SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SOURCE: Glanzman R et al. Abstract P034.

SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SOURCE: Glanzman R et al. Abstract P034.

SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SOURCE: Glanzman R et al. Abstract P034.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.

Despite the rhetorical winds blowing out of Washington, 92% of Americans believe that they have the right to affordable health care, according to a recent survey by the Commonwealth Fund.

Political affiliation, it turns out, does not appear to determine support for such a right. Democrats aged 19-64 years voiced their support to the tune of 99% in favor of a right to affordable care, compared with 82% of Republicans and 92% of independents, the Commonwealth Fund said in a survey brief released March 1.

The survey showed that 36% of those who have health care insurance through the Affordable Care Act marketplaces are pessimistic about their chances of keeping that coverage, compared with 27% of those with Medicaid and 9% of adults with employer-sponsored health benefits.

Among those who lacked confidence about maintaining their coverage, the largest proportion (32%) of respondents believe that they will lose it because the “Trump administration will not carry out the law” and 19% think that they won’t be able to afford it in the future, they said.

“Signals of support for this coverage from both [the executive and legislative] branches of government would reassure consumers about their access to health care. Such a shift also would provide a more stable regulatory environment for insurers participating in both the marketplaces and Medicaid,” according to the report.

The Commonwealth Fund’s sixth Affordable Care Act Tracking Survey was conducted by the research firm SSRS between Nov. 2 and Dec. 27, 2017, with responses from 2,410 adults aged 19-64 years. The overall margin of error was ±2.7 percentage points at the 95% confidence level.

rfranki@frontlinemedcom.com

Despite the rhetorical winds blowing out of Washington, 92% of Americans believe that they have the right to affordable health care, according to a recent survey by the Commonwealth Fund.

Political affiliation, it turns out, does not appear to determine support for such a right. Democrats aged 19-64 years voiced their support to the tune of 99% in favor of a right to affordable care, compared with 82% of Republicans and 92% of independents, the Commonwealth Fund said in a survey brief released March 1.

The survey showed that 36% of those who have health care insurance through the Affordable Care Act marketplaces are pessimistic about their chances of keeping that coverage, compared with 27% of those with Medicaid and 9% of adults with employer-sponsored health benefits.

Among those who lacked confidence about maintaining their coverage, the largest proportion (32%) of respondents believe that they will lose it because the “Trump administration will not carry out the law” and 19% think that they won’t be able to afford it in the future, they said.

“Signals of support for this coverage from both [the executive and legislative] branches of government would reassure consumers about their access to health care. Such a shift also would provide a more stable regulatory environment for insurers participating in both the marketplaces and Medicaid,” according to the report.

The Commonwealth Fund’s sixth Affordable Care Act Tracking Survey was conducted by the research firm SSRS between Nov. 2 and Dec. 27, 2017, with responses from 2,410 adults aged 19-64 years. The overall margin of error was ±2.7 percentage points at the 95% confidence level.

rfranki@frontlinemedcom.com

Despite the rhetorical winds blowing out of Washington, 92% of Americans believe that they have the right to affordable health care, according to a recent survey by the Commonwealth Fund.

Political affiliation, it turns out, does not appear to determine support for such a right. Democrats aged 19-64 years voiced their support to the tune of 99% in favor of a right to affordable care, compared with 82% of Republicans and 92% of independents, the Commonwealth Fund said in a survey brief released March 1.

The survey showed that 36% of those who have health care insurance through the Affordable Care Act marketplaces are pessimistic about their chances of keeping that coverage, compared with 27% of those with Medicaid and 9% of adults with employer-sponsored health benefits.

Among those who lacked confidence about maintaining their coverage, the largest proportion (32%) of respondents believe that they will lose it because the “Trump administration will not carry out the law” and 19% think that they won’t be able to afford it in the future, they said.

“Signals of support for this coverage from both [the executive and legislative] branches of government would reassure consumers about their access to health care. Such a shift also would provide a more stable regulatory environment for insurers participating in both the marketplaces and Medicaid,” according to the report.

The Commonwealth Fund’s sixth Affordable Care Act Tracking Survey was conducted by the research firm SSRS between Nov. 2 and Dec. 27, 2017, with responses from 2,410 adults aged 19-64 years. The overall margin of error was ±2.7 percentage points at the 95% confidence level.

rfranki@frontlinemedcom.com

Interest in aesthetic procedures among skin of color patients is on the rise, Andrew F. Alexis, MD, said in a presentation at the Caribbean Dermatology Symposium.

In 2015, ethnic minority patients accounted for 25% of aesthetic procedures in the United States, up from 20% in 2010, according to data from the American Society for Aesthetic Plastic Surgery, said Dr. Alexis, chair of dermatology and director of the Skin of Color Center at Mount Sinai St. Luke’s and Mount Sinai West hospitals in New York.

Dr. Alexis shared several treatment pearls to promote successful peels in skin of color patients:

• Salicylic acid: Resist the urge to overapply and “titrate according to patient tolerability.” The endpoint of a salicylic acid peel is white precipitate, not frost; cool compresses can be used for patient comfort and for later removal of the white precipitate.
• Glycolic acid: Stick to a contact time of 2-4 minutes to avoid epidermolysis. “Completely neutralize all areas of application to avoid overpeeling.”
• Trichloroacetic acid (TCA): TCA carries a greater risk of dyspigmentation, and should be reserved for patients who have not been successfully treated with salicylic or glycolic acid; a 10%-15% concentration of TCA, applied conservatively, is recommended.

Regardless of the type of chemical, potential pitfalls of peels in patients of color include using too much product, allowing too long of an application time, and applying the chemical to an inflamed or excoriated area, Dr. Alexis said. Patients who don’t discontinue retinoids before a peel are at increased risk of developing erosions or crusting, he added.

Dr. Alexis disclosed relationships with Allergan, BioPharmX, Dermira, Galderma, Novan, Novartis, RXi, Unilever, and Valeant.

Global Academy and this news organization are owned by the same parent company.

Interest in aesthetic procedures among skin of color patients is on the rise, Andrew F. Alexis, MD, said in a presentation at the Caribbean Dermatology Symposium.

In 2015, ethnic minority patients accounted for 25% of aesthetic procedures in the United States, up from 20% in 2010, according to data from the American Society for Aesthetic Plastic Surgery, said Dr. Alexis, chair of dermatology and director of the Skin of Color Center at Mount Sinai St. Luke’s and Mount Sinai West hospitals in New York.

Dr. Alexis shared several treatment pearls to promote successful peels in skin of color patients:

• Salicylic acid: Resist the urge to overapply and “titrate according to patient tolerability.” The endpoint of a salicylic acid peel is white precipitate, not frost; cool compresses can be used for patient comfort and for later removal of the white precipitate.
• Glycolic acid: Stick to a contact time of 2-4 minutes to avoid epidermolysis. “Completely neutralize all areas of application to avoid overpeeling.”
• Trichloroacetic acid (TCA): TCA carries a greater risk of dyspigmentation, and should be reserved for patients who have not been successfully treated with salicylic or glycolic acid; a 10%-15% concentration of TCA, applied conservatively, is recommended.

Regardless of the type of chemical, potential pitfalls of peels in patients of color include using too much product, allowing too long of an application time, and applying the chemical to an inflamed or excoriated area, Dr. Alexis said. Patients who don’t discontinue retinoids before a peel are at increased risk of developing erosions or crusting, he added.

Dr. Alexis disclosed relationships with Allergan, BioPharmX, Dermira, Galderma, Novan, Novartis, RXi, Unilever, and Valeant.

Global Academy and this news organization are owned by the same parent company.

Interest in aesthetic procedures among skin of color patients is on the rise, Andrew F. Alexis, MD, said in a presentation at the Caribbean Dermatology Symposium.

In 2015, ethnic minority patients accounted for 25% of aesthetic procedures in the United States, up from 20% in 2010, according to data from the American Society for Aesthetic Plastic Surgery, said Dr. Alexis, chair of dermatology and director of the Skin of Color Center at Mount Sinai St. Luke’s and Mount Sinai West hospitals in New York.

