the effects of the raised metabolism persist for hours.⁴⁴

Aerobic exercise is the foundation

Aerobic exercises that involve large muscle groups, especially walking, should be the foundation of cardiopulmonary exercise for obese persons.⁴⁵ Many patients can tolerate weight-bearing exercises such as walking or bike riding, but for some, exercises with limited or no weight-bearing such as swimming or aqua-aerobics are better.⁴⁶

Tips for prescribing. Patients should exercise:

• On 5 or 6 days each week
• At low to moderate intensity (30%–60% of maximum oxygen consumption [Vo₂ max])
• For at least 150 minutes per week, with a long-term goal of 300 minutes per week
• By walking, riding a stationary bicycle, or swimming.^38,47

To mobilize and use free fatty acids as an energy source, lower-intensity longer-duration aerobic exercise is preferred.⁵ Thus, frequent, low-intensity or moderate-intensity training (30%–60% of Vo₂ max) of longer duration (at least 60 minutes) may be the best approach to losing body fat in obese persons.^5,48 Early on in the exercise program, keep the intensity low, as high-intensity training will preferentially use stored glycogen or carbohydrate as an energy substrate rather than free fatty acids or fat.⁵

With light-moderate exercise, the heart rate will increase and patients will perspire, but they still should be able to carry on a conversation.

Measure (or have patients measure) the heart rate using the radial artery in their wrist after 6 minutes of walking. A pulse of 100 beats per minute or more is associated with an exercise intensity of approximately 50% (or more) of Vo₂ max.⁵

A study of 136 obese men and women who exercised for 6 months found that those doing aerobic exercise only and those doing a combination of aerobic and resistance exercise had greater cardiopulmonary fitness, greater reductions in abdominal and visceral fat, and more improved insulin sensitivity than those doing resistance exercise only.⁴¹ Although the aerobic­only group lost more weight (6 lb) than the aerobic-plus-resistance group (5.1 lb) and the resistance-only group (1.4 lb), combining aerobic and resistance exercise is considered optimal.

'SMART' goals: specific, measurable, attainable, realistic, timelyAll physical activity is beneficial, but activities that have less impact on the joints are less likely to cause injuries and joint pain. Aerobic activities that are especially useful in obese adults include walking at a speed of at least 2.5 miles per hour, bicycling, jogging, treadmill walking, swimming, aqua-aerobics, rowing, and low-impact aerobics classes.

Walking is the easiest way for most people to start their program, as it is safe, accessible, and relatively cheap with respect to equipment.³⁵ Adding a simple pedometer or smartphone app to measure the amount of exercise, together with physician counseling, may improve compliance and thus weight loss.^49,50

Obese patients may have been inactive for quite a while. Therefore, the sessions should be short and low-intensity at first, then steadily progress.⁵¹ To minimize dropout, avoid hard exercise too soon for people with a low exercise capacity or high body mass index at baseline, and give positive feedback and encouragement at each visit.⁵²

It is reasonable to introduce other aerobic exercises to vary the routine, use other muscle groups, and reduce the chance of injury from overuse of one muscle or joint group. Then, as cardiorespiratory fitness improves, the patient will be more confident about trying activities  that are more challenging, such as jogging and aerobics classes. An aerobic exercise program consisting only of swimming is less efficacious for weight loss in this population.⁵³

High-intensity interval training

High-intensity interval training involves relatively brief bursts of vigorous exercise separated by periods of recovery and is a time-efficient, novel alternative to continuous exercise.⁵⁴ The exercise component is anaerobic, meaning muscle movement that does not require oxygen. Anaerobic exercise uses fast-twitch muscle fibers, and thus helps that musculature to become stronger, larger, and more toned. Evidence suggests that high-intensity interval training induces health-enhancing adaptations similar to those of continuous exercise, despite a substantially lower time commitment.⁴¹

The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for at least 30 minutes a day on at least 5 days a week for a total of at least 150 minutes per week, or high-intensity cardiorespiratory exercise training for at least 20 minutes a day on at least 3 days a week for a goal of 75 minutes a week.³⁸ Thus, high-intensity interval training may be attractive for obese patients because it entails a shorter time commitment to achieve similar weight loss and improved insulin sensitivity than low-intensity or moderate-intensity continuous exercise.

