The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.

“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.

As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH: 

•For treatment-naive patients with PAH who are World Health Organization (WHO)  functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).

•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD. 

The complete guideline article is free to view in the Online First section of the journal CHEST®.

The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.

“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.

As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH: 

•For treatment-naive patients with PAH who are World Health Organization (WHO)  functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).

•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD. 

The complete guideline article is free to view in the Online First section of the journal CHEST®.

The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.

“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.

As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH: 

•For treatment-naive patients with PAH who are World Health Organization (WHO)  functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).

•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD. 

The complete guideline article is free to view in the Online First section of the journal CHEST®.

The American College of Chest Physicians (CHEST) received reaccreditation from the Society for Simulation in Healthcare (SSH) for the 2018-2023 term in the areas of Teaching/Education, Assessment, and Research. In 2013, CHEST became the first and only medical specialty society to achieve SSH accreditation, a distinction that continues today. Currently, CHEST joins over 125 SSH-accredited programs worldwide, including universities, hospitals, and medical education companies.

The reaccreditation process was the result of months of preparation on behalf of CHEST Simulation Program staff, CHEST Accreditation staff, CHEST Outcomes staff, as well as CHEST’s Live Learning Domain Task Force chairs and other education leadership. This culminated in mid-November at a face-to-face on-site interview with site reviewers representing SSH and CHEST Simulation Program faculty and staff and CHEST leadership. Throughout the process, CHEST was given the opportunity to highlight the unique and innovative ways in which we are utilizing simulation-based education to provide greater clinical insights to enhance patient care.

We recognize that this isn’t only an every-4-year commitment, but it is resultant of the ongoing efforts from a group of dedicated individuals. Thank you to all whose contributions ensured our success! 

The American College of Chest Physicians (CHEST) received reaccreditation from the Society for Simulation in Healthcare (SSH) for the 2018-2023 term in the areas of Teaching/Education, Assessment, and Research. In 2013, CHEST became the first and only medical specialty society to achieve SSH accreditation, a distinction that continues today. Currently, CHEST joins over 125 SSH-accredited programs worldwide, including universities, hospitals, and medical education companies.

The reaccreditation process was the result of months of preparation on behalf of CHEST Simulation Program staff, CHEST Accreditation staff, CHEST Outcomes staff, as well as CHEST’s Live Learning Domain Task Force chairs and other education leadership. This culminated in mid-November at a face-to-face on-site interview with site reviewers representing SSH and CHEST Simulation Program faculty and staff and CHEST leadership. Throughout the process, CHEST was given the opportunity to highlight the unique and innovative ways in which we are utilizing simulation-based education to provide greater clinical insights to enhance patient care.

We recognize that this isn’t only an every-4-year commitment, but it is resultant of the ongoing efforts from a group of dedicated individuals. Thank you to all whose contributions ensured our success! 

The American College of Chest Physicians (CHEST) received reaccreditation from the Society for Simulation in Healthcare (SSH) for the 2018-2023 term in the areas of Teaching/Education, Assessment, and Research. In 2013, CHEST became the first and only medical specialty society to achieve SSH accreditation, a distinction that continues today. Currently, CHEST joins over 125 SSH-accredited programs worldwide, including universities, hospitals, and medical education companies.

The reaccreditation process was the result of months of preparation on behalf of CHEST Simulation Program staff, CHEST Accreditation staff, CHEST Outcomes staff, as well as CHEST’s Live Learning Domain Task Force chairs and other education leadership. This culminated in mid-November at a face-to-face on-site interview with site reviewers representing SSH and CHEST Simulation Program faculty and staff and CHEST leadership. Throughout the process, CHEST was given the opportunity to highlight the unique and innovative ways in which we are utilizing simulation-based education to provide greater clinical insights to enhance patient care.

We recognize that this isn’t only an every-4-year commitment, but it is resultant of the ongoing efforts from a group of dedicated individuals. Thank you to all whose contributions ensured our success! 

CHEST has been notified of the following deaths.

We extend our sincere condolences.



Faroque A. Khan, MBBS

Venessa Holland, MD, FCCP
 

CHEST has been notified of the following deaths.

We extend our sincere condolences.



Faroque A. Khan, MBBS

Venessa Holland, MD, FCCP
 

CHEST has been notified of the following deaths.

We extend our sincere condolences.



Faroque A. Khan, MBBS

Venessa Holland, MD, FCCP
 

One-time, universal hepatitis C testing is cost effective. Poor asthma control during pregnancy trims live birth rates. Fluorouracil beats other actinic keratosis treatments in a head-to-head trial. And vitamin C for sepsis? Experts take sides in a sharp debate.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

One-time, universal hepatitis C testing is cost effective. Poor asthma control during pregnancy trims live birth rates. Fluorouracil beats other actinic keratosis treatments in a head-to-head trial. And vitamin C for sepsis? Experts take sides in a sharp debate.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

One-time, universal hepatitis C testing is cost effective. Poor asthma control during pregnancy trims live birth rates. Fluorouracil beats other actinic keratosis treatments in a head-to-head trial. And vitamin C for sepsis? Experts take sides in a sharp debate.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

Thoracic endovascular aortic repair (TEVAR) is a “young technology with several unknowns,” say researchers from Shantou University Medical College, and Wuhan Asia Heart Hospital, both China. One of those unknowns is the risk factors for prognosis after TEVAR.

After all, thyroid hormones are critical to many areas of heart health, such as vascular remodeling; hypothyroidism can aggravate hypertension; and low levels of free thyroxine (FT4) influence arterial stiffness and C-reactive protein. In spite of the many links, however, the relationship between subclinical hypothyroidism and cardiovascular disease has not been fully elucidated, the researchers say. They conducted a study to evaluate whether thyroid hormones predicted early (30 days) and mid-term (12 months) aorta-related adverse events (AEs), such as death, progression of aortic disease, organ failure, or lower limb ischemia; and aorta-related readmissions.

In their study, 338 patients were stratified according to their levels of FT4 before undergoing TEVAR. Of the enrolled patients, 288 were followed up at 12 months for readmission; 292 were followed up on AEs.

Patients with low normal levels of FT4 had a greater risk of readmission after thoracic endovascular aortic repair. Within 30 days, the incidence of AEs and readmission were 2.7% and 4.1%; within 12 months, 8.9% and 13.5%. After the researchers adjusted for confounders, the patients with the lowest FT4 quartile were at significantly greater risk for readmission than those in the highest-quartile group, at both early and mid-term follow-up. 

The same did not hold true for AEs. The researchers say this is not uncommon in studies of predictors of AEs and readmission: Factors that are weak predictors of readmission tend to be strong predictors of AEs, and vice versa.

Thoracic endovascular aortic repair (TEVAR) is a “young technology with several unknowns,” say researchers from Shantou University Medical College, and Wuhan Asia Heart Hospital, both China. One of those unknowns is the risk factors for prognosis after TEVAR.