Dr. Alexis shared several treatment pearls to promote successful peels in skin of color patients:

• Salicylic acid: Resist the urge to overapply and “titrate according to patient tolerability.” The endpoint of a salicylic acid peel is white precipitate, not frost; cool compresses can be used for patient comfort and for later removal of the white precipitate.
• Glycolic acid: Stick to a contact time of 2-4 minutes to avoid epidermolysis. “Completely neutralize all areas of application to avoid overpeeling.”
• Trichloroacetic acid (TCA): TCA carries a greater risk of dyspigmentation, and should be reserved for patients who have not been successfully treated with salicylic or glycolic acid; a 10%-15% concentration of TCA, applied conservatively, is recommended.

Regardless of the type of chemical, potential pitfalls of peels in patients of color include using too much product, allowing too long of an application time, and applying the chemical to an inflamed or excoriated area, Dr. Alexis said. Patients who don’t discontinue retinoids before a peel are at increased risk of developing erosions or crusting, he added.

Dr. Alexis disclosed relationships with Allergan, BioPharmX, Dermira, Galderma, Novan, Novartis, RXi, Unilever, and Valeant.

Global Academy and this news organization are owned by the same parent company.

TAMPA – The growth of telepsychiatry has been driven largely by needs of access, particularly in rural areas without specialists. But telemedicine is convenient, and those growing up with computers, smartphones, and other technology are going to demand this type of access to their clinicians, according to a leader of a course on telepsychiatry at the annual meeting of the American College of Psychiatrists.

“Digital natives – the consumers – are going to drive the use of technology more and more. They are used to videoconferencing. They want to see their doctors over video. They want to communicate via text and email. They want that convenience, and they are much more comfortable with it,” said James (Jay) H. Shore, MD, director of telemedicine at the Johnson Depression Center at the University of Colorado Denver.

“When we started doing video conferencing technologies, we basically were taking what we do in person and just doing that over video,” Dr. Shore said. “Where we are now, we are actually using the technologies to change how we interact with patients, deliver structured care, and get reimbursement.”

A prolific author on the topic of telepsychiatry and long involved in this practice, Dr. Shore has said that the widespread introduction of fiber optic networks and other technological advances over the last 15 years has advanced all forms of digital technology. These are enabling and will likely accelerate synergies possible with integration of different platforms, such as electronic health records, patient portals, videoconferencing, and various methods of communication.

In his own experience, which includes providing remote services from his office in Denver to native populations in Alaska, he has discovered some unexpected advantages to telepsychiatry. For example, some victims recounting histories of domestic abuse feel more secure during videoconferencing than during a face-to-face interview, facilitating capture of a complete history. In general, he now prefers telepsychiatry in those situations.

As telepsychiatry advances, it will be increasingly integrated into hybrid models of care that involve communicating with both the patient and other clinicians over multiple platforms (for example, in-person, video, patient portals). This is not just relevant to patients in a geographically distant facility. With greater acceptance and integration, videoconferencing will be part of this mix of communication tools that might also include in-person consultations. The goal will be to use the most convenient communication strategies to coordinate the diagnosis, a treatment plan, and follow-up.

“The neat thing about telepsychiatry is really the virtual teaming models that we can create,” Dr. Shore said. However, he acknowledged that this type of team participation requires an adjustment in reimbursement models for psychiatrists that traditionally have centered on psychopharmacology. The problem with the models limited to prescription writing is that they “do not tap into the psychiatrist’s leadership of the mental health team, knowledge of human behavior, and they are not, at least for me, as personally rewarding.”

He believes that the growing array of technologies contained in telepsychiatry will increase opportunities for psychiatrists in a host of such settings such as crisis management in emergency care settings or coordination of psychiatric care in residential treatment settings.

The expansion of telemedicine already is reflected in the growing number of companies marketing services directly to consumers. Dr. Shore listed several offering virtual health care that may contribute to both acceptance and demand for medical care delivered digitally. Although telepsychiatry already is associated with many effective applications, Dr. Shore reiterated that consumer demand will be a driver for further expansion of telemedicine in general.

He also emphasized that change involving digital advances in psychiatry is inevitable. According to Dr. Shore, artificial intelligence, virtual reality treatments, and social networking are among potential tools for altering care. Inside and outside of medicine, the pace of change driven by advances in digital exchange of information has been and is expected to continue to be brisk.

Dr. Shore reported that he is chief medical officer of AccessCare Services, which provides telehealth services and technologies.

TAMPA – The growth of telepsychiatry has been driven largely by needs of access, particularly in rural areas without specialists. But telemedicine is convenient, and those growing up with computers, smartphones, and other technology are going to demand this type of access to their clinicians, according to a leader of a course on telepsychiatry at the annual meeting of the American College of Psychiatrists.

“Digital natives – the consumers – are going to drive the use of technology more and more. They are used to videoconferencing. They want to see their doctors over video. They want to communicate via text and email. They want that convenience, and they are much more comfortable with it,” said James (Jay) H. Shore, MD, director of telemedicine at the Johnson Depression Center at the University of Colorado Denver.

“When we started doing video conferencing technologies, we basically were taking what we do in person and just doing that over video,” Dr. Shore said. “Where we are now, we are actually using the technologies to change how we interact with patients, deliver structured care, and get reimbursement.”

A prolific author on the topic of telepsychiatry and long involved in this practice, Dr. Shore has said that the widespread introduction of fiber optic networks and other technological advances over the last 15 years has advanced all forms of digital technology. These are enabling and will likely accelerate synergies possible with integration of different platforms, such as electronic health records, patient portals, videoconferencing, and various methods of communication.

In his own experience, which includes providing remote services from his office in Denver to native populations in Alaska, he has discovered some unexpected advantages to telepsychiatry. For example, some victims recounting histories of domestic abuse feel more secure during videoconferencing than during a face-to-face interview, facilitating capture of a complete history. In general, he now prefers telepsychiatry in those situations.

As telepsychiatry advances, it will be increasingly integrated into hybrid models of care that involve communicating with both the patient and other clinicians over multiple platforms (for example, in-person, video, patient portals). This is not just relevant to patients in a geographically distant facility. With greater acceptance and integration, videoconferencing will be part of this mix of communication tools that might also include in-person consultations. The goal will be to use the most convenient communication strategies to coordinate the diagnosis, a treatment plan, and follow-up.

“The neat thing about telepsychiatry is really the virtual teaming models that we can create,” Dr. Shore said. However, he acknowledged that this type of team participation requires an adjustment in reimbursement models for psychiatrists that traditionally have centered on psychopharmacology. The problem with the models limited to prescription writing is that they “do not tap into the psychiatrist’s leadership of the mental health team, knowledge of human behavior, and they are not, at least for me, as personally rewarding.”

He believes that the growing array of technologies contained in telepsychiatry will increase opportunities for psychiatrists in a host of such settings such as crisis management in emergency care settings or coordination of psychiatric care in residential treatment settings.

The expansion of telemedicine already is reflected in the growing number of companies marketing services directly to consumers. Dr. Shore listed several offering virtual health care that may contribute to both acceptance and demand for medical care delivered digitally. Although telepsychiatry already is associated with many effective applications, Dr. Shore reiterated that consumer demand will be a driver for further expansion of telemedicine in general.

He also emphasized that change involving digital advances in psychiatry is inevitable. According to Dr. Shore, artificial intelligence, virtual reality treatments, and social networking are among potential tools for altering care. Inside and outside of medicine, the pace of change driven by advances in digital exchange of information has been and is expected to continue to be brisk.

Dr. Shore reported that he is chief medical officer of AccessCare Services, which provides telehealth services and technologies.

TAMPA – The growth of telepsychiatry has been driven largely by needs of access, particularly in rural areas without specialists. But telemedicine is convenient, and those growing up with computers, smartphones, and other technology are going to demand this type of access to their clinicians, according to a leader of a course on telepsychiatry at the annual meeting of the American College of Psychiatrists.

“Digital natives – the consumers – are going to drive the use of technology more and more. They are used to videoconferencing. They want to see their doctors over video. They want to communicate via text and email. They want that convenience, and they are much more comfortable with it,” said James (Jay) H. Shore, MD, director of telemedicine at the Johnson Depression Center at the University of Colorado Denver.