High-intensity exercise has been shown to be effective for obese patients if they can do it.^54–56 In one study,⁵⁷ 134 obese patients, mean age 53, underwent supervised high-intensity interval training with resistance training two or three times a week, were encouraged to perform one or two additional exercise sessions a week (unsupervised), and were counseled to follow a Mediterranean diet. At 9 months, investigators noted a significant reduction in body mass, waist circumference, and fat mass.

Exercise targets: 30 to 60 minutes a day, most days of the weekA study of 12 weeks of high-intensity interval training, moderate-intensity interval training, or no exercise in 34 obese adolescent girls noted that body mass and percentage body fat were significantly decreased with both interval training regimens. However, the high-intensity group had greater reductions in waist circumference and more significant improvements in blood lipid levels, adiponectin levels, and insulin sensitivity.⁵⁸

Of 62 overweight and obese patients (mean age 53.3, mean body mass index 35.8 kg/m²), 97% adhered to a program of high-intensity interval training over 9 months, which resulted in an average weekly energy expenditure of 1,582 kcal.⁵⁵ Clinically and statistically significant improvements occurred in body mass (–5.3 kg), body mass index (–1.9 kg/m²), and waist circumference (–5.8 cm) (P < .0001 for all variables). Total fat mass, trunk fat mass, and lipid levels also significantly improved (P < .0001), and the prevalence of metabolic syndrome was reduced by 32.5% (P < .05).

In a meta-analysis of the effect of exercise on overweight adults, training of moderate or high intensity was noted to have the highest potential to reduce visceral adipose tissue in overweight men and women.¹³ Another meta-analysis noted that high-intensity interval training appeared to promote more improvement in fitness and similar improvements in some cardiometabolic risk factors than moderate exercise performed for at least 8 to 12 weeks in overweight patients.⁵⁶

A typical progressive exercise program for obese adults is shown in Table 1.

Progressive resistance exercise

Progressive resistance exercises are generally easier for obese patients, as they are not aerobically challenging, allow patients to exercise around physically active people who thus motivate them, and encourage positive feelings about completing their exercise sets.⁵⁹ The result is improved muscular fitness, socialization, and increased confidence in their abilities (self-efficacy).⁵⁹

Progressive resistance exercises also promote favorable energy balance and reduced visceral fat deposition through enhanced basal metabolism and activity levels while counteracting age- and disease-related muscle wasting.⁵⁹ They have been shown to improve cognitive ability, self-esteem, movement control, muscle mass, strength, glucose control, insulin sensitivity, resting blood pressure, lipid profile, and bone mineral density and to reduce fat weight, low back pain, arthritic discomfort, insomnia, anxiety, and depression.⁶⁰

Gym neophytes should spend a few sessions with a personal trainer to learn how to use the equipment.

While the primary goal of resistance training is more muscle strength, it can reduce fat and weight, burning up to 170 kcal in a 20-minute intense exercise session.⁶¹ It reduces both total body fat and visceral adipose tissue, thus benefiting obese persons by reducing insulin resistance.⁶² All exercise, and especially resistance exercise, can help to strengthen the musculoskeletal system, reduce muscle atrophy, and improve bone mineral density.⁶³

The ACSM guidelines³⁸ recommend progressive resistance exercise on 2 or 3 nonconsecutive days a week. It should involve:

• Exercises that work 8 to 10 muscle groups per session
• Two to four sets of 8 to 12 repetitions for each muscle group.

