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CHEST 2023 Master Classes offer advanced learning from big names in chest medicine
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Take this chance to be a mentor at CHEST 2023
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
CPAP for OSA: What is the verdict?
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
AGA Research Scholar Awards advance the GI field
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
Lobar vs. sublobar resection in stage 1 lung cancer
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Beating jet lag at CHEST 2023
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
The STELLAR Travel to BMPR2-based therapies for pulmonary arterial hypertension
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large
RSV: Current patterns and future directions
CHEST INFECTIONS & DISASTER RESPONSE NETWORK
Chest Infections Section
(Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).
Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.
There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).
Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large
Paige Marty, MD – Section Fellow-in-Training
CHEST INFECTIONS & DISASTER RESPONSE NETWORK
Chest Infections Section
(Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).
Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.
There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).
Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large
Paige Marty, MD – Section Fellow-in-Training
CHEST INFECTIONS & DISASTER RESPONSE NETWORK
Chest Infections Section
(Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).
Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.
There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).
Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large
Paige Marty, MD – Section Fellow-in-Training
Cardiopulmonary exercise testing for unexplained dyspnea
Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.
Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.
(Palange P, et al. Eur Respir J. 2007;29:185).
Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo2), carbon dioxide output (Vco2), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo2) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.
What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo2, low Vo2 at anaerobic threshold, decreased O2 pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.
There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.
A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.
More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.
We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.
So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.
Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.
Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.
(Palange P, et al. Eur Respir J. 2007;29:185).
Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo2), carbon dioxide output (Vco2), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo2) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.
What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo2, low Vo2 at anaerobic threshold, decreased O2 pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.
There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.
A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.
More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.
We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.
So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.
Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.
Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.
(Palange P, et al. Eur Respir J. 2007;29:185).
Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo2), carbon dioxide output (Vco2), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo2) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.
What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo2, low Vo2 at anaerobic threshold, decreased O2 pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.
There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.
A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.
More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.
We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.
So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.
Fluids or vasopressors: Is sepsis management that simple?
In recent months, we have seen the results of the much awaited Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial showing that a restrictive fluid and early vasopressor strategy initiated on arrival of patients with sepsis and hypotension in the ED did not result in decreased mortality compared with a liberal fluid approach (PETAL Network. www.nejm.org/doi/10.1056/NEJMoa2202707). The March 2023 issue of CHEST Physician provided a synopsis of the trial highlighting several limitations (Splete H. CHEST Physician. 2023;18[3]:1). Last year in 2022, the Conservative versus Liberal Approach to Fluid Therapy in Septic Shock (CLASSIC) trial also showed no difference in mortality with restrictive fluid compared with standard fluid in patients with septic shock in the ICU already receiving vasopressor therapy (Meyhoff TS, et al. N Engl J Med. 2022;386[26]:2459). Did their results suggest a “you can do what you want” approach? Is the management of sepsis and septic shock limited to fluids vs vasopressors? Hopefully, the ongoing studies ARISE FLUIDS (NCT04569942), EVIS (NCT05179499), FRESHLY (NCT05453565), 1BED (NCT05273034), and REDUCE (NCT04931485) will further address these questions.
In the meantime, I continue to admit and care for patients with sepsis in the ICU. One example was a 72-year-old woman with a history of stroke, coronary artery disease, diabetes, and chronic kidney disease presenting with 3 days of progressive cough and dyspnea. In the ED, temperature was 38.2° C, heart rate 120 beats per min, respiratory rate 28/min, blood pressure 82/48 mm Hg, and weight 92 kg. She had audible crackles in the left lower lung. Her laboratory and imaging results supported a diagnosis of sepsis due to severe community-acquired pneumonia, including the following values: white blood cell 18.2 million/mm3; lactate 3.8 mmol/L; and creatinine 4.3 mg/dL.
While in the ED, the patient received 1 liter of crystalloid fluids and appropriate broad spectrum antibiotics. Repeat lactate value was 2.8 mmol/L. Patient’s blood pressure then decreased to 85/42 mm Hg. Norepinephrine was started peripherally and titrated to 6 mcg/min to achieve blood pressure 104/56 mm Hg. No further fluid administration was given, and the patient was admitted to the medical ICU. On admission, a repeat lactate had increased to 3.4 mmol/L with blood pressure of 80/45 mm Hg. Instead of further escalating vasopressor administration, she received 2 L of fluid and continued at 150 mL/h. Shortly after, norepinephrine was titrated off. Fluid resuscitation was then deescalated. We transfered the patient to the general ward within 12 hours of ICU admission.
