*This version has been corrected. In the original version the first sentence incorrectly referred to moral injury instead of burnout.

For more than a decade, the term burnout has been used to describe clinician distress.^1,2 Although some clinicians in federal health care systems may be protected from some of the drivers of burnout, other federal practitioners suffer from rule-driven health care practices and distant, top-down administration. The demand for health