“When we started doing video conferencing technologies, we basically were taking what we do in person and just doing that over video,” Dr. Shore said. “Where we are now, we are actually using the technologies to change how we interact with patients, deliver structured care, and get reimbursement.”

A prolific author on the topic of telepsychiatry and long involved in this practice, Dr. Shore has said that the widespread introduction of fiber optic networks and other technological advances over the last 15 years has advanced all forms of digital technology. These are enabling and will likely accelerate synergies possible with integration of different platforms, such as electronic health records, patient portals, videoconferencing, and various methods of communication.

In his own experience, which includes providing remote services from his office in Denver to native populations in Alaska, he has discovered some unexpected advantages to telepsychiatry. For example, some victims recounting histories of domestic abuse feel more secure during videoconferencing than during a face-to-face interview, facilitating capture of a complete history. In general, he now prefers telepsychiatry in those situations.

As telepsychiatry advances, it will be increasingly integrated into hybrid models of care that involve communicating with both the patient and other clinicians over multiple platforms (for example, in-person, video, patient portals). This is not just relevant to patients in a geographically distant facility. With greater acceptance and integration, videoconferencing will be part of this mix of communication tools that might also include in-person consultations. The goal will be to use the most convenient communication strategies to coordinate the diagnosis, a treatment plan, and follow-up.

“The neat thing about telepsychiatry is really the virtual teaming models that we can create,” Dr. Shore said. However, he acknowledged that this type of team participation requires an adjustment in reimbursement models for psychiatrists that traditionally have centered on psychopharmacology. The problem with the models limited to prescription writing is that they “do not tap into the psychiatrist’s leadership of the mental health team, knowledge of human behavior, and they are not, at least for me, as personally rewarding.”

He believes that the growing array of technologies contained in telepsychiatry will increase opportunities for psychiatrists in a host of such settings such as crisis management in emergency care settings or coordination of psychiatric care in residential treatment settings.

The expansion of telemedicine already is reflected in the growing number of companies marketing services directly to consumers. Dr. Shore listed several offering virtual health care that may contribute to both acceptance and demand for medical care delivered digitally. Although telepsychiatry already is associated with many effective applications, Dr. Shore reiterated that consumer demand will be a driver for further expansion of telemedicine in general.

He also emphasized that change involving digital advances in psychiatry is inevitable. According to Dr. Shore, artificial intelligence, virtual reality treatments, and social networking are among potential tools for altering care. Inside and outside of medicine, the pace of change driven by advances in digital exchange of information has been and is expected to continue to be brisk.

Dr. Shore reported that he is chief medical officer of AccessCare Services, which provides telehealth services and technologies.

As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.¹

See related editorial

Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.

A GROUP OF LINKED DISORDERS

Two types of acute cardiac dysfunction

Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.³ Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.

Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.⁴ The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m² is typically used to define cardiogenic shock.⁴

Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.⁵ Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.

These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.

The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.⁶ Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.

PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME

Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.^7,8

Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.⁷

The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.

However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.

Elevated venous pressure, not reduced cardiac output, drives kidney injury

The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.

As evidence of this, acute heart failure is not always associated with reduced cardiac output.⁵ Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.⁹ Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.

Hanberg et al¹⁰ performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.

 

 

How venous congestion impairs the kidney

In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.⁸ Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.

Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.¹¹

Firth et al,¹⁴ in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.

Mullens et al,¹⁵ in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.

DIAGNOSIS AND CLINICAL ASSESSMENT

Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.

Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.¹⁶ Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.

Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.

Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.

Signs of acute heart failure

Wang et al,¹⁷ in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:

• History of paroxysmal nocturnal dyspnea
• A third heart sound
• Evidence of pulmonary venous congestion on chest radiography.

Features that most strongly suggested the patient did not have acute heart failure were:

• Absence of exertional dyspnea
• Absence of rales
• Absence of radiographic evidence of cardiomegaly.

Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.¹⁸ Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.¹⁹

Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.

Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.²⁰

Acute cardiorenal syndrome vs renal injury due to hypovolemia

The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.

Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.

Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.

 

 

TREATMENT

Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.

Diuretics

The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.

Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.²¹

Oral bioavailability of diuretics may be reduced due to intestinal edema.

Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,²² whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.²³ In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.²⁴

Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.

Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.²⁵ This effect warrants dose adjustment of diuretics during uremia.

Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.

The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.²⁶ There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.²⁷ However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.

Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.²⁸ Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.

The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.

Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.

Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.

The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.²⁹ Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.³⁰ Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.³¹

The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.³²

In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.³³

 

 

Ultrafiltration

Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.³⁴ Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.³⁵

Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.³⁶ Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.

Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.³⁷ For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.

In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.

Inotropes

Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.⁷

Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.

The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.³⁸ However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.

Vasodilators

Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.

Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.

However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.^39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.

Preventive strategies

Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.

TAKE-HOME POINTS

• A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
• Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
• Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
• Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
• Fluid removal by various strategies is the mainstay of treatment.
• Temporary inotropic support should be saved for the last resort.

As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.¹

See related editorial

Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.

A GROUP OF LINKED DISORDERS

Two types of acute cardiac dysfunction

Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.³ Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.

Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.⁴ The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m² is typically used to define cardiogenic shock.⁴

Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.⁵ Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.

These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.

The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.⁶ Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.

PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME

Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.^7,8

Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.⁷

The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.

However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.

Elevated venous pressure, not reduced cardiac output, drives kidney injury

The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.

As evidence of this, acute heart failure is not always associated with reduced cardiac output.⁵ Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.⁹ Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.

Hanberg et al¹⁰ performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.

 

 

How venous congestion impairs the kidney

In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.⁸ Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.

Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.¹¹

Firth et al,¹⁴ in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.

Mullens et al,¹⁵ in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.

DIAGNOSIS AND CLINICAL ASSESSMENT

Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.

Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.¹⁶ Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.

Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.

Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.

Signs of acute heart failure

Wang et al,¹⁷ in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:

• History of paroxysmal nocturnal dyspnea
• A third heart sound
• Evidence of pulmonary venous congestion on chest radiography.

Features that most strongly suggested the patient did not have acute heart failure were:

• Absence of exertional dyspnea
• Absence of rales
• Absence of radiographic evidence of cardiomegaly.

Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.¹⁸ Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.¹⁹

Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.

Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.²⁰

Acute cardiorenal syndrome vs renal injury due to hypovolemia

The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.

Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.

Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.

 

 

TREATMENT

Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.

Diuretics

The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.

Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.²¹

Oral bioavailability of diuretics may be reduced due to intestinal edema.

Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,²² whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.²³ In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.²⁴

Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.

Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.²⁵ This effect warrants dose adjustment of diuretics during uremia.

Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.

The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.²⁶ There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.²⁷ However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.

Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.²⁸ Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.

The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.

Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.

Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.

The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.²⁹ Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.³⁰ Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.³¹

The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.³²

In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.³³

 

 

Ultrafiltration

Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.³⁴ Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.³⁵

Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.³⁶ Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.

Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.³⁷ For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.

In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.

Inotropes

Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.⁷

Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.

The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.³⁸ However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.

Vasodilators

Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.

Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.

However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.^39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.

Preventive strategies

Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.

TAKE-HOME POINTS

• A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
• Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
• Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
• Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
• Fluid removal by various strategies is the mainstay of treatment.
• Temporary inotropic support should be saved for the last resort.

As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.¹

See related editorial

Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.

A GROUP OF LINKED DISORDERS

Two types of acute cardiac dysfunction

Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.³ Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.

Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.⁴ The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m² is typically used to define cardiogenic shock.⁴

Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.⁵ Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.

These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.

The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.⁶ Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.

PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME

Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.^7,8

Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.⁷

The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.

However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.

Elevated venous pressure, not reduced cardiac output, drives kidney injury

The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.

As evidence of this, acute heart failure is not always associated with reduced cardiac output.⁵ Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.⁹ Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.

Hanberg et al¹⁰ performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.

 

 

How venous congestion impairs the kidney

In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.⁸ Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.

Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.¹¹

Firth et al,¹⁴ in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.

Mullens et al,¹⁵ in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.

DIAGNOSIS AND CLINICAL ASSESSMENT

Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.

Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.¹⁶ Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.

Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.

Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.

Signs of acute heart failure

Wang et al,¹⁷ in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:

• History of paroxysmal nocturnal dyspnea
• A third heart sound
• Evidence of pulmonary venous congestion on chest radiography.

Features that most strongly suggested the patient did not have acute heart failure were:

• Absence of exertional dyspnea
• Absence of rales
• Absence of radiographic evidence of cardiomegaly.

Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.¹⁸ Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.¹⁹

Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.

Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.²⁰

Acute cardiorenal syndrome vs renal injury due to hypovolemia

The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.

Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.

Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.

 

 

TREATMENT

Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.

Diuretics

The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.

Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.²¹

Oral bioavailability of diuretics may be reduced due to intestinal edema.

Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,²² whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.²³ In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.²⁴

Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.

Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.²⁵ This effect warrants dose adjustment of diuretics during uremia.

Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.

The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.²⁶ There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.²⁷ However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.

Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.²⁸ Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.

The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.

Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.

Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.

The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.²⁹ Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.³⁰ Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.³¹

The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.³²

In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.³³

 

 

Ultrafiltration

Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.³⁴ Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.³⁵

Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.³⁶ Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.

Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.³⁷ For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.

In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.

Inotropes

Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.⁷

Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.

The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.³⁸ However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.

Vasodilators

Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.

Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.

However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.^39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.

Preventive strategies

Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.

TAKE-HOME POINTS

• A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
• Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
• Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
• Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
• Fluid removal by various strategies is the mainstay of treatment.
• Temporary inotropic support should be saved for the last resort.

In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”

See related article

Although classically defined by a reduction in the glomerular filtration rate (GFR),¹ cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.

The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.

DETERMINANTS OF GFR

The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations²:

GFR = K_f × (P_G – P_B – π_G + π_B)

K_f = N × L_p × S

K_f is the filtration constant, N the number of functional nephrons, L_p the hydraulic conductivity of the glomerular capillary, S the filtration area, P_G the hydrostatic pressure in the glomerular capillaries, P_B the hydrostatic pressure in the Bowman capsule, and π_G and π_B the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.

Based on this relationship, the GFR is reduced when P_G is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when P_B is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase P_G (improve perfusion) and reduce P_B (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.

In this issue, Thind et al³ highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.

 

 

VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT

Returning to the GFR equation, it is clear that an imbalance in P_G and P_B can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”

A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.^4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.^6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.^5,8,9

How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?

The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.^10,11

In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).^12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,^6,15 and the impact of cardiac output on renal function remains uncertain.¹⁶

The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.^17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.

 

 

TREATMENT IS CHALLENGING

The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.

On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.²⁰ Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.

Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.²¹ Furthermore, routine use of ino­tropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.^22,23

Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.²⁴

With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.

However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing P_B), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (P_G).

In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.

In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”

See related article

Although classically defined by a reduction in the glomerular filtration rate (GFR),¹ cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.

The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.

DETERMINANTS OF GFR

The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations²:

GFR = K_f × (P_G – P_B – π_G + π_B)

K_f = N × L_p × S

K_f is the filtration constant, N the number of functional nephrons, L_p the hydraulic conductivity of the glomerular capillary, S the filtration area, P_G the hydrostatic pressure in the glomerular capillaries, P_B the hydrostatic pressure in the Bowman capsule, and π_G and π_B the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.

Based on this relationship, the GFR is reduced when P_G is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when P_B is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase P_G (improve perfusion) and reduce P_B (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.

In this issue, Thind et al³ highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.

 

 

VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT

Returning to the GFR equation, it is clear that an imbalance in P_G and P_B can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”

A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.^4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.^6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.^5,8,9

How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?

The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.^10,11

In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).^12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,^6,15 and the impact of cardiac output on renal function remains uncertain.¹⁶

The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.^17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.

 

 

TREATMENT IS CHALLENGING

The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.

On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.²⁰ Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.

Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.²¹ Furthermore, routine use of ino­tropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.^22,23

Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.²⁴

With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.

However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing P_B), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (P_G).

In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.

In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”

See related article

Although classically defined by a reduction in the glomerular filtration rate (GFR),¹ cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.

The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.

DETERMINANTS OF GFR

The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations²:

GFR = K_f × (P_G – P_B – π_G + π_B)

K_f = N × L_p × S

K_f is the filtration constant, N the number of functional nephrons, L_p the hydraulic conductivity of the glomerular capillary, S the filtration area, P_G the hydrostatic pressure in the glomerular capillaries, P_B the hydrostatic pressure in the Bowman capsule, and π_G and π_B the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.

Based on this relationship, the GFR is reduced when P_G is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when P_B is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase P_G (improve perfusion) and reduce P_B (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.

In this issue, Thind et al³ highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.

 

 

VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT

Returning to the GFR equation, it is clear that an imbalance in P_G and P_B can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”

A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.^4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.^6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.^5,8,9

How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?

The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.^10,11

In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).^12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,^6,15 and the impact of cardiac output on renal function remains uncertain.¹⁶

The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.^17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.

 

 

TREATMENT IS CHALLENGING

The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.

On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.²⁰ Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.

Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.²¹ Furthermore, routine use of ino­tropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.^22,23

Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.²⁴

With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.

However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing P_B), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (P_G).

In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.

A 62-year-old woman with hypertension and type 2 diabetes mellitus has been experiencing shortness of breath on exertion and chest discomfort for 2 months. Her hypertension has been suboptimally controlled, and her most recent hemoglobin A_1c measurement was 7.0%. She has never smoked and has no family history of premature coronary artery disease (CAD). She is otherwise well and walks for 30 minutes 3 times per week. A 12-lead electrocardiogram demonstrated normal sinus rhythm with left bundle branch block. Her physician suspects she has CAD. What testing does this patient need?

LIMITED DATA, GUIDELINES

For clinicians investigating suspected obstructive CAD in patients with left bundle branch block on resting electrocardiography, the data and guidelines are limited regarding the optimal noninvasive tests and how to interpret them.

Here, we present a practical review of the diagnostic utility of exercise stress electrocardiography, exercise stress echocardiography, dobutamine stress echocardiography, nuclear myocardial perfusion imaging, and computed tomographic (CT) angiography for assessing suspected obstructive CAD in patients with resting left bundle branch block.

WHAT IS LEFT BUNDLE BRANCH BLOCK?

In left bundle branch block, as the name implies, electrical conduction along the left bundle branch is blocked or delayed. Ventricular activation therefore begins in the right ventricle and the right side of the interventricular septum.¹ Transseptal activation from the right ventricle to the left ventricle is slow, because it is transmyocardial.¹ Left ventricular basal and posterolateral wall segments become activated last.¹ Due to delay in the onset of left ventricular contraction, ventricular contraction is dyssynchronous. Classically, interventricular septal motion during systole has been described as paradoxical, with anterior septal motion.^2–4

On electrocardiography, the QRS duration is widened (≥ 120 ms), with a distinctive morphology as shown in Figure 1. Left bundle branch block makes it difficult to accurately assess for dynamic ST-segment changes with exercise, rendering exercise stress electrocardiography a suboptimal test for obstructive CAD if left bundle branch block is present.

LEFT BUNDLE BRANCH BLOCK AND RISK OF DEATH

Although left bundle branch block can be an isolated finding, it can also be associated with underlying obstructive CAD⁵ or cardiomyopathy.⁶ When it occurs at rest, the risk of death from a cardiovascular event is 3 to 4 times higher.⁷ However, the exact incidence of significant obstructive CAD in asymptomatic patients with incidentally detected left bundle branch block is unknown.

Acute left bundle branch block accompanying acute myocardial infarction is associated with a high risk of death. Hindman et al,⁸ in a 1978 multicenter study, described 432 patients with acute myocardial infarction and left or right bundle branch block. In the 163 patients who had left bundle branch block, the in-hospital mortality rate was 24% and the 1-year mortality rate was 32%.

Freedman et al⁹ in 1987 reviewed 15,609 patients with chronic CAD who underwent coronary angiography, of whom 522 had left or right bundle branch block. During a follow-up of nearly 5 years, 2,386 patients died. The actuarial probability of death at 2 years in patients with left bundle branch block was more than 5 times that of patients without it (P < .0001).

During 18 years of observation in the Framingham study,¹⁰ 55 participants developed left bundle branch block, at a mean age at onset of 62. Twenty-six (48%) of these participants developed clinically significant CAD or heart failure coincident with or subsequent to the onset of left bundle branch block. Fifty percent of the participants who developed left bundle branch block died of cardiovascular disease within 10 years of its onset.