After all, thyroid hormones are critical to many areas of heart health, such as vascular remodeling; hypothyroidism can aggravate hypertension; and low levels of free thyroxine (FT4) influence arterial stiffness and C-reactive protein. In spite of the many links, however, the relationship between subclinical hypothyroidism and cardiovascular disease has not been fully elucidated, the researchers say. They conducted a study to evaluate whether thyroid hormones predicted early (30 days) and mid-term (12 months) aorta-related adverse events (AEs), such as death, progression of aortic disease, organ failure, or lower limb ischemia; and aorta-related readmissions.

In their study, 338 patients were stratified according to their levels of FT4 before undergoing TEVAR. Of the enrolled patients, 288 were followed up at 12 months for readmission; 292 were followed up on AEs.

Patients with low normal levels of FT4 had a greater risk of readmission after thoracic endovascular aortic repair. Within 30 days, the incidence of AEs and readmission were 2.7% and 4.1%; within 12 months, 8.9% and 13.5%. After the researchers adjusted for confounders, the patients with the lowest FT4 quartile were at significantly greater risk for readmission than those in the highest-quartile group, at both early and mid-term follow-up. 

The same did not hold true for AEs. The researchers say this is not uncommon in studies of predictors of AEs and readmission: Factors that are weak predictors of readmission tend to be strong predictors of AEs, and vice versa.

Thoracic endovascular aortic repair (TEVAR) is a “young technology with several unknowns,” say researchers from Shantou University Medical College, and Wuhan Asia Heart Hospital, both China. One of those unknowns is the risk factors for prognosis after TEVAR.

After all, thyroid hormones are critical to many areas of heart health, such as vascular remodeling; hypothyroidism can aggravate hypertension; and low levels of free thyroxine (FT4) influence arterial stiffness and C-reactive protein. In spite of the many links, however, the relationship between subclinical hypothyroidism and cardiovascular disease has not been fully elucidated, the researchers say. They conducted a study to evaluate whether thyroid hormones predicted early (30 days) and mid-term (12 months) aorta-related adverse events (AEs), such as death, progression of aortic disease, organ failure, or lower limb ischemia; and aorta-related readmissions.

In their study, 338 patients were stratified according to their levels of FT4 before undergoing TEVAR. Of the enrolled patients, 288 were followed up at 12 months for readmission; 292 were followed up on AEs.

Patients with low normal levels of FT4 had a greater risk of readmission after thoracic endovascular aortic repair. Within 30 days, the incidence of AEs and readmission were 2.7% and 4.1%; within 12 months, 8.9% and 13.5%. After the researchers adjusted for confounders, the patients with the lowest FT4 quartile were at significantly greater risk for readmission than those in the highest-quartile group, at both early and mid-term follow-up. 

The same did not hold true for AEs. The researchers say this is not uncommon in studies of predictors of AEs and readmission: Factors that are weak predictors of readmission tend to be strong predictors of AEs, and vice versa.

“Time-specific” dosing of insulin can be an obstacle to adherence for patients with complicated, busy lives. More than half of patients with type 2 diabetes do not achieve their target HbA_1c of 7% after insulin is added to their treatment regimen. Researchers from CAPHRI School for Public Health and Primary Care, and CARIM Institute in The Netherlands, who surveyed 1,483 adults with diabetes suggest that it may be time to rethink both prescribing and patient education, in part because of who fell into the nonadherent group.

The researchers conducted a web-based self-report survey. Of the respondents, 58% used bolus insulin before meals, 24% after meals, and 18% before, during, or after meals. The researchers excluded the “mixed” cohort, including 1,218 in the analysis.

Half the respondents in the postmeal cohort reported experiencing minor hypoglycemic events at least once a week compared with 35% of the premeal cohort. Similarly, more in the postmeal group had had major hypoglycemic events (38% vs 26%). The postmeal respondents also were more likely to have HbA_1c ≥ 9% (40% vs 29%). And they were less likely to report always testing their blood glucose before injecting insulin (36% vs 54%).

Perhaps contrary to some expectations, the respondents who injected insulin postmeal were younger, had shorter duration of diabetes, had the highest level of college or university education, were more likely to be employed, and more frequently participated in diabetes education programs (including one-on-one programs).

The researchers say those data suggest that factors other than lack of diabetes education, education, or low socioeconomic status should be considered in explaining the nonadherence. They add that some research has shown that education programs have an “inconsistent relationship with patient adherence.” They suggest that such programs might be improved by placing greater emphasis on the importance of dosing insulin before meals.

Of the nearly 20% of patients who use insulin treatment, >  90% receive bolus insulin. The researchers note that respondents preferred a form of bolus insulin they can administer before, after, or during meals as they see fit. The respondents who injected postmeal were more likely than the premeal respondents to prefer this formulation.

“Time-specific” dosing of insulin can be an obstacle to adherence for patients with complicated, busy lives. More than half of patients with type 2 diabetes do not achieve their target HbA_1c of 7% after insulin is added to their treatment regimen. Researchers from CAPHRI School for Public Health and Primary Care, and CARIM Institute in The Netherlands, who surveyed 1,483 adults with diabetes suggest that it may be time to rethink both prescribing and patient education, in part because of who fell into the nonadherent group.

The researchers conducted a web-based self-report survey. Of the respondents, 58% used bolus insulin before meals, 24% after meals, and 18% before, during, or after meals. The researchers excluded the “mixed” cohort, including 1,218 in the analysis.

Half the respondents in the postmeal cohort reported experiencing minor hypoglycemic events at least once a week compared with 35% of the premeal cohort. Similarly, more in the postmeal group had had major hypoglycemic events (38% vs 26%). The postmeal respondents also were more likely to have HbA_1c ≥ 9% (40% vs 29%). And they were less likely to report always testing their blood glucose before injecting insulin (36% vs 54%).

Perhaps contrary to some expectations, the respondents who injected insulin postmeal were younger, had shorter duration of diabetes, had the highest level of college or university education, were more likely to be employed, and more frequently participated in diabetes education programs (including one-on-one programs).

The researchers say those data suggest that factors other than lack of diabetes education, education, or low socioeconomic status should be considered in explaining the nonadherence. They add that some research has shown that education programs have an “inconsistent relationship with patient adherence.” They suggest that such programs might be improved by placing greater emphasis on the importance of dosing insulin before meals.

Of the nearly 20% of patients who use insulin treatment, >  90% receive bolus insulin. The researchers note that respondents preferred a form of bolus insulin they can administer before, after, or during meals as they see fit. The respondents who injected postmeal were more likely than the premeal respondents to prefer this formulation.

“Time-specific” dosing of insulin can be an obstacle to adherence for patients with complicated, busy lives. More than half of patients with type 2 diabetes do not achieve their target HbA_1c of 7% after insulin is added to their treatment regimen. Researchers from CAPHRI School for Public Health and Primary Care, and CARIM Institute in The Netherlands, who surveyed 1,483 adults with diabetes suggest that it may be time to rethink both prescribing and patient education, in part because of who fell into the nonadherent group.

The researchers conducted a web-based self-report survey. Of the respondents, 58% used bolus insulin before meals, 24% after meals, and 18% before, during, or after meals. The researchers excluded the “mixed” cohort, including 1,218 in the analysis.