Exercising on nonconsecutive days allows time for the complete cycle of muscle tissue remodeling.⁶⁴ Such self-regulated intensity reduces the likelihood of excessive delayed-onset muscle soreness, which can discourage new participants.⁶⁵

To prevent muscle injury, obese people should begin with low-intensity workouts using lower resistance, one set of 8 to 12 repetitions 2 days a week. Then, they should gradually but progressively increase the intensity, volume, and frequency of the training.⁴⁷ This will obviate a plateau in training and will maximize musculoskeletal adaptation. The prescription should include exercises for the upper body (eg, biceps curls), lower body (eg, leg presses), and the midsection (eg, abdominal curl-ups, which give better abdominal muscle engagement and less risk to the back than crunches) and focus on the correct exercise form and function rather than the amount of resistance or weight lifted.

A typical progressive resistance exercise program for obese adults is shown in Table 2.

Flexibility exercise

Flexibility exercise involves stretching to improve the movement of muscles, joints, and ligaments.⁴⁵ While not specifically used in an energy-expenditure strategy, flexibility (or mobility) exercises help to increase or maintain joint range of motion and can reduce muscle and joint pain associated with obesity and exercise.⁶⁶

The ACSM recommends that stretching exercises be done when the muscles are warm after a brief warm-up or exercise session.³⁸ Typically, muscles should be stretched for at least 15 seconds, and stretching is recommended at a frequency of 2 to 4 days per week.³⁸

A good way to incorporate flexibility exercise is to join a yoga class, as yoga has been shown to improve strength and flexibility and may help control physiologic variables such as blood pressure, lipids, respiration, heart rate, and metabolic rate to improve overall exercise capacity in obese patients.⁶⁷

Balance exercise

Balance exercises help obese patients improve their stability. Poor balance is associated with injuries, accidents, and falls during activities of daily living.⁶⁸

Balance, the ability to maintain the body’s center of gravity within its base of support, can be categorized as static (sustaining the body in static equilibrium or within its base of support) or dynamic (maintaining equilibrium during a transition from a dynamic to a static state), which is more challenging.⁶⁹ Doing both static and dynamic balance training maximizes balance and stability.⁶⁹ While most activities that involve moving the body or body parts (such as walking) will improve balance, some additional balance exercises can be beneficial.

Balance exercises can be done without any equipment. Examples are balancing on one foot for 15 seconds and standing up and sitting down without using the hands. However, specific equipment can help, including physioballs, stability balls, cut-in-half stability balls, balance discs, balance wedges, wobble boards, rocker boards, and Indo boards.⁷⁰ In fact, balance boards and stability balls engage more muscle fibers in other areas of the body (lower back, lower abs, quads, hamstrings, and calves) than exercises done without those balancing devices.⁷¹

Balance training for at least 10 minutes a day, 3 days a week, for 4 weeks that incorporates various methods of balance training appears to improve balance.⁵⁶ Obese patients commencing a program should start with static balance exercises and then progress to dynamic ones. In addition, as balance training progresses, obese patients can integrate balance and stability training exercises with other pieces of equipment, such as performing squats on a balance board, and then gradually add weights (eg, dumbbells) to the exercise.

An example of a weekly comprehensive exercise program for an obese patient that incorporates all major exercise types is provided  in Table 3. In addition, some smartphone apps that are especially helpful in overweight newcomers to exercise include Couch-to-5K, GymGoal 2, Moves, Fitbit, Workout Trainer, Endomondo, MapMyFitness, Fitocracy, and Fitness Buddy.