Could we have avoided ICU admission and critical care resource utilization if the patient had received more optimal fluid resuscitation in the ED?
While our fear of fluids (or hydrophobia) may be unwarranted, the management of this patient was a common example of fluid restriction in sepsis (Jaehne AK, et al. Crit Care Med. 2016;44[12]:2263). By clinical criteria, she was in septic shock (requiring vasopressor) and appropriately required ICU admission. But, I would posit that the patient had severe sepsis based on pre-Sepsis 3 criteria. Optimal initial fluid resuscitation would have prevented her from requiring vasopressor and progressing to septic shock with ICU admission. Unfortunately, the patient’s care reflected the objective of CLOVERS and its results. Other than the lack of decreased mortality, decreased ventilator use, decreased renal replacement therapy, and decreased hospital length of stay, restricting fluids resulted in an increase of 8.1% (95% confidence interval 3.3 to 12.8) ICU utilization. Furthermore, the data and safety monitoring committee halted the trial for futility at two-thirds of enrollment. One must wonder if CLOVERS had completed its intended enrollment of 2,320 patients, negative outcomes would have occurred.
Should an astute clinician interpret the results of the CLOVERS and CLASSIC trials as “Fluids, it doesn’t matter, so I can do what I want?” Absolutely not! The literature is abundant with studies showing that increasing dose and/or number of vasopressors is associated with higher mortality in septic shock. One example is a recent multicenter prospective cohort study examining the association of vasopressor dosing during the first 24 hours and 30-day mortality in septic shock over 33 hospitals (Roberts RJ, et al. Crit Care Med. 2020;48[10]:1445).
Six hundred and sixteen patients were enrolled with 31% 30-day mortality. In 24 hours after shock diagnosis, patients received a median of 3.4 (1.9-5.3) L of fluids and 8.5 mcg/min norepinephrine equivalent. During the first 6 hours, increasing vasopressor dosing was associated with increased odds of mortality. Every 10 mcg/min increase in norepinephrine over the 24-hour period was associated with a 33% increased odds of mortality. Patients who received no fluids but 35 mcg/min norepinephrine in 6 hours had the highest mortality of 50%. As fluid volume increased, the association between vasopressor dosing and mortality decreased, such that at least 2 L of fluid during the first 6 hours was required for this association to become nonsignificant. Based on these results and a number of past studies, we should be cautious in believing that a resuscitation strategy favoring vasopressors would result in a better outcome.
Shock resuscitation is complex, and there is no one-size-fits-all approach. With the present climate, the success of resuscitation has been simplified to assessing fluid responsiveness. Trainees learn to identify the inferior vena cava and lung B-lines by ultrasound. With more advanced technology, stroke volume variation is considered. And, let us not forget the passive leg raise. Rarely can our fellows and residents recite the components of oxygen delivery as targets of shock resuscitation: preload, afterload, contractility, hemoglobin, and oxygen saturation. Another patient example comes to mind when fluid responsiveness alone is inadequate.
Our patient was a 46-year-old man now day 4 in the ICU with Klebsiella bacteremia and acute cholecystitis undergoing medical management. His comorbidities included diabetes, obesity, hypertension, and cardiomyopathy with ejection fraction 35%. He was supported sson mechanical ventilation, norepinephrine 20 mcg/min, and receiving appropriate antibiotics. For hemodynamic monitoring, a central venous and arterial catheter have been placed. The patient had a heart rate 92 beats per min, mean arterial pressure (MAP) 57 mm Hg, central venous pressure (CVP) 26 mm Hg, stroke volume variation (SVV) 9%, cardiac output (CO) 2.5 L/min, and central venous oxygen saturation (ScvO2) 42%.