Half the respondents in the postmeal cohort reported experiencing minor hypoglycemic events at least once a week compared with 35% of the premeal cohort. Similarly, more in the postmeal group had had major hypoglycemic events (38% vs 26%). The postmeal respondents also were more likely to have HbA_1c ≥ 9% (40% vs 29%). And they were less likely to report always testing their blood glucose before injecting insulin (36% vs 54%).

Perhaps contrary to some expectations, the respondents who injected insulin postmeal were younger, had shorter duration of diabetes, had the highest level of college or university education, were more likely to be employed, and more frequently participated in diabetes education programs (including one-on-one programs).

The researchers say those data suggest that factors other than lack of diabetes education, education, or low socioeconomic status should be considered in explaining the nonadherence. They add that some research has shown that education programs have an “inconsistent relationship with patient adherence.” They suggest that such programs might be improved by placing greater emphasis on the importance of dosing insulin before meals.

Of the nearly 20% of patients who use insulin treatment, >  90% receive bolus insulin. The researchers note that respondents preferred a form of bolus insulin they can administer before, after, or during meals as they see fit. The respondents who injected postmeal were more likely than the premeal respondents to prefer this formulation.

Giants in Chest Medicine – Paul D. Stein, MD, Master FCCP’



Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. By Dr. E. J. Schenck, et al.



The Accuracy of Clinical Staging of Stage I-IIIa Non-Small Cell Lung Cancer: An Analysis

Based on Individual Participant Data. By Dr. N. Navani, et al.



A Simple Clinical Risk Score (C2HEST) for Predicting Incident Atrial Fibrillation in Asian

Subjects: Derivation in 471,446 Chinese Subjects, With Internal Validation and External

Application in 451,199 Korean Subjects. By Dr. Y-G Li, et al.



A Sleep Medicine Curriculum for Pulmonary and Pulmonary/Critical Care Fellowship

Programs: A Multisociety Expert Panel Report. By Dr. D. A. Schulman, et al.

Giants in Chest Medicine – Paul D. Stein, MD, Master FCCP’



Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. By Dr. E. J. Schenck, et al.



The Accuracy of Clinical Staging of Stage I-IIIa Non-Small Cell Lung Cancer: An Analysis

Based on Individual Participant Data. By Dr. N. Navani, et al.



A Simple Clinical Risk Score (C2HEST) for Predicting Incident Atrial Fibrillation in Asian

Subjects: Derivation in 471,446 Chinese Subjects, With Internal Validation and External

Application in 451,199 Korean Subjects. By Dr. Y-G Li, et al.



A Sleep Medicine Curriculum for Pulmonary and Pulmonary/Critical Care Fellowship

Programs: A Multisociety Expert Panel Report. By Dr. D. A. Schulman, et al.

Giants in Chest Medicine – Paul D. Stein, MD, Master FCCP’



Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. By Dr. E. J. Schenck, et al.



The Accuracy of Clinical Staging of Stage I-IIIa Non-Small Cell Lung Cancer: An Analysis

Based on Individual Participant Data. By Dr. N. Navani, et al.



A Simple Clinical Risk Score (C2HEST) for Predicting Incident Atrial Fibrillation in Asian

Subjects: Derivation in 471,446 Chinese Subjects, With Internal Validation and External

Application in 451,199 Korean Subjects. By Dr. Y-G Li, et al.



A Sleep Medicine Curriculum for Pulmonary and Pulmonary/Critical Care Fellowship

Programs: A Multisociety Expert Panel Report. By Dr. D. A. Schulman, et al.

Disaster Response and Global Health
Epigenetics and Disasters
The configuration of the DNA bordering a gene dictates under what conditions a gene is expressed. Random errors or mutations affecting the neighboring DNA or the gene itself can affect how the gene functions. Epigenetics is an emerging field of science looking at environmental and psychosocial factors that do not directly cause mutations but still affect how genes are expressed with implications for the development and inheritance of disease. These external influences are thought to affect why some segments of DNA become accessible for protein production while other segments may not.

Disasters represent stressors with potential for epigenetic impact. Women who were pregnant during the 1998 Quebec ice storm were found to have a correlation between maternal objective stress and a distinctive pattern of DNA methylation in their children 13 years later (Cao-Lei L, et al. PLoS ONE. 2014;9[9] e10765). Methylation is known to affect the activity of a DNA segment and how genes are expressed. Associations have also been found between the severity of hurricanes and the prevalence of autism in the offspring of pregnant women experiencing these disasters (Kinney DK, et al. J Autism Dev Disord. 2008;38:481).

Anthropogenic hazards may also affect the offspring of survivors as suggested by studies of civil war POWs and Dutch Hunger Winter during WW II (Costa, DL, et al. Proc Nat Acad Sci 2018;. 115:44; Heijmans BT et al. Proc Nat Acad Sci. 2008;105[44]: 17046-9).

Epigenetics represents an area for additional research as natural and man-made disasters increase.

Omesh Toolsie, MBBS
Steering Committee Fellow-in-Training

Practice Operations
Medicare Competitive Bidding Process Update

Medicare’s Competitive Bidding Program (CBP), mandated since 2003, asks providers of specific durable medical equipment (including oxygen) to submit competing proposals for services. The best offer is then awarded a 3-year contract. Recently, several reforms to CBP have been proposed. The payment structure has changed to “lead-item pricing,” where a single bid in each category is selected and payment amounts for each product are then calculated based on pricing ratios and fee schedules (CMS DMEPOS Competitive Bidding).

This is in contrast to the prior method of median pricing, which caused financial difficulty and access concerns (Council for Quality Respiratory Care. The Rationale for Reforming Medicare Home Respiratory Therapy Payment Methodology. 2018). Budget neutrality requirements should relax, and oxygen payment structures improve. These proposed changes also include improved coverage of liquid oxygen and addition of home ventilator supplies.

However, effective January 1, 2019, all CBP is suspended through CMS. During the anticipated 2-year gap, any Medicare-enrolled supplier will be able to provide items until new contracts are awarded. Pricing during the gap period is based on a current single price plus consumer price index. These changes will impact CHEST members and their patients moving forward. During the temporary gap period, some areas are seeing decreased accessibility of some DME due to demand. Once reinstated, the changes to the oxygen payment structure should improve access and reduce out-of-pocket costs. The Practice Operations NetWork will continue to provide updates on this topic as they become available.

Timothy Dempsey, MD, MPH
Steering Committee Fellow-in-Training

Megan Sisk, DO
Steering Committee Member

Women’s Health
Cannabis Use Affects Women Differently

As we enter an era of legalization, cannabis use is increasingly prevalent. Variances in the risks for women and men have been observed. For most age groups, men have higher rates of use or dependence on illicit drugs than women. However, women are equally likely as men to progress to a substance use disorder. Women may be more susceptible to craving and relapse , which are key phases of the addiction cycle. A study on use among adolescents concluded there was preliminary evidence of a faster transition from initiation of marijuana use to regular use in women, when compared with men (Schepis, et al. J Addict Med. 2011;5[1]:65).