 

 

EXERCISE STRESS ELECTROCARDIOGRAPHY

Exercise stress electrocardiography, although valuable for assessing functional capacity, cannot be used to diagnose obstructive CAD in patients with left bundle branch block.¹¹

EXERCISE STRESS ECHOCARDIOGRAPHY

Exercise stress echocardiography is proven and widely used for assessing myocardial ischemia in patients with suspected obstructive CAD. But the data are limited on its diagnostic utility in patients with left bundle branch block. Until recently, recommendations for its use in this situation were based on only 1 small study.¹²

Peteiro et al¹² in 2000 described 35 patients who underwent exercise stress echocardiography and coronary angiography. Detection of wall-motion abnormalities had high sensitivity (76%), specificity (83%), and diagnostic accuracy (80%).

Of note, 8 (23%) of the patients could not achieve at least 85% of the maximum predicted heart rate, and for them, the study was not diagnostic for ischemia. (Technically, the study is said to be nondiagnostic when the patient fails to achieve the target heart rate of at least 85% of the maximum predicted heart rate.)

Additionally, 18 of the 35 patients—over half—had a decrease in left ventricular ejection fraction in response to exercise. These 18 patients included 12 of the 17 patients with obstructive CAD and 6 of the 18 patients without obstructive CAD.¹² It is unclear whether a significant proportion of these 18 patients would have been otherwise categorized as having a globally abnormal left ventricular contractile response to exercise according to contemporary (2007) reporting standards.¹³

Xu et al^14,15 in 2016 examined the diagnostic utility of exercise stress echocardiography in assessing suspected obstructive CAD in 191 patients with resting left bundle branch block; 17 patients who failed to achieve a heart rate of at least 85% of the age-predicted maximum heart rate were excluded. Of the remaining 174 patients, 82 demonstrated a normal left ventricular contractile response to exercise and 92 had an abnormal response. In the abnormal group, 70 patients had a globally abnormal response, and 22 patients had a regional ischemic response. Of those who had a globally abnormal left ventricular contractile response who subsequently underwent angiography, only 30% were found to have obstructive CAD.

Although the sensitivity of exercise stress echocardiography was high (94%), its specificity and diagnostic accuracy were poor (specificity 21%, diagnostic accuracy 52%).^14,15 These results suggest that for patients with resting left bundle branch block undergoing exercise stress echocardiography, obstructive CAD cannot be reliably diagnosed in those who develop a globally abnormal left ventricular contractile response. Therefore, an alternative imaging strategy should be considered.

DOBUTAMINE STRESS ECHOCARDIOGRAPHY

The evidence base for dobutamine stress echocardiography in patients with left bundle branch block is more robust than that for exercise stress echocardiography.

Geleijnse et al¹ studied 64 patients with left bundle branch block undergoing dobutamine stress echocardiography who also underwent coronary angiography. Dobutamine stress echocardiography was moderately sensitive for detecting anterior and posterior myocardial wall ischemia (60% and 67%, respectively). Its specificity and diagnostic accuracy were high, at 94% and 98%, respectively.

Yanik et al¹⁶ studied 30 patients with left bundle branch block undergoing both dobutamine stress echocardiography and coronary angiography. The sensitivity of dobutamine stress echocardiography for identifying ischemia in the left anterior descending territory was 82%, the specificity was 95%, and the diagnostic accuracy was 90%. For identifying ischemia in the circumflex and right coronary artery territories, the sensitivity was 88%, specificity 96%, and accuracy 93%.

Mairesse et al¹⁷ studied 24 patients with left bundle branch block undergoing dobutamine stress echocardiography, myocardial perfusion tomography, and coronary angiography. Dobutamine stress echocardiography performed well in detecting ischemia in the left anterior descending territory, with a sensitivity of 83%, specificity 92%, and diagnostic accuracy 87%.

Of note, the available data come from very small studies published more than 15 years ago, and pharmacologic stress testing cannot provide the very important prognostic information derived from treadmill testing.

NUCLEAR MYOCARDIAL PERFUSION IMAGING

Exercise nuclear single-photon emission computed tomography (SPECT) myocardial perfusion imaging in patients with left bundle branch block is challenging, due to the development of septal perfusion defects at rest and during exercise in the absence of obstructive disease in the left anterior descending artery (Figure 2).^18,19 Asynchronous contraction of the septum, with resulting compression of the septal arteries, decreased flow demands to the septal region, and attenuation artifacts are possible explanations for this phenomenon.²⁰

Pharmacologic stress has been reported to improve the diagnostic accuracy of SPECT myocardial perfusion imaging.²¹

Biagini et al,²¹ in a meta-analysis of noninvasive techniques for diagnosing CAD in patients with left bundle branch block, found 1,785 patients from 39 studies who underwent nuclear myocardial perfusion imaging (48.8% with exercise, 41.9% with pharmacologic stress). Overall, sensitivity was high for both exercise and pharmacologic stress (92.9% and 88.5%). However, the reported specificity with exercise stress was significantly lower than with pharmacologic stress (23.3% vs 74.2%, P < .01).

Nuclear positron-emission tomography (PET) may further improve the diagnostic utility of nuclear myocardial perfusion imaging in patients with left bundle branch block. In a study of 440 patients with left bundle branch block undergoing myocardial perfusion imaging, 67 underwent PET and 373 underwent SPECT.²² Possible septal perfusion artifacts were significantly less common with PET than with SPECT (1.5% vs 19.3%, P < .001).

CT ANGIOGRAPHY

CT angiography has a high sensitivity and specificity for detecting significant obstructive CAD.^23,24 Machines with 320 detector rows have been reported to have a sensitivity of 94% and specificity of 87% for detecting significant CAD and are not affected by resting left bundle branch block.²⁵

Of note, coronary artery calcification increases in older patients, especially those age 65 and older,²⁶ and this confers a higher likelihood of “bystander” CAD. Significant coronary artery calcification limits the diagnostic accuracy of multidetector cardiac CT. Additionally, the detection of bystander CAD leads to positive findings of uncertain clinical significance.

 

 

CURRENT GUIDELINES

Exercise stress echocardiography

American College of Cardiology Foundation/American Heart Association guidelines for diagnosis and management of patients with stable ischemic heart disease recommend exercise stress echocardiography for patients with an intermediate to high pretest probability of ischemic heart disease who have an uninterpretable electrocardiogram and at least moderate physical functioning or no disabling comorbidity (class 1 indication, level of evidence B).¹¹

Current American Society of Echocardiography guidelines also support exercise stress echocardiography as an appropriate test for suspected obstructive CAD in patients with resting left bundle branch block.²⁷ However, this recommendation is based on limited data.

Pharmacologic stress nuclear myocardial perfusion imaging

American Society of Nuclear Cardiology guidelines endorse pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators for evaluating suspected obstructive CAD in patients with resting left bundle branch block.^28,29

THE POSSIBLE HARMS OF TESTING

Although current guidelines recommend it, recent data show that exercise stress echocardiography has poor specificity and diagnostic accuracy for significant obstructive CAD in patients with resting left bundle branch block. And performing this test in patients with left bundle branch block may result in further downstream investigations.

Based on limited data from a small number of studies published more than 15 years ago, dobutamine stress echocardiography has moderate sensitivity and specificity for significant CAD in patients with resting left bundle branch block. However, this test does not provide functional information about the patient’s exercise performance.

Pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators is an appropriate investigation strategy. However, radiation exposure is a limitation.³⁰

CT angiography can assess for significant obstructive CAD in patients with resting left bundle branch block. However, its diagnostic accuracy can be affected by coronary calcification in older patients. Additionally, each scan is associated with a small amount of radiation exposure,³¹ and a small number of patients will have a true contrast allergy.³²

CLINICAL BOTTOM LINE

For patients with typical ischemic symptoms and new left bundle branch block on electrocardiography, specialist cardiology consultation should be sought, with consideration given to proceeding directly to coronary angiography. For stable outpatients, we propose the following diagnostic approach (Figure 3).

Exercise stress echocardiography is recommended by current guidelines, but it cannot reliably detect significant obstructive CAD in patients with resting left bundle branch block—its specificity and diagnostic accuracy are poor.^14,15 Alternative imaging strategies include CT angiography, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators, and dobutamine stress echocardiography.