Based on these parameters, we initiated dobutamine at 2.5 mcg/kg/min, which was then titrated to 20 mcg/kg/min over 2 hours to achieve ScvO2 72%. Interestingly, CVP had decreased to 18 mm Hg, SVV increased to 16%, with CO 4.5 L/min. MAP also increased to 68 mm Hg. We then administered 1-L fluid bolus with the elevated SVV. Given the patient’s underlying cardiomyopathy, CVP < 20 mm Hg appeared to indicate a state of fluid responsiveness. After our fluid administration, heart rate 98 beats per min, MAP 70 mm Hg, CVP increased to 21 mm Hg, SVV 12%, CO 4.7 L/min, and ScvO2 74%. In acknowledging a mixed hypovolemic, cardiogenic, and septic shock, we had optimized his hemodynamic state. Importantly, during this exercise of hemodynamic manipulation, we were able to decrease norepinephrine to 8 mcg/min, maintaining dobutamine at 20 mcg/kg/min.
The above case illustrates that the hemodynamic perturbations in sepsis and septic shock are not simple. Patients do not present with a single shock state. An infection progressing to shock often is confounded by hypovolemia and underlying comorbidities, such as cardiac dysfunction. Without considering the complex physiology, our desire to continue the debate of fluids vs vasopressors is on the brink of taking us back several decades when the management of sepsis was to start a fluid bolus, administer “Rocephin,” and initiate dopamine. But I remind myself that we have made advances – now it’s 1 L lactated Ringer’s, administer “vanco and zosyn,” and initiate norepinephrine.
In recent months, we have seen the results of the much awaited Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial showing that a restrictive fluid and early vasopressor strategy initiated on arrival of patients with sepsis and hypotension in the ED did not result in decreased mortality compared with a liberal fluid approach (PETAL Network. www.nejm.org/doi/10.1056/NEJMoa2202707). The March 2023 issue of CHEST Physician provided a synopsis of the trial highlighting several limitations (Splete H. CHEST Physician. 2023;18[3]:1). Last year in 2022, the Conservative versus Liberal Approach to Fluid Therapy in Septic Shock (CLASSIC) trial also showed no difference in mortality with restrictive fluid compared with standard fluid in patients with septic shock in the ICU already receiving vasopressor therapy (Meyhoff TS, et al. N Engl J Med. 2022;386[26]:2459). Did their results suggest a “you can do what you want” approach? Is the management of sepsis and septic shock limited to fluids vs vasopressors? Hopefully, the ongoing studies ARISE FLUIDS (NCT04569942), EVIS (NCT05179499), FRESHLY (NCT05453565), 1BED (NCT05273034), and REDUCE (NCT04931485) will further address these questions.
In the meantime, I continue to admit and care for patients with sepsis in the ICU. One example was a 72-year-old woman with a history of stroke, coronary artery disease, diabetes, and chronic kidney disease presenting with 3 days of progressive cough and dyspnea. In the ED, temperature was 38.2° C, heart rate 120 beats per min, respiratory rate 28/min, blood pressure 82/48 mm Hg, and weight 92 kg. She had audible crackles in the left lower lung. Her laboratory and imaging results supported a diagnosis of sepsis due to severe community-acquired pneumonia, including the following values: white blood cell 18.2 million/mm3; lactate 3.8 mmol/L; and creatinine 4.3 mg/dL.
While in the ED, the patient received 1 liter of crystalloid fluids and appropriate broad spectrum antibiotics. Repeat lactate value was 2.8 mmol/L. Patient’s blood pressure then decreased to 85/42 mm Hg. Norepinephrine was started peripherally and titrated to 6 mcg/min to achieve blood pressure 104/56 mm Hg. No further fluid administration was given, and the patient was admitted to the medical ICU. On admission, a repeat lactate had increased to 3.4 mmol/L with blood pressure of 80/45 mm Hg. Instead of further escalating vasopressor administration, she received 2 L of fluid and continued at 150 mL/h. Shortly after, norepinephrine was titrated off. Fluid resuscitation was then deescalated. We transfered the patient to the general ward within 12 hours of ICU admission.
Could we have avoided ICU admission and critical care resource utilization if the patient had received more optimal fluid resuscitation in the ED?