Disaster Response and Global Health
Epigenetics and Disasters
The configuration of the DNA bordering a gene dictates under what conditions a gene is expressed. Random errors or mutations affecting the neighboring DNA or the gene itself can affect how the gene functions. Epigenetics is an emerging field of science looking at environmental and psychosocial factors that do not directly cause mutations but still affect how genes are expressed with implications for the development and inheritance of disease. These external influences are thought to affect why some segments of DNA become accessible for protein production while other segments may not.

Disasters represent stressors with potential for epigenetic impact. Women who were pregnant during the 1998 Quebec ice storm were found to have a correlation between maternal objective stress and a distinctive pattern of DNA methylation in their children 13 years later (Cao-Lei L, et al. PLoS ONE. 2014;9[9] e10765). Methylation is known to affect the activity of a DNA segment and how genes are expressed. Associations have also been found between the severity of hurricanes and the prevalence of autism in the offspring of pregnant women experiencing these disasters (Kinney DK, et al. J Autism Dev Disord. 2008;38:481).

Anthropogenic hazards may also affect the offspring of survivors as suggested by studies of civil war POWs and Dutch Hunger Winter during WW II (Costa, DL, et al. Proc Nat Acad Sci 2018;. 115:44; Heijmans BT et al. Proc Nat Acad Sci. 2008;105[44]: 17046-9).

Epigenetics represents an area for additional research as natural and man-made disasters increase.

Omesh Toolsie, MBBS
Steering Committee Fellow-in-Training

Practice Operations
Medicare Competitive Bidding Process Update

Medicare’s Competitive Bidding Program (CBP), mandated since 2003, asks providers of specific durable medical equipment (including oxygen) to submit competing proposals for services. The best offer is then awarded a 3-year contract. Recently, several reforms to CBP have been proposed. The payment structure has changed to “lead-item pricing,” where a single bid in each category is selected and payment amounts for each product are then calculated based on pricing ratios and fee schedules (CMS DMEPOS Competitive Bidding).

This is in contrast to the prior method of median pricing, which caused financial difficulty and access concerns (Council for Quality Respiratory Care. The Rationale for Reforming Medicare Home Respiratory Therapy Payment Methodology. 2018). Budget neutrality requirements should relax, and oxygen payment structures improve. These proposed changes also include improved coverage of liquid oxygen and addition of home ventilator supplies.

However, effective January 1, 2019, all CBP is suspended through CMS. During the anticipated 2-year gap, any Medicare-enrolled supplier will be able to provide items until new contracts are awarded. Pricing during the gap period is based on a current single price plus consumer price index. These changes will impact CHEST members and their patients moving forward. During the temporary gap period, some areas are seeing decreased accessibility of some DME due to demand. Once reinstated, the changes to the oxygen payment structure should improve access and reduce out-of-pocket costs. The Practice Operations NetWork will continue to provide updates on this topic as they become available.

Timothy Dempsey, MD, MPH
Steering Committee Fellow-in-Training

Megan Sisk, DO
Steering Committee Member

Women’s Health
Cannabis Use Affects Women Differently

As we enter an era of legalization, cannabis use is increasingly prevalent. Variances in the risks for women and men have been observed. For most age groups, men have higher rates of use or dependence on illicit drugs than women. However, women are equally likely as men to progress to a substance use disorder. Women may be more susceptible to craving and relapse , which are key phases of the addiction cycle. A study on use among adolescents concluded there was preliminary evidence of a faster transition from initiation of marijuana use to regular use in women, when compared with men (Schepis, et al. J Addict Med. 2011;5[1]:65).

Disaster Response and Global Health
Epigenetics and Disasters
The configuration of the DNA bordering a gene dictates under what conditions a gene is expressed. Random errors or mutations affecting the neighboring DNA or the gene itself can affect how the gene functions. Epigenetics is an emerging field of science looking at environmental and psychosocial factors that do not directly cause mutations but still affect how genes are expressed with implications for the development and inheritance of disease. These external influences are thought to affect why some segments of DNA become accessible for protein production while other segments may not.

Disasters represent stressors with potential for epigenetic impact. Women who were pregnant during the 1998 Quebec ice storm were found to have a correlation between maternal objective stress and a distinctive pattern of DNA methylation in their children 13 years later (Cao-Lei L, et al. PLoS ONE. 2014;9[9] e10765). Methylation is known to affect the activity of a DNA segment and how genes are expressed. Associations have also been found between the severity of hurricanes and the prevalence of autism in the offspring of pregnant women experiencing these disasters (Kinney DK, et al. J Autism Dev Disord. 2008;38:481).

Anthropogenic hazards may also affect the offspring of survivors as suggested by studies of civil war POWs and Dutch Hunger Winter during WW II (Costa, DL, et al. Proc Nat Acad Sci 2018;. 115:44; Heijmans BT et al. Proc Nat Acad Sci. 2008;105[44]: 17046-9).

Epigenetics represents an area for additional research as natural and man-made disasters increase.

Omesh Toolsie, MBBS
Steering Committee Fellow-in-Training

Practice Operations
Medicare Competitive Bidding Process Update

Medicare’s Competitive Bidding Program (CBP), mandated since 2003, asks providers of specific durable medical equipment (including oxygen) to submit competing proposals for services. The best offer is then awarded a 3-year contract. Recently, several reforms to CBP have been proposed. The payment structure has changed to “lead-item pricing,” where a single bid in each category is selected and payment amounts for each product are then calculated based on pricing ratios and fee schedules (CMS DMEPOS Competitive Bidding).

This is in contrast to the prior method of median pricing, which caused financial difficulty and access concerns (Council for Quality Respiratory Care. The Rationale for Reforming Medicare Home Respiratory Therapy Payment Methodology. 2018). Budget neutrality requirements should relax, and oxygen payment structures improve. These proposed changes also include improved coverage of liquid oxygen and addition of home ventilator supplies.

However, effective January 1, 2019, all CBP is suspended through CMS. During the anticipated 2-year gap, any Medicare-enrolled supplier will be able to provide items until new contracts are awarded. Pricing during the gap period is based on a current single price plus consumer price index. These changes will impact CHEST members and their patients moving forward. During the temporary gap period, some areas are seeing decreased accessibility of some DME due to demand. Once reinstated, the changes to the oxygen payment structure should improve access and reduce out-of-pocket costs. The Practice Operations NetWork will continue to provide updates on this topic as they become available.

Timothy Dempsey, MD, MPH
Steering Committee Fellow-in-Training

Megan Sisk, DO
Steering Committee Member

Women’s Health
Cannabis Use Affects Women Differently

As we enter an era of legalization, cannabis use is increasingly prevalent. Variances in the risks for women and men have been observed. For most age groups, men have higher rates of use or dependence on illicit drugs than women. However, women are equally likely as men to progress to a substance use disorder. Women may be more susceptible to craving and relapse , which are key phases of the addiction cycle. A study on use among adolescents concluded there was preliminary evidence of a faster transition from initiation of marijuana use to regular use in women, when compared with men (Schepis, et al. J Addict Med. 2011;5[1]:65).