For investigating suspected obstructive CAD in patients with resting left bundle branch block, we propose CT angiography as the first-line imaging test for patients under age 65 and pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators or dobutamine stress echocardiography for those age 65 and older. For patients who cannot tolerate contrast due to renal impairment or who have a true contrast allergy, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators and dobutamine stress echocardiography may be used as alternatives.

A 62-year-old woman with hypertension and type 2 diabetes mellitus has been experiencing shortness of breath on exertion and chest discomfort for 2 months. Her hypertension has been suboptimally controlled, and her most recent hemoglobin A_1c measurement was 7.0%. She has never smoked and has no family history of premature coronary artery disease (CAD). She is otherwise well and walks for 30 minutes 3 times per week. A 12-lead electrocardiogram demonstrated normal sinus rhythm with left bundle branch block. Her physician suspects she has CAD. What testing does this patient need?

LIMITED DATA, GUIDELINES

For clinicians investigating suspected obstructive CAD in patients with left bundle branch block on resting electrocardiography, the data and guidelines are limited regarding the optimal noninvasive tests and how to interpret them.

Here, we present a practical review of the diagnostic utility of exercise stress electrocardiography, exercise stress echocardiography, dobutamine stress echocardiography, nuclear myocardial perfusion imaging, and computed tomographic (CT) angiography for assessing suspected obstructive CAD in patients with resting left bundle branch block.

WHAT IS LEFT BUNDLE BRANCH BLOCK?

In left bundle branch block, as the name implies, electrical conduction along the left bundle branch is blocked or delayed. Ventricular activation therefore begins in the right ventricle and the right side of the interventricular septum.¹ Transseptal activation from the right ventricle to the left ventricle is slow, because it is transmyocardial.¹ Left ventricular basal and posterolateral wall segments become activated last.¹ Due to delay in the onset of left ventricular contraction, ventricular contraction is dyssynchronous. Classically, interventricular septal motion during systole has been described as paradoxical, with anterior septal motion.^2–4

On electrocardiography, the QRS duration is widened (≥ 120 ms), with a distinctive morphology as shown in Figure 1. Left bundle branch block makes it difficult to accurately assess for dynamic ST-segment changes with exercise, rendering exercise stress electrocardiography a suboptimal test for obstructive CAD if left bundle branch block is present.

LEFT BUNDLE BRANCH BLOCK AND RISK OF DEATH

Although left bundle branch block can be an isolated finding, it can also be associated with underlying obstructive CAD⁵ or cardiomyopathy.⁶ When it occurs at rest, the risk of death from a cardiovascular event is 3 to 4 times higher.⁷ However, the exact incidence of significant obstructive CAD in asymptomatic patients with incidentally detected left bundle branch block is unknown.

Acute left bundle branch block accompanying acute myocardial infarction is associated with a high risk of death. Hindman et al,⁸ in a 1978 multicenter study, described 432 patients with acute myocardial infarction and left or right bundle branch block. In the 163 patients who had left bundle branch block, the in-hospital mortality rate was 24% and the 1-year mortality rate was 32%.

Freedman et al⁹ in 1987 reviewed 15,609 patients with chronic CAD who underwent coronary angiography, of whom 522 had left or right bundle branch block. During a follow-up of nearly 5 years, 2,386 patients died. The actuarial probability of death at 2 years in patients with left bundle branch block was more than 5 times that of patients without it (P < .0001).

During 18 years of observation in the Framingham study,¹⁰ 55 participants developed left bundle branch block, at a mean age at onset of 62. Twenty-six (48%) of these participants developed clinically significant CAD or heart failure coincident with or subsequent to the onset of left bundle branch block. Fifty percent of the participants who developed left bundle branch block died of cardiovascular disease within 10 years of its onset.

 

 

EXERCISE STRESS ELECTROCARDIOGRAPHY

Exercise stress electrocardiography, although valuable for assessing functional capacity, cannot be used to diagnose obstructive CAD in patients with left bundle branch block.¹¹

EXERCISE STRESS ECHOCARDIOGRAPHY

Exercise stress echocardiography is proven and widely used for assessing myocardial ischemia in patients with suspected obstructive CAD. But the data are limited on its diagnostic utility in patients with left bundle branch block. Until recently, recommendations for its use in this situation were based on only 1 small study.¹²

Peteiro et al¹² in 2000 described 35 patients who underwent exercise stress echocardiography and coronary angiography. Detection of wall-motion abnormalities had high sensitivity (76%), specificity (83%), and diagnostic accuracy (80%).

Of note, 8 (23%) of the patients could not achieve at least 85% of the maximum predicted heart rate, and for them, the study was not diagnostic for ischemia. (Technically, the study is said to be nondiagnostic when the patient fails to achieve the target heart rate of at least 85% of the maximum predicted heart rate.)

Additionally, 18 of the 35 patients—over half—had a decrease in left ventricular ejection fraction in response to exercise. These 18 patients included 12 of the 17 patients with obstructive CAD and 6 of the 18 patients without obstructive CAD.¹² It is unclear whether a significant proportion of these 18 patients would have been otherwise categorized as having a globally abnormal left ventricular contractile response to exercise according to contemporary (2007) reporting standards.¹³

Xu et al^14,15 in 2016 examined the diagnostic utility of exercise stress echocardiography in assessing suspected obstructive CAD in 191 patients with resting left bundle branch block; 17 patients who failed to achieve a heart rate of at least 85% of the age-predicted maximum heart rate were excluded. Of the remaining 174 patients, 82 demonstrated a normal left ventricular contractile response to exercise and 92 had an abnormal response. In the abnormal group, 70 patients had a globally abnormal response, and 22 patients had a regional ischemic response. Of those who had a globally abnormal left ventricular contractile response who subsequently underwent angiography, only 30% were found to have obstructive CAD.

Although the sensitivity of exercise stress echocardiography was high (94%), its specificity and diagnostic accuracy were poor (specificity 21%, diagnostic accuracy 52%).^14,15 These results suggest that for patients with resting left bundle branch block undergoing exercise stress echocardiography, obstructive CAD cannot be reliably diagnosed in those who develop a globally abnormal left ventricular contractile response. Therefore, an alternative imaging strategy should be considered.

DOBUTAMINE STRESS ECHOCARDIOGRAPHY

The evidence base for dobutamine stress echocardiography in patients with left bundle branch block is more robust than that for exercise stress echocardiography.

Geleijnse et al¹ studied 64 patients with left bundle branch block undergoing dobutamine stress echocardiography who also underwent coronary angiography. Dobutamine stress echocardiography was moderately sensitive for detecting anterior and posterior myocardial wall ischemia (60% and 67%, respectively). Its specificity and diagnostic accuracy were high, at 94% and 98%, respectively.

Yanik et al¹⁶ studied 30 patients with left bundle branch block undergoing both dobutamine stress echocardiography and coronary angiography. The sensitivity of dobutamine stress echocardiography for identifying ischemia in the left anterior descending territory was 82%, the specificity was 95%, and the diagnostic accuracy was 90%. For identifying ischemia in the circumflex and right coronary artery territories, the sensitivity was 88%, specificity 96%, and accuracy 93%.

Mairesse et al¹⁷ studied 24 patients with left bundle branch block undergoing dobutamine stress echocardiography, myocardial perfusion tomography, and coronary angiography. Dobutamine stress echocardiography performed well in detecting ischemia in the left anterior descending territory, with a sensitivity of 83%, specificity 92%, and diagnostic accuracy 87%.

Of note, the available data come from very small studies published more than 15 years ago, and pharmacologic stress testing cannot provide the very important prognostic information derived from treadmill testing.

NUCLEAR MYOCARDIAL PERFUSION IMAGING

Exercise nuclear single-photon emission computed tomography (SPECT) myocardial perfusion imaging in patients with left bundle branch block is challenging, due to the development of septal perfusion defects at rest and during exercise in the absence of obstructive disease in the left anterior descending artery (Figure 2).^18,19 Asynchronous contraction of the septum, with resulting compression of the septal arteries, decreased flow demands to the septal region, and attenuation artifacts are possible explanations for this phenomenon.²⁰

Pharmacologic stress has been reported to improve the diagnostic accuracy of SPECT myocardial perfusion imaging.²¹

Biagini et al,²¹ in a meta-analysis of noninvasive techniques for diagnosing CAD in patients with left bundle branch block, found 1,785 patients from 39 studies who underwent nuclear myocardial perfusion imaging (48.8% with exercise, 41.9% with pharmacologic stress). Overall, sensitivity was high for both exercise and pharmacologic stress (92.9% and 88.5%). However, the reported specificity with exercise stress was significantly lower than with pharmacologic stress (23.3% vs 74.2%, P < .01).