While our fear of fluids (or hydrophobia) may be unwarranted, the management of this patient was a common example of fluid restriction in sepsis (Jaehne AK, et al. Crit Care Med. 2016;44[12]:2263). By clinical criteria, she was in septic shock (requiring vasopressor) and appropriately required ICU admission. But, I would posit that the patient had severe sepsis based on pre-Sepsis 3 criteria. Optimal initial fluid resuscitation would have prevented her from requiring vasopressor and progressing to septic shock with ICU admission. Unfortunately, the patient’s care reflected the objective of CLOVERS and its results. Other than the lack of decreased mortality, decreased ventilator use, decreased renal replacement therapy, and decreased hospital length of stay, restricting fluids resulted in an increase of 8.1% (95% confidence interval 3.3 to 12.8) ICU utilization. Furthermore, the data and safety monitoring committee halted the trial for futility at two-thirds of enrollment. One must wonder if CLOVERS had completed its intended enrollment of 2,320 patients, negative outcomes would have occurred.
Should an astute clinician interpret the results of the CLOVERS and CLASSIC trials as “Fluids, it doesn’t matter, so I can do what I want?” Absolutely not! The literature is abundant with studies showing that increasing dose and/or number of vasopressors is associated with higher mortality in septic shock. One example is a recent multicenter prospective cohort study examining the association of vasopressor dosing during the first 24 hours and 30-day mortality in septic shock over 33 hospitals (Roberts RJ, et al. Crit Care Med. 2020;48[10]:1445).
Six hundred and sixteen patients were enrolled with 31% 30-day mortality. In 24 hours after shock diagnosis, patients received a median of 3.4 (1.9-5.3) L of fluids and 8.5 mcg/min norepinephrine equivalent. During the first 6 hours, increasing vasopressor dosing was associated with increased odds of mortality. Every 10 mcg/min increase in norepinephrine over the 24-hour period was associated with a 33% increased odds of mortality. Patients who received no fluids but 35 mcg/min norepinephrine in 6 hours had the highest mortality of 50%. As fluid volume increased, the association between vasopressor dosing and mortality decreased, such that at least 2 L of fluid during the first 6 hours was required for this association to become nonsignificant. Based on these results and a number of past studies, we should be cautious in believing that a resuscitation strategy favoring vasopressors would result in a better outcome.
Shock resuscitation is complex, and there is no one-size-fits-all approach. With the present climate, the success of resuscitation has been simplified to assessing fluid responsiveness. Trainees learn to identify the inferior vena cava and lung B-lines by ultrasound. With more advanced technology, stroke volume variation is considered. And, let us not forget the passive leg raise. Rarely can our fellows and residents recite the components of oxygen delivery as targets of shock resuscitation: preload, afterload, contractility, hemoglobin, and oxygen saturation. Another patient example comes to mind when fluid responsiveness alone is inadequate.
Our patient was a 46-year-old man now day 4 in the ICU with Klebsiella bacteremia and acute cholecystitis undergoing medical management. His comorbidities included diabetes, obesity, hypertension, and cardiomyopathy with ejection fraction 35%. He was supported sson mechanical ventilation, norepinephrine 20 mcg/min, and receiving appropriate antibiotics. For hemodynamic monitoring, a central venous and arterial catheter have been placed. The patient had a heart rate 92 beats per min, mean arterial pressure (MAP) 57 mm Hg, central venous pressure (CVP) 26 mm Hg, stroke volume variation (SVV) 9%, cardiac output (CO) 2.5 L/min, and central venous oxygen saturation (ScvO2) 42%.
Based on these parameters, we initiated dobutamine at 2.5 mcg/kg/min, which was then titrated to 20 mcg/kg/min over 2 hours to achieve ScvO2 72%. Interestingly, CVP had decreased to 18 mm Hg, SVV increased to 16%, with CO 4.5 L/min. MAP also increased to 68 mm Hg. We then administered 1-L fluid bolus with the elevated SVV. Given the patient’s underlying cardiomyopathy, CVP < 20 mm Hg appeared to indicate a state of fluid responsiveness. After our fluid administration, heart rate 98 beats per min, MAP 70 mm Hg, CVP increased to 21 mm Hg, SVV 12%, CO 4.7 L/min, and ScvO2 74%. In acknowledging a mixed hypovolemic, cardiogenic, and septic shock, we had optimized his hemodynamic state. Importantly, during this exercise of hemodynamic manipulation, we were able to decrease norepinephrine to 8 mcg/min, maintaining dobutamine at 20 mcg/kg/min.