The NetWorks Challenge is an annual fundraising competition that encourages NetWork members to contribute to the CHEST Foundation - supporting clinical research grants and community service programs and creating patient education materials - while earning travel grants for their NetWork members to the CHEST Annual Meeting 2019 in New Orleans. Because of your generosity throughout the 2018 NetWorks Challenge, the CHEST Foundation was able to send 59 early career clinicians to CHEST 2018 in San Antonio - marked growth from the 25 clinicians who received the travel grants in 2017.

As we further improve this program based on feedback from NetWorks members, a few elements of the fundraiser are changing in 2019.

Length: This year, the NetWorks Challenge will span 3 months. Contributions made between April 1 and June 30 count toward your NetWork’s fundraising total! Just be sure to list your NetWork when making your contribution on chestfoundation.org/donate. Each month has a unique theme related to CHEST, so be sure to watch our social media profiles to engage with us and each other during the drive.

Additionally, ANY contributions made to the CHEST Foundation during your membership renewal will count toward your NetWorks total amount raised - no matter when your membership is up for renewal. Contributions made in this manner after June 30 will count toward your Network’s 2020 amount raised.

Prizes: This year, every NetWork is eligible to receive travel grants to CHEST 2019 in New Orleans based on the amount raised by the NetWork. Our final winners – the NetWork with the highest amount raised, and the NetWork with the highest percentage of participation from their NetWork, will each receive two additional travel grants to CHEST 2019. Plus, the NetWork with the highest amount raised over the course of the challenge receives an additional prize – a seat in a CHEST Live Learning course of the winner’s choosing, offered at CHEST’s Innovation, Simulation, and Training Center in Glenview, Illinois.

Visit chestfoundation.org/nc for more detailed information.


 

The NetWorks Challenge is an annual fundraising competition that encourages NetWork members to contribute to the CHEST Foundation - supporting clinical research grants and community service programs and creating patient education materials - while earning travel grants for their NetWork members to the CHEST Annual Meeting 2019 in New Orleans. Because of your generosity throughout the 2018 NetWorks Challenge, the CHEST Foundation was able to send 59 early career clinicians to CHEST 2018 in San Antonio - marked growth from the 25 clinicians who received the travel grants in 2017.

As we further improve this program based on feedback from NetWorks members, a few elements of the fundraiser are changing in 2019.

Length: This year, the NetWorks Challenge will span 3 months. Contributions made between April 1 and June 30 count toward your NetWork’s fundraising total! Just be sure to list your NetWork when making your contribution on chestfoundation.org/donate. Each month has a unique theme related to CHEST, so be sure to watch our social media profiles to engage with us and each other during the drive.

Additionally, ANY contributions made to the CHEST Foundation during your membership renewal will count toward your NetWorks total amount raised - no matter when your membership is up for renewal. Contributions made in this manner after June 30 will count toward your Network’s 2020 amount raised.

Prizes: This year, every NetWork is eligible to receive travel grants to CHEST 2019 in New Orleans based on the amount raised by the NetWork. Our final winners – the NetWork with the highest amount raised, and the NetWork with the highest percentage of participation from their NetWork, will each receive two additional travel grants to CHEST 2019. Plus, the NetWork with the highest amount raised over the course of the challenge receives an additional prize – a seat in a CHEST Live Learning course of the winner’s choosing, offered at CHEST’s Innovation, Simulation, and Training Center in Glenview, Illinois.

Visit chestfoundation.org/nc for more detailed information.


 

The NetWorks Challenge is an annual fundraising competition that encourages NetWork members to contribute to the CHEST Foundation - supporting clinical research grants and community service programs and creating patient education materials - while earning travel grants for their NetWork members to the CHEST Annual Meeting 2019 in New Orleans. Because of your generosity throughout the 2018 NetWorks Challenge, the CHEST Foundation was able to send 59 early career clinicians to CHEST 2018 in San Antonio - marked growth from the 25 clinicians who received the travel grants in 2017.

As we further improve this program based on feedback from NetWorks members, a few elements of the fundraiser are changing in 2019.

Length: This year, the NetWorks Challenge will span 3 months. Contributions made between April 1 and June 30 count toward your NetWork’s fundraising total! Just be sure to list your NetWork when making your contribution on chestfoundation.org/donate. Each month has a unique theme related to CHEST, so be sure to watch our social media profiles to engage with us and each other during the drive.

Additionally, ANY contributions made to the CHEST Foundation during your membership renewal will count toward your NetWorks total amount raised - no matter when your membership is up for renewal. Contributions made in this manner after June 30 will count toward your Network’s 2020 amount raised.

Prizes: This year, every NetWork is eligible to receive travel grants to CHEST 2019 in New Orleans based on the amount raised by the NetWork. Our final winners – the NetWork with the highest amount raised, and the NetWork with the highest percentage of participation from their NetWork, will each receive two additional travel grants to CHEST 2019. Plus, the NetWork with the highest amount raised over the course of the challenge receives an additional prize – a seat in a CHEST Live Learning course of the winner’s choosing, offered at CHEST’s Innovation, Simulation, and Training Center in Glenview, Illinois.

Visit chestfoundation.org/nc for more detailed information.


 

Compared with obstructive sleep apnea (OSA), the prevalence of central sleep apnea (CSA) is low in the general population. However, in adults, CSA may be highly prevalent in certain conditions, most commonly among those with left ventricular systolic dysfunction, left ventricular diastolic dysfunction, atrial fibrillation, stroke, and opioid users (Javaheri S, et al. J Am Coll Cardiol. 2017; 69:841). CSA may also be found in patients with carotid artery stenosis, cervical neck injury, and renal dysfunction. CSA can occur when OSA is treated (treatment-emergent central sleep apnea, or TECA), notably, and most frequently, with continuous positive airway pressure (CPAP) devices. Though in many individuals, this frequently resolves with continued use of the device.

In addition, unlike OSA, adequate treatment of CSA has proven difficult. Specifically, the response to CPAP, oxygen, theophylline, acetazolamide, and adaptive-servo ventilation (ASV) is highly variable, with individuals who respond well, and individuals in whom therapy fails to fully suppress the disorder.

Our interest in phrenic nerve stimulation increased after it was shown that CPAP therapy failed to improve morbidity and mortality of CSA in patients with heart failure and reduced ejection fraction (HFrEF) (CANPAP trial, Bradley et al. N Engl J Med. 2005;353(19):2025). In fact, in this trial, treatment with CPAP was associated with significantly increased mortality during the first few months of therapy. We reason that a potential mechanism was positive airway pressure that had adverse cardiovascular effects (Javaheri S. J Clin Sleep Med. 2006;2:399). This is because positive airway pressure therapy decreases venous return to the right side of the heart and increases lung volume. This could increase pulmonary vascular resistance (right ventricular afterload), which is lung volume-dependent. Therefore, the subgroup of individuals with heart failure whose right ventricular function is preload-dependent and has pulmonary hypertension is at risk for premature mortality with any PAP device.

Interestingly, investigators of the SERVE-HF trial (Cowie MR, et al. N Engl J Med. 2015;373:1095) also hypothesized that one reason for excess mortality associated with ASV use might have been due to an ASV-associated excessive rise in intrathoracic pressure, similar to the hypothesis we proposed earlier for CPAP. We expanded on this hypothesis and reasoned that based on the algorithm of the device, in some patients, it could have generated excessive minute ventilation and pressure contributing to excess mortality, either at night or daytime (Javaheri S, et al. Chest. 2016;149:900). Other deficiencies of the algorithm of the ASV device could have contributed to excess mortality as well (Javaheri S, et al. Chest. 2014;146:514). These deficiencies of the ASV device used in the SERVE-HF trial have been significantly improved in the new generation of ASV devices.

Undoubtedly, therefore, mask therapy with positive airway pressures increases intrathoracic pressure and will adversely affect cardiovascular function in some patients with heart failure. Another issue for mask therapy is adherence to the device remains poor, as demonstrated both in the CANPAP and SERVE-HF trials, confirming the need for new approaches utilizing non-mask therapies both for CSA and OSA.

Given the limitations of mask-based therapies, over the last several years, we have performed studies exploring the use of oxygen, acetazolamide, theophylline, and, most recently, phrenic nerve stimulation (PNS). In general, these therapies are devoid of increasing intrathoracic pressure and are expected to be less reliant on patients’ adherence than PAP therapy. Long-term randomized clinical trials are needed, and, most recently, the NIH approved a phase 3 trial for a randomized placebo-controlled low flow oxygen therapy for treatment of CSA in HFrEF. This is a modified trial proposed by one of us more than 20 years ago!

Regarding PNS, CSA is characterized by intermittent phrenic nerve (and intercostal nerves) deactivation. It, therefore, makes sense to have an implanted stimulator for the phrenic nerve to prevent development of central apneas during sleep. This is not a new idea. In 1948, Sarnoff and colleagues demonstrated for the first time that artificial respiration could be effectively administered to the cat, dog, monkey, and rabbit in the absence of spontaneous respiration by electrical stimulation of one (or both) phrenic nerves (Sarnoff SJ, et al. Science. 1948;108:482). In later experiments, these investigators showed that unilateral phrenic nerve stimulation is also equally effective in man as that shown in animal models.

The phrenic nerves comes in contact with veins on both the right (brachiocephalic) and the left (pericardiophrenic vein) side of the mediastinum. Like a cardiac pacemaker, an electrophysiologist places the stimulator within the vein at the point of encounter with the phrenic nerve. Only unilateral stimulation is needed for the therapy. The device is typically placed on the right side of the chest as many patients may already have a cardiac implanted electronic device such as a pacemaker. Like the hypoglossal nerve stimulation, the FDA approved this device for the treatment of OSA. The system can be programmed using an external programmer in the office.

Phrenic nerve stimulation system is initially activated 1 month after the device is placed. It is programmed to be automatically activated at night when the patient is at rest. First, a time is set on the device for when the patient typically goes to bed and awakens. This allows the therapy to activate. The device contains a position sensor and accelerometer, which determine position and activity level. Once appropriate time, position, and activity are confirmed, the device activates automatically. Therapy comes on and can increase in level over several minutes. The device senses transthoracic impedance and can use this measurement to make changes in the therapy output and activity. If the patient gets up at night, the device automatically stops and restarts when the patient is back in a sleeping position. How quickly the therapy restarts and at what energy is programmable. The device may allow from 1 to 15 minutes for the patient to get back to sleep before beginning therapy. These programming changes allow for patient acceptance and comfort with the therapy even in very sensitive patients. Importantly, no patient activation is needed, so that therapy delivery is independent of patient’s adherence over time.

In the prospective, randomized pivotal trial (Costanzo et al. Lancet. 2016;388:974), 151 eligible patients with moderate-severe central sleep apnea were implanted and randomly assigned to the treatment (n=73) or control (n=78) groups. Participants in the active arm received PNS for 6 months. All polysomnograms were centrally and blindly scored. There were significant decreases in AHI (50 to 26/per hour of sleep), CAI (32 to 6), arousal index (46 to 25), and ODI (44 to 25). Two points should be emphasized: first, changes in AHI with PNS are similar to those in CANPAP trial, and there remained a significant number of hypopneas (some of these hypopneas are at least in part related to the speed of the titration when the subject sits up and the device automatically is deactivated, only to resume therapy in supine position); second, in contrast to the CANPAP trial, there was a significant reduction in arousals. Probably for this reason, subjective daytime sleepiness, as measured by the ESS, improved. In addition, PNS improved quality of life, in contrast to lack of effect of CPAP or ASV in this domain. Regarding side effects, 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group.—3.4% needed lead repositioning, a rate which is like that of cardiac implantable devices. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomization period when neurostimulation was delivered to only the treatment and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. Of 73 patients in the treatment group, 27 (37%) reported nonserious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients but was unresolved in one (1%) patient.

Long-term studies have shown sustained effects of PNS on CSA with improvement in both sleep metrics and QOL, as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) and patient global assessment (PGA). Furthermore, in the subgroup of patients with concomitant heart failure with LVEF ≤ 45%, PNS was associated with both improvements in LVEF and a trend toward lower hospitalization rates (Costanzo et al. Eur J Heart Fail. 2018; doi:10.1002/ejhf.1312).

Several issues must be emphasized. One advantage of PNS is complete adherence resulting in a major reduction in apnea burden across the whole night. Second, the mechanism of action prevents any potential adverse consequences related to increased intrathoracic pressure. However, the cost of this therapy is high, similar to that of hypoglossal nerve stimulation. Large scale, long-term studies related to mortality are not yet available, and continued research should help identify those patients most likely to benefit from this therapeutic approach.

Compared with obstructive sleep apnea (OSA), the prevalence of central sleep apnea (CSA) is low in the general population. However, in adults, CSA may be highly prevalent in certain conditions, most commonly among those with left ventricular systolic dysfunction, left ventricular diastolic dysfunction, atrial fibrillation, stroke, and opioid users (Javaheri S, et al. J Am Coll Cardiol. 2017; 69:841). CSA may also be found in patients with carotid artery stenosis, cervical neck injury, and renal dysfunction. CSA can occur when OSA is treated (treatment-emergent central sleep apnea, or TECA), notably, and most frequently, with continuous positive airway pressure (CPAP) devices. Though in many individuals, this frequently resolves with continued use of the device.

In addition, unlike OSA, adequate treatment of CSA has proven difficult. Specifically, the response to CPAP, oxygen, theophylline, acetazolamide, and adaptive-servo ventilation (ASV) is highly variable, with individuals who respond well, and individuals in whom therapy fails to fully suppress the disorder.