Nuclear positron-emission tomography (PET) may further improve the diagnostic utility of nuclear myocardial perfusion imaging in patients with left bundle branch block. In a study of 440 patients with left bundle branch block undergoing myocardial perfusion imaging, 67 underwent PET and 373 underwent SPECT.²² Possible septal perfusion artifacts were significantly less common with PET than with SPECT (1.5% vs 19.3%, P < .001).

CT ANGIOGRAPHY

CT angiography has a high sensitivity and specificity for detecting significant obstructive CAD.^23,24 Machines with 320 detector rows have been reported to have a sensitivity of 94% and specificity of 87% for detecting significant CAD and are not affected by resting left bundle branch block.²⁵

Of note, coronary artery calcification increases in older patients, especially those age 65 and older,²⁶ and this confers a higher likelihood of “bystander” CAD. Significant coronary artery calcification limits the diagnostic accuracy of multidetector cardiac CT. Additionally, the detection of bystander CAD leads to positive findings of uncertain clinical significance.

 

 

CURRENT GUIDELINES

Exercise stress echocardiography

American College of Cardiology Foundation/American Heart Association guidelines for diagnosis and management of patients with stable ischemic heart disease recommend exercise stress echocardiography for patients with an intermediate to high pretest probability of ischemic heart disease who have an uninterpretable electrocardiogram and at least moderate physical functioning or no disabling comorbidity (class 1 indication, level of evidence B).¹¹

Current American Society of Echocardiography guidelines also support exercise stress echocardiography as an appropriate test for suspected obstructive CAD in patients with resting left bundle branch block.²⁷ However, this recommendation is based on limited data.

Pharmacologic stress nuclear myocardial perfusion imaging

American Society of Nuclear Cardiology guidelines endorse pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators for evaluating suspected obstructive CAD in patients with resting left bundle branch block.^28,29

THE POSSIBLE HARMS OF TESTING

Although current guidelines recommend it, recent data show that exercise stress echocardiography has poor specificity and diagnostic accuracy for significant obstructive CAD in patients with resting left bundle branch block. And performing this test in patients with left bundle branch block may result in further downstream investigations.

Based on limited data from a small number of studies published more than 15 years ago, dobutamine stress echocardiography has moderate sensitivity and specificity for significant CAD in patients with resting left bundle branch block. However, this test does not provide functional information about the patient’s exercise performance.

Pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators is an appropriate investigation strategy. However, radiation exposure is a limitation.³⁰

CT angiography can assess for significant obstructive CAD in patients with resting left bundle branch block. However, its diagnostic accuracy can be affected by coronary calcification in older patients. Additionally, each scan is associated with a small amount of radiation exposure,³¹ and a small number of patients will have a true contrast allergy.³²

CLINICAL BOTTOM LINE

For patients with typical ischemic symptoms and new left bundle branch block on electrocardiography, specialist cardiology consultation should be sought, with consideration given to proceeding directly to coronary angiography. For stable outpatients, we propose the following diagnostic approach (Figure 3).

Exercise stress echocardiography is recommended by current guidelines, but it cannot reliably detect significant obstructive CAD in patients with resting left bundle branch block—its specificity and diagnostic accuracy are poor.^14,15 Alternative imaging strategies include CT angiography, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators, and dobutamine stress echocardiography.

For investigating suspected obstructive CAD in patients with resting left bundle branch block, we propose CT angiography as the first-line imaging test for patients under age 65 and pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators or dobutamine stress echocardiography for those age 65 and older. For patients who cannot tolerate contrast due to renal impairment or who have a true contrast allergy, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators and dobutamine stress echocardiography may be used as alternatives.

A 62-year-old woman with hypertension and type 2 diabetes mellitus has been experiencing shortness of breath on exertion and chest discomfort for 2 months. Her hypertension has been suboptimally controlled, and her most recent hemoglobin A_1c measurement was 7.0%. She has never smoked and has no family history of premature coronary artery disease (CAD). She is otherwise well and walks for 30 minutes 3 times per week. A 12-lead electrocardiogram demonstrated normal sinus rhythm with left bundle branch block. Her physician suspects she has CAD. What testing does this patient need?

LIMITED DATA, GUIDELINES

For clinicians investigating suspected obstructive CAD in patients with left bundle branch block on resting electrocardiography, the data and guidelines are limited regarding the optimal noninvasive tests and how to interpret them.

Here, we present a practical review of the diagnostic utility of exercise stress electrocardiography, exercise stress echocardiography, dobutamine stress echocardiography, nuclear myocardial perfusion imaging, and computed tomographic (CT) angiography for assessing suspected obstructive CAD in patients with resting left bundle branch block.

WHAT IS LEFT BUNDLE BRANCH BLOCK?

In left bundle branch block, as the name implies, electrical conduction along the left bundle branch is blocked or delayed. Ventricular activation therefore begins in the right ventricle and the right side of the interventricular septum.¹ Transseptal activation from the right ventricle to the left ventricle is slow, because it is transmyocardial.¹ Left ventricular basal and posterolateral wall segments become activated last.¹ Due to delay in the onset of left ventricular contraction, ventricular contraction is dyssynchronous. Classically, interventricular septal motion during systole has been described as paradoxical, with anterior septal motion.^2–4

On electrocardiography, the QRS duration is widened (≥ 120 ms), with a distinctive morphology as shown in Figure 1. Left bundle branch block makes it difficult to accurately assess for dynamic ST-segment changes with exercise, rendering exercise stress electrocardiography a suboptimal test for obstructive CAD if left bundle branch block is present.

LEFT BUNDLE BRANCH BLOCK AND RISK OF DEATH

Although left bundle branch block can be an isolated finding, it can also be associated with underlying obstructive CAD⁵ or cardiomyopathy.⁶ When it occurs at rest, the risk of death from a cardiovascular event is 3 to 4 times higher.⁷ However, the exact incidence of significant obstructive CAD in asymptomatic patients with incidentally detected left bundle branch block is unknown.

Acute left bundle branch block accompanying acute myocardial infarction is associated with a high risk of death. Hindman et al,⁸ in a 1978 multicenter study, described 432 patients with acute myocardial infarction and left or right bundle branch block. In the 163 patients who had left bundle branch block, the in-hospital mortality rate was 24% and the 1-year mortality rate was 32%.

Freedman et al⁹ in 1987 reviewed 15,609 patients with chronic CAD who underwent coronary angiography, of whom 522 had left or right bundle branch block. During a follow-up of nearly 5 years, 2,386 patients died. The actuarial probability of death at 2 years in patients with left bundle branch block was more than 5 times that of patients without it (P < .0001).

During 18 years of observation in the Framingham study,¹⁰ 55 participants developed left bundle branch block, at a mean age at onset of 62. Twenty-six (48%) of these participants developed clinically significant CAD or heart failure coincident with or subsequent to the onset of left bundle branch block. Fifty percent of the participants who developed left bundle branch block died of cardiovascular disease within 10 years of its onset.

 

 

EXERCISE STRESS ELECTROCARDIOGRAPHY

Exercise stress electrocardiography, although valuable for assessing functional capacity, cannot be used to diagnose obstructive CAD in patients with left bundle branch block.¹¹

EXERCISE STRESS ECHOCARDIOGRAPHY

Exercise stress echocardiography is proven and widely used for assessing myocardial ischemia in patients with suspected obstructive CAD. But the data are limited on its diagnostic utility in patients with left bundle branch block. Until recently, recommendations for its use in this situation were based on only 1 small study.¹²

Peteiro et al¹² in 2000 described 35 patients who underwent exercise stress echocardiography and coronary angiography. Detection of wall-motion abnormalities had high sensitivity (76%), specificity (83%), and diagnostic accuracy (80%).