The above case illustrates that the hemodynamic perturbations in sepsis and septic shock are not simple. Patients do not present with a single shock state. An infection progressing to shock often is confounded by hypovolemia and underlying comorbidities, such as cardiac dysfunction. Without considering the complex physiology, our desire to continue the debate of fluids vs vasopressors is on the brink of taking us back several decades when the management of sepsis was to start a fluid bolus, administer “Rocephin,” and initiate dopamine. But I remind myself that we have made advances – now it’s 1 L lactated Ringer’s, administer “vanco and zosyn,” and initiate norepinephrine.
In recent months, we have seen the results of the much awaited Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial showing that a restrictive fluid and early vasopressor strategy initiated on arrival of patients with sepsis and hypotension in the ED did not result in decreased mortality compared with a liberal fluid approach (PETAL Network. www.nejm.org/doi/10.1056/NEJMoa2202707). The March 2023 issue of CHEST Physician provided a synopsis of the trial highlighting several limitations (Splete H. CHEST Physician. 2023;18[3]:1). Last year in 2022, the Conservative versus Liberal Approach to Fluid Therapy in Septic Shock (CLASSIC) trial also showed no difference in mortality with restrictive fluid compared with standard fluid in patients with septic shock in the ICU already receiving vasopressor therapy (Meyhoff TS, et al. N Engl J Med. 2022;386[26]:2459). Did their results suggest a “you can do what you want” approach? Is the management of sepsis and septic shock limited to fluids vs vasopressors? Hopefully, the ongoing studies ARISE FLUIDS (NCT04569942), EVIS (NCT05179499), FRESHLY (NCT05453565), 1BED (NCT05273034), and REDUCE (NCT04931485) will further address these questions.
In the meantime, I continue to admit and care for patients with sepsis in the ICU. One example was a 72-year-old woman with a history of stroke, coronary artery disease, diabetes, and chronic kidney disease presenting with 3 days of progressive cough and dyspnea. In the ED, temperature was 38.2° C, heart rate 120 beats per min, respiratory rate 28/min, blood pressure 82/48 mm Hg, and weight 92 kg. She had audible crackles in the left lower lung. Her laboratory and imaging results supported a diagnosis of sepsis due to severe community-acquired pneumonia, including the following values: white blood cell 18.2 million/mm3; lactate 3.8 mmol/L; and creatinine 4.3 mg/dL.
While in the ED, the patient received 1 liter of crystalloid fluids and appropriate broad spectrum antibiotics. Repeat lactate value was 2.8 mmol/L. Patient’s blood pressure then decreased to 85/42 mm Hg. Norepinephrine was started peripherally and titrated to 6 mcg/min to achieve blood pressure 104/56 mm Hg. No further fluid administration was given, and the patient was admitted to the medical ICU. On admission, a repeat lactate had increased to 3.4 mmol/L with blood pressure of 80/45 mm Hg. Instead of further escalating vasopressor administration, she received 2 L of fluid and continued at 150 mL/h. Shortly after, norepinephrine was titrated off. Fluid resuscitation was then deescalated. We transfered the patient to the general ward within 12 hours of ICU admission.
Could we have avoided ICU admission and critical care resource utilization if the patient had received more optimal fluid resuscitation in the ED?
While our fear of fluids (or hydrophobia) may be unwarranted, the management of this patient was a common example of fluid restriction in sepsis (Jaehne AK, et al. Crit Care Med. 2016;44[12]:2263). By clinical criteria, she was in septic shock (requiring vasopressor) and appropriately required ICU admission. But, I would posit that the patient had severe sepsis based on pre-Sepsis 3 criteria. Optimal initial fluid resuscitation would have prevented her from requiring vasopressor and progressing to septic shock with ICU admission. Unfortunately, the patient’s care reflected the objective of CLOVERS and its results. Other than the lack of decreased mortality, decreased ventilator use, decreased renal replacement therapy, and decreased hospital length of stay, restricting fluids resulted in an increase of 8.1% (95% confidence interval 3.3 to 12.8) ICU utilization. Furthermore, the data and safety monitoring committee halted the trial for futility at two-thirds of enrollment. One must wonder if CLOVERS had completed its intended enrollment of 2,320 patients, negative outcomes would have occurred.