Our interest in phrenic nerve stimulation increased after it was shown that CPAP therapy failed to improve morbidity and mortality of CSA in patients with heart failure and reduced ejection fraction (HFrEF) (CANPAP trial, Bradley et al. N Engl J Med. 2005;353(19):2025). In fact, in this trial, treatment with CPAP was associated with significantly increased mortality during the first few months of therapy. We reason that a potential mechanism was positive airway pressure that had adverse cardiovascular effects (Javaheri S. J Clin Sleep Med. 2006;2:399). This is because positive airway pressure therapy decreases venous return to the right side of the heart and increases lung volume. This could increase pulmonary vascular resistance (right ventricular afterload), which is lung volume-dependent. Therefore, the subgroup of individuals with heart failure whose right ventricular function is preload-dependent and has pulmonary hypertension is at risk for premature mortality with any PAP device.

Interestingly, investigators of the SERVE-HF trial (Cowie MR, et al. N Engl J Med. 2015;373:1095) also hypothesized that one reason for excess mortality associated with ASV use might have been due to an ASV-associated excessive rise in intrathoracic pressure, similar to the hypothesis we proposed earlier for CPAP. We expanded on this hypothesis and reasoned that based on the algorithm of the device, in some patients, it could have generated excessive minute ventilation and pressure contributing to excess mortality, either at night or daytime (Javaheri S, et al. Chest. 2016;149:900). Other deficiencies of the algorithm of the ASV device could have contributed to excess mortality as well (Javaheri S, et al. Chest. 2014;146:514). These deficiencies of the ASV device used in the SERVE-HF trial have been significantly improved in the new generation of ASV devices.

Undoubtedly, therefore, mask therapy with positive airway pressures increases intrathoracic pressure and will adversely affect cardiovascular function in some patients with heart failure. Another issue for mask therapy is adherence to the device remains poor, as demonstrated both in the CANPAP and SERVE-HF trials, confirming the need for new approaches utilizing non-mask therapies both for CSA and OSA.

Given the limitations of mask-based therapies, over the last several years, we have performed studies exploring the use of oxygen, acetazolamide, theophylline, and, most recently, phrenic nerve stimulation (PNS). In general, these therapies are devoid of increasing intrathoracic pressure and are expected to be less reliant on patients’ adherence than PAP therapy. Long-term randomized clinical trials are needed, and, most recently, the NIH approved a phase 3 trial for a randomized placebo-controlled low flow oxygen therapy for treatment of CSA in HFrEF. This is a modified trial proposed by one of us more than 20 years ago!

Regarding PNS, CSA is characterized by intermittent phrenic nerve (and intercostal nerves) deactivation. It, therefore, makes sense to have an implanted stimulator for the phrenic nerve to prevent development of central apneas during sleep. This is not a new idea. In 1948, Sarnoff and colleagues demonstrated for the first time that artificial respiration could be effectively administered to the cat, dog, monkey, and rabbit in the absence of spontaneous respiration by electrical stimulation of one (or both) phrenic nerves (Sarnoff SJ, et al. Science. 1948;108:482). In later experiments, these investigators showed that unilateral phrenic nerve stimulation is also equally effective in man as that shown in animal models.

The phrenic nerves comes in contact with veins on both the right (brachiocephalic) and the left (pericardiophrenic vein) side of the mediastinum. Like a cardiac pacemaker, an electrophysiologist places the stimulator within the vein at the point of encounter with the phrenic nerve. Only unilateral stimulation is needed for the therapy. The device is typically placed on the right side of the chest as many patients may already have a cardiac implanted electronic device such as a pacemaker. Like the hypoglossal nerve stimulation, the FDA approved this device for the treatment of OSA. The system can be programmed using an external programmer in the office.

Phrenic nerve stimulation system is initially activated 1 month after the device is placed. It is programmed to be automatically activated at night when the patient is at rest. First, a time is set on the device for when the patient typically goes to bed and awakens. This allows the therapy to activate. The device contains a position sensor and accelerometer, which determine position and activity level. Once appropriate time, position, and activity are confirmed, the device activates automatically. Therapy comes on and can increase in level over several minutes. The device senses transthoracic impedance and can use this measurement to make changes in the therapy output and activity. If the patient gets up at night, the device automatically stops and restarts when the patient is back in a sleeping position. How quickly the therapy restarts and at what energy is programmable. The device may allow from 1 to 15 minutes for the patient to get back to sleep before beginning therapy. These programming changes allow for patient acceptance and comfort with the therapy even in very sensitive patients. Importantly, no patient activation is needed, so that therapy delivery is independent of patient’s adherence over time.

In the prospective, randomized pivotal trial (Costanzo et al. Lancet. 2016;388:974), 151 eligible patients with moderate-severe central sleep apnea were implanted and randomly assigned to the treatment (n=73) or control (n=78) groups. Participants in the active arm received PNS for 6 months. All polysomnograms were centrally and blindly scored. There were significant decreases in AHI (50 to 26/per hour of sleep), CAI (32 to 6), arousal index (46 to 25), and ODI (44 to 25). Two points should be emphasized: first, changes in AHI with PNS are similar to those in CANPAP trial, and there remained a significant number of hypopneas (some of these hypopneas are at least in part related to the speed of the titration when the subject sits up and the device automatically is deactivated, only to resume therapy in supine position); second, in contrast to the CANPAP trial, there was a significant reduction in arousals. Probably for this reason, subjective daytime sleepiness, as measured by the ESS, improved. In addition, PNS improved quality of life, in contrast to lack of effect of CPAP or ASV in this domain. Regarding side effects, 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group.—3.4% needed lead repositioning, a rate which is like that of cardiac implantable devices. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomization period when neurostimulation was delivered to only the treatment and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. Of 73 patients in the treatment group, 27 (37%) reported nonserious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients but was unresolved in one (1%) patient.

Long-term studies have shown sustained effects of PNS on CSA with improvement in both sleep metrics and QOL, as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) and patient global assessment (PGA). Furthermore, in the subgroup of patients with concomitant heart failure with LVEF ≤ 45%, PNS was associated with both improvements in LVEF and a trend toward lower hospitalization rates (Costanzo et al. Eur J Heart Fail. 2018; doi:10.1002/ejhf.1312).

Several issues must be emphasized. One advantage of PNS is complete adherence resulting in a major reduction in apnea burden across the whole night. Second, the mechanism of action prevents any potential adverse consequences related to increased intrathoracic pressure. However, the cost of this therapy is high, similar to that of hypoglossal nerve stimulation. Large scale, long-term studies related to mortality are not yet available, and continued research should help identify those patients most likely to benefit from this therapeutic approach.

Compared with obstructive sleep apnea (OSA), the prevalence of central sleep apnea (CSA) is low in the general population. However, in adults, CSA may be highly prevalent in certain conditions, most commonly among those with left ventricular systolic dysfunction, left ventricular diastolic dysfunction, atrial fibrillation, stroke, and opioid users (Javaheri S, et al. J Am Coll Cardiol. 2017; 69:841). CSA may also be found in patients with carotid artery stenosis, cervical neck injury, and renal dysfunction. CSA can occur when OSA is treated (treatment-emergent central sleep apnea, or TECA), notably, and most frequently, with continuous positive airway pressure (CPAP) devices. Though in many individuals, this frequently resolves with continued use of the device.