Of note, 8 (23%) of the patients could not achieve at least 85% of the maximum predicted heart rate, and for them, the study was not diagnostic for ischemia. (Technically, the study is said to be nondiagnostic when the patient fails to achieve the target heart rate of at least 85% of the maximum predicted heart rate.)

Additionally, 18 of the 35 patients—over half—had a decrease in left ventricular ejection fraction in response to exercise. These 18 patients included 12 of the 17 patients with obstructive CAD and 6 of the 18 patients without obstructive CAD.¹² It is unclear whether a significant proportion of these 18 patients would have been otherwise categorized as having a globally abnormal left ventricular contractile response to exercise according to contemporary (2007) reporting standards.¹³

Xu et al^14,15 in 2016 examined the diagnostic utility of exercise stress echocardiography in assessing suspected obstructive CAD in 191 patients with resting left bundle branch block; 17 patients who failed to achieve a heart rate of at least 85% of the age-predicted maximum heart rate were excluded. Of the remaining 174 patients, 82 demonstrated a normal left ventricular contractile response to exercise and 92 had an abnormal response. In the abnormal group, 70 patients had a globally abnormal response, and 22 patients had a regional ischemic response. Of those who had a globally abnormal left ventricular contractile response who subsequently underwent angiography, only 30% were found to have obstructive CAD.

Although the sensitivity of exercise stress echocardiography was high (94%), its specificity and diagnostic accuracy were poor (specificity 21%, diagnostic accuracy 52%).^14,15 These results suggest that for patients with resting left bundle branch block undergoing exercise stress echocardiography, obstructive CAD cannot be reliably diagnosed in those who develop a globally abnormal left ventricular contractile response. Therefore, an alternative imaging strategy should be considered.

DOBUTAMINE STRESS ECHOCARDIOGRAPHY

The evidence base for dobutamine stress echocardiography in patients with left bundle branch block is more robust than that for exercise stress echocardiography.

Geleijnse et al¹ studied 64 patients with left bundle branch block undergoing dobutamine stress echocardiography who also underwent coronary angiography. Dobutamine stress echocardiography was moderately sensitive for detecting anterior and posterior myocardial wall ischemia (60% and 67%, respectively). Its specificity and diagnostic accuracy were high, at 94% and 98%, respectively.

Yanik et al¹⁶ studied 30 patients with left bundle branch block undergoing both dobutamine stress echocardiography and coronary angiography. The sensitivity of dobutamine stress echocardiography for identifying ischemia in the left anterior descending territory was 82%, the specificity was 95%, and the diagnostic accuracy was 90%. For identifying ischemia in the circumflex and right coronary artery territories, the sensitivity was 88%, specificity 96%, and accuracy 93%.

Mairesse et al¹⁷ studied 24 patients with left bundle branch block undergoing dobutamine stress echocardiography, myocardial perfusion tomography, and coronary angiography. Dobutamine stress echocardiography performed well in detecting ischemia in the left anterior descending territory, with a sensitivity of 83%, specificity 92%, and diagnostic accuracy 87%.

Of note, the available data come from very small studies published more than 15 years ago, and pharmacologic stress testing cannot provide the very important prognostic information derived from treadmill testing.

NUCLEAR MYOCARDIAL PERFUSION IMAGING

Exercise nuclear single-photon emission computed tomography (SPECT) myocardial perfusion imaging in patients with left bundle branch block is challenging, due to the development of septal perfusion defects at rest and during exercise in the absence of obstructive disease in the left anterior descending artery (Figure 2).^18,19 Asynchronous contraction of the septum, with resulting compression of the septal arteries, decreased flow demands to the septal region, and attenuation artifacts are possible explanations for this phenomenon.²⁰

Pharmacologic stress has been reported to improve the diagnostic accuracy of SPECT myocardial perfusion imaging.²¹

Biagini et al,²¹ in a meta-analysis of noninvasive techniques for diagnosing CAD in patients with left bundle branch block, found 1,785 patients from 39 studies who underwent nuclear myocardial perfusion imaging (48.8% with exercise, 41.9% with pharmacologic stress). Overall, sensitivity was high for both exercise and pharmacologic stress (92.9% and 88.5%). However, the reported specificity with exercise stress was significantly lower than with pharmacologic stress (23.3% vs 74.2%, P < .01).

Nuclear positron-emission tomography (PET) may further improve the diagnostic utility of nuclear myocardial perfusion imaging in patients with left bundle branch block. In a study of 440 patients with left bundle branch block undergoing myocardial perfusion imaging, 67 underwent PET and 373 underwent SPECT.²² Possible septal perfusion artifacts were significantly less common with PET than with SPECT (1.5% vs 19.3%, P < .001).

CT ANGIOGRAPHY

CT angiography has a high sensitivity and specificity for detecting significant obstructive CAD.^23,24 Machines with 320 detector rows have been reported to have a sensitivity of 94% and specificity of 87% for detecting significant CAD and are not affected by resting left bundle branch block.²⁵

Of note, coronary artery calcification increases in older patients, especially those age 65 and older,²⁶ and this confers a higher likelihood of “bystander” CAD. Significant coronary artery calcification limits the diagnostic accuracy of multidetector cardiac CT. Additionally, the detection of bystander CAD leads to positive findings of uncertain clinical significance.

 

 

CURRENT GUIDELINES

Exercise stress echocardiography

American College of Cardiology Foundation/American Heart Association guidelines for diagnosis and management of patients with stable ischemic heart disease recommend exercise stress echocardiography for patients with an intermediate to high pretest probability of ischemic heart disease who have an uninterpretable electrocardiogram and at least moderate physical functioning or no disabling comorbidity (class 1 indication, level of evidence B).¹¹

Current American Society of Echocardiography guidelines also support exercise stress echocardiography as an appropriate test for suspected obstructive CAD in patients with resting left bundle branch block.²⁷ However, this recommendation is based on limited data.

Pharmacologic stress nuclear myocardial perfusion imaging

American Society of Nuclear Cardiology guidelines endorse pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators for evaluating suspected obstructive CAD in patients with resting left bundle branch block.^28,29

THE POSSIBLE HARMS OF TESTING

Although current guidelines recommend it, recent data show that exercise stress echocardiography has poor specificity and diagnostic accuracy for significant obstructive CAD in patients with resting left bundle branch block. And performing this test in patients with left bundle branch block may result in further downstream investigations.

Based on limited data from a small number of studies published more than 15 years ago, dobutamine stress echocardiography has moderate sensitivity and specificity for significant CAD in patients with resting left bundle branch block. However, this test does not provide functional information about the patient’s exercise performance.

Pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators is an appropriate investigation strategy. However, radiation exposure is a limitation.³⁰

CT angiography can assess for significant obstructive CAD in patients with resting left bundle branch block. However, its diagnostic accuracy can be affected by coronary calcification in older patients. Additionally, each scan is associated with a small amount of radiation exposure,³¹ and a small number of patients will have a true contrast allergy.³²

CLINICAL BOTTOM LINE

For patients with typical ischemic symptoms and new left bundle branch block on electrocardiography, specialist cardiology consultation should be sought, with consideration given to proceeding directly to coronary angiography. For stable outpatients, we propose the following diagnostic approach (Figure 3).

Exercise stress echocardiography is recommended by current guidelines, but it cannot reliably detect significant obstructive CAD in patients with resting left bundle branch block—its specificity and diagnostic accuracy are poor.^14,15 Alternative imaging strategies include CT angiography, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators, and dobutamine stress echocardiography.

For investigating suspected obstructive CAD in patients with resting left bundle branch block, we propose CT angiography as the first-line imaging test for patients under age 65 and pharmacologic stress nuclear myocardial perfusion imaging using coronary vasodilators or dobutamine stress echocardiography for those age 65 and older. For patients who cannot tolerate contrast due to renal impairment or who have a true contrast allergy, pharmacologic nuclear myocardial perfusion imaging using coronary vasodilators and dobutamine stress echocardiography may be used as alternatives.

Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

 

 

CONSIDERATIONS FOR OTHER DEMENTIA THERAPY

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

 

 

CONSIDERATIONS FOR OTHER DEMENTIA THERAPY

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

 

 

CONSIDERATIONS FOR OTHER DEMENTIA THERAPY

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.