Should an astute clinician interpret the results of the CLOVERS and CLASSIC trials as “Fluids, it doesn’t matter, so I can do what I want?” Absolutely not! The literature is abundant with studies showing that increasing dose and/or number of vasopressors is associated with higher mortality in septic shock. One example is a recent multicenter prospective cohort study examining the association of vasopressor dosing during the first 24 hours and 30-day mortality in septic shock over 33 hospitals (Roberts RJ, et al. Crit Care Med. 2020;48[10]:1445).
Six hundred and sixteen patients were enrolled with 31% 30-day mortality. In 24 hours after shock diagnosis, patients received a median of 3.4 (1.9-5.3) L of fluids and 8.5 mcg/min norepinephrine equivalent. During the first 6 hours, increasing vasopressor dosing was associated with increased odds of mortality. Every 10 mcg/min increase in norepinephrine over the 24-hour period was associated with a 33% increased odds of mortality. Patients who received no fluids but 35 mcg/min norepinephrine in 6 hours had the highest mortality of 50%. As fluid volume increased, the association between vasopressor dosing and mortality decreased, such that at least 2 L of fluid during the first 6 hours was required for this association to become nonsignificant. Based on these results and a number of past studies, we should be cautious in believing that a resuscitation strategy favoring vasopressors would result in a better outcome.
Shock resuscitation is complex, and there is no one-size-fits-all approach. With the present climate, the success of resuscitation has been simplified to assessing fluid responsiveness. Trainees learn to identify the inferior vena cava and lung B-lines by ultrasound. With more advanced technology, stroke volume variation is considered. And, let us not forget the passive leg raise. Rarely can our fellows and residents recite the components of oxygen delivery as targets of shock resuscitation: preload, afterload, contractility, hemoglobin, and oxygen saturation. Another patient example comes to mind when fluid responsiveness alone is inadequate.
Our patient was a 46-year-old man now day 4 in the ICU with Klebsiella bacteremia and acute cholecystitis undergoing medical management. His comorbidities included diabetes, obesity, hypertension, and cardiomyopathy with ejection fraction 35%. He was supported sson mechanical ventilation, norepinephrine 20 mcg/min, and receiving appropriate antibiotics. For hemodynamic monitoring, a central venous and arterial catheter have been placed. The patient had a heart rate 92 beats per min, mean arterial pressure (MAP) 57 mm Hg, central venous pressure (CVP) 26 mm Hg, stroke volume variation (SVV) 9%, cardiac output (CO) 2.5 L/min, and central venous oxygen saturation (ScvO2) 42%.
Based on these parameters, we initiated dobutamine at 2.5 mcg/kg/min, which was then titrated to 20 mcg/kg/min over 2 hours to achieve ScvO2 72%. Interestingly, CVP had decreased to 18 mm Hg, SVV increased to 16%, with CO 4.5 L/min. MAP also increased to 68 mm Hg. We then administered 1-L fluid bolus with the elevated SVV. Given the patient’s underlying cardiomyopathy, CVP < 20 mm Hg appeared to indicate a state of fluid responsiveness. After our fluid administration, heart rate 98 beats per min, MAP 70 mm Hg, CVP increased to 21 mm Hg, SVV 12%, CO 4.7 L/min, and ScvO2 74%. In acknowledging a mixed hypovolemic, cardiogenic, and septic shock, we had optimized his hemodynamic state. Importantly, during this exercise of hemodynamic manipulation, we were able to decrease norepinephrine to 8 mcg/min, maintaining dobutamine at 20 mcg/kg/min.
The above case illustrates that the hemodynamic perturbations in sepsis and septic shock are not simple. Patients do not present with a single shock state. An infection progressing to shock often is confounded by hypovolemia and underlying comorbidities, such as cardiac dysfunction. Without considering the complex physiology, our desire to continue the debate of fluids vs vasopressors is on the brink of taking us back several decades when the management of sepsis was to start a fluid bolus, administer “Rocephin,” and initiate dopamine. But I remind myself that we have made advances – now it’s 1 L lactated Ringer’s, administer “vanco and zosyn,” and initiate norepinephrine.