In addition, unlike OSA, adequate treatment of CSA has proven difficult. Specifically, the response to CPAP, oxygen, theophylline, acetazolamide, and adaptive-servo ventilation (ASV) is highly variable, with individuals who respond well, and individuals in whom therapy fails to fully suppress the disorder.

Our interest in phrenic nerve stimulation increased after it was shown that CPAP therapy failed to improve morbidity and mortality of CSA in patients with heart failure and reduced ejection fraction (HFrEF) (CANPAP trial, Bradley et al. N Engl J Med. 2005;353(19):2025). In fact, in this trial, treatment with CPAP was associated with significantly increased mortality during the first few months of therapy. We reason that a potential mechanism was positive airway pressure that had adverse cardiovascular effects (Javaheri S. J Clin Sleep Med. 2006;2:399). This is because positive airway pressure therapy decreases venous return to the right side of the heart and increases lung volume. This could increase pulmonary vascular resistance (right ventricular afterload), which is lung volume-dependent. Therefore, the subgroup of individuals with heart failure whose right ventricular function is preload-dependent and has pulmonary hypertension is at risk for premature mortality with any PAP device.

Interestingly, investigators of the SERVE-HF trial (Cowie MR, et al. N Engl J Med. 2015;373:1095) also hypothesized that one reason for excess mortality associated with ASV use might have been due to an ASV-associated excessive rise in intrathoracic pressure, similar to the hypothesis we proposed earlier for CPAP. We expanded on this hypothesis and reasoned that based on the algorithm of the device, in some patients, it could have generated excessive minute ventilation and pressure contributing to excess mortality, either at night or daytime (Javaheri S, et al. Chest. 2016;149:900). Other deficiencies of the algorithm of the ASV device could have contributed to excess mortality as well (Javaheri S, et al. Chest. 2014;146:514). These deficiencies of the ASV device used in the SERVE-HF trial have been significantly improved in the new generation of ASV devices.

Undoubtedly, therefore, mask therapy with positive airway pressures increases intrathoracic pressure and will adversely affect cardiovascular function in some patients with heart failure. Another issue for mask therapy is adherence to the device remains poor, as demonstrated both in the CANPAP and SERVE-HF trials, confirming the need for new approaches utilizing non-mask therapies both for CSA and OSA.

Given the limitations of mask-based therapies, over the last several years, we have performed studies exploring the use of oxygen, acetazolamide, theophylline, and, most recently, phrenic nerve stimulation (PNS). In general, these therapies are devoid of increasing intrathoracic pressure and are expected to be less reliant on patients’ adherence than PAP therapy. Long-term randomized clinical trials are needed, and, most recently, the NIH approved a phase 3 trial for a randomized placebo-controlled low flow oxygen therapy for treatment of CSA in HFrEF. This is a modified trial proposed by one of us more than 20 years ago!

Regarding PNS, CSA is characterized by intermittent phrenic nerve (and intercostal nerves) deactivation. It, therefore, makes sense to have an implanted stimulator for the phrenic nerve to prevent development of central apneas during sleep. This is not a new idea. In 1948, Sarnoff and colleagues demonstrated for the first time that artificial respiration could be effectively administered to the cat, dog, monkey, and rabbit in the absence of spontaneous respiration by electrical stimulation of one (or both) phrenic nerves (Sarnoff SJ, et al. Science. 1948;108:482). In later experiments, these investigators showed that unilateral phrenic nerve stimulation is also equally effective in man as that shown in animal models.

The phrenic nerves comes in contact with veins on both the right (brachiocephalic) and the left (pericardiophrenic vein) side of the mediastinum. Like a cardiac pacemaker, an electrophysiologist places the stimulator within the vein at the point of encounter with the phrenic nerve. Only unilateral stimulation is needed for the therapy. The device is typically placed on the right side of the chest as many patients may already have a cardiac implanted electronic device such as a pacemaker. Like the hypoglossal nerve stimulation, the FDA approved this device for the treatment of OSA. The system can be programmed using an external programmer in the office.

Phrenic nerve stimulation system is initially activated 1 month after the device is placed. It is programmed to be automatically activated at night when the patient is at rest. First, a time is set on the device for when the patient typically goes to bed and awakens. This allows the therapy to activate. The device contains a position sensor and accelerometer, which determine position and activity level. Once appropriate time, position, and activity are confirmed, the device activates automatically. Therapy comes on and can increase in level over several minutes. The device senses transthoracic impedance and can use this measurement to make changes in the therapy output and activity. If the patient gets up at night, the device automatically stops and restarts when the patient is back in a sleeping position. How quickly the therapy restarts and at what energy is programmable. The device may allow from 1 to 15 minutes for the patient to get back to sleep before beginning therapy. These programming changes allow for patient acceptance and comfort with the therapy even in very sensitive patients. Importantly, no patient activation is needed, so that therapy delivery is independent of patient’s adherence over time.

In the prospective, randomized pivotal trial (Costanzo et al. Lancet. 2016;388:974), 151 eligible patients with moderate-severe central sleep apnea were implanted and randomly assigned to the treatment (n=73) or control (n=78) groups. Participants in the active arm received PNS for 6 months. All polysomnograms were centrally and blindly scored. There were significant decreases in AHI (50 to 26/per hour of sleep), CAI (32 to 6), arousal index (46 to 25), and ODI (44 to 25). Two points should be emphasized: first, changes in AHI with PNS are similar to those in CANPAP trial, and there remained a significant number of hypopneas (some of these hypopneas are at least in part related to the speed of the titration when the subject sits up and the device automatically is deactivated, only to resume therapy in supine position); second, in contrast to the CANPAP trial, there was a significant reduction in arousals. Probably for this reason, subjective daytime sleepiness, as measured by the ESS, improved. In addition, PNS improved quality of life, in contrast to lack of effect of CPAP or ASV in this domain. Regarding side effects, 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group.—3.4% needed lead repositioning, a rate which is like that of cardiac implantable devices. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomization period when neurostimulation was delivered to only the treatment and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. Of 73 patients in the treatment group, 27 (37%) reported nonserious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients but was unresolved in one (1%) patient.

Long-term studies have shown sustained effects of PNS on CSA with improvement in both sleep metrics and QOL, as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) and patient global assessment (PGA). Furthermore, in the subgroup of patients with concomitant heart failure with LVEF ≤ 45%, PNS was associated with both improvements in LVEF and a trend toward lower hospitalization rates (Costanzo et al. Eur J Heart Fail. 2018; doi:10.1002/ejhf.1312).

Several issues must be emphasized. One advantage of PNS is complete adherence resulting in a major reduction in apnea burden across the whole night. Second, the mechanism of action prevents any potential adverse consequences related to increased intrathoracic pressure. However, the cost of this therapy is high, similar to that of hypoglossal nerve stimulation. Large scale, long-term studies related to mortality are not yet available, and continued research should help identify those patients most likely to benefit from this therapeutic approach.