BARIATRIC SURGERY AND LIFESTYLE MANAGEMENT FOR OBESITY

Bariatric surgery is a safe and effective treatment for severe obesity and comorbidities including type 2 diabetes mellitus, but weight loss and health outcomes vary considerably among individuals.^72,73 Of importance, postoperative weight loss after bariatric surgery and long-term weight loss largely depend on the extent to which patients can make and sustain changes to their lifestyle, including diet, exercise, and behavior modification.^72,74

Exercise, especially supervised, is associated with more weight loss after bariatric surgery.⁶¹ In a meta-analysis of bariatric patients, exercise participants involved in moderate or greater levels of exercise lost a mean of 3.6 kg more than the minimal exercise groups.⁷⁵ Another meta-analysis noted the beneficial effects of exercise incorporating more than 30 minutes a day of moderate physical activity following bariatric surgery and was associated with a greater weight loss of over 4% of body mass index.⁷⁶ These findings were consistent with those of yet another meta-analysis.⁷⁷

In summary, exercise appears to significantly increase weight loss after bariatric surgery.

TREATMENT CONSIDERATIONS IN MORBID OBESITY

Challenges faced by severely obese or morbidly obese patients affect their exercise options. The types of exercise they are able to perform are limited in most cases to very-low-impact, low-intensity exercises, which may not be as efficient in weight loss or weight maintenance.⁴⁸ Therefore, it may be prudent to set more conservative weight-loss goals for them, especially early in the program. Compliance and success rates may be better with low-impact activities such as walking, water aerobics, stationary cycling, and resistance training in the severely obese population.

The more severe the obesity, the more comorbidities such as diabetes, hypertension, hyperlipidemia, arthritis, sleep apnea, gastroesophageal reflux disease, and the greater the risk of metabolic syndrome—and conversely, the greater the potential benefit from bariatric surgery followed by exercise.⁷⁴

A LONG-TERM ENDEAVOR

For obese patients, a comprehensive exercise program will improve functional status, favorably influence cardiovascular risk factors, and help with weight loss or weight maintenance.

Managing obesity is a long-term endeavor.⁷⁸ For it to succeed, both the patient and the physician need to keep up their efforts. To keep the patient from becoming discouraged, the clinician should focus not just on weight, but also on improvements in metabolic profile and cardiorespiratory fitness. In addition, a careful evaluation, a clear exercise prescription, defined goals, ongoing monitoring (by the patient and the provider), frequent feedback, and charting of progress will improve daily performance and the chance of long-term success.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).

Flexibility exercises are a type of stretching that improves the movements of your muscles, joints, and ligaments.

Balance exercises improve your stability and reduce the chance of falling or other injuries. These exercises can be done without any equipment. For example, with single-leg balance, you balance on one foot for 15 seconds. A stand-sit involves standing up and sitting down without using your hands.

Your provider will design an exercise program for you that includes the frequency, intensity, time, and types of exercise. Typically, you’ll want to lose about 10% of your weight over a 6-month period. Be sure to set SMART goals (Specific, Measurable, Attainable, Realistic, Timely) to sustain the self-discipline required for long-term success. Also consider tracking your physical activity using a wearable device (eg, Fitbit) or a smartphone app. It lets you see your progress over time, helps you set new goals, and helps keep you motivated.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints available by calling 216-444-2661.

For patient information on hundreds of health topics, visit the Center for Consumer Health Information website, www.clevelandclinic.org/health.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).

Flexibility exercises are a type of stretching that improves the movements of your muscles, joints, and ligaments.

Balance exercises improve your stability and reduce the chance of falling or other injuries. These exercises can be done without any equipment. For example, with single-leg balance, you balance on one foot for 15 seconds. A stand-sit involves standing up and sitting down without using your hands.

Your provider will design an exercise program for you that includes the frequency, intensity, time, and types of exercise. Typically, you’ll want to lose about 10% of your weight over a 6-month period. Be sure to set SMART goals (Specific, Measurable, Attainable, Realistic, Timely) to sustain the self-discipline required for long-term success. Also consider tracking your physical activity using a wearable device (eg, Fitbit) or a smartphone app. It lets you see your progress over time, helps you set new goals, and helps keep you motivated.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints available by calling 216-444-2661.

For patient information on hundreds of health topics, visit the Center for Consumer Health Information website, www.clevelandclinic.org/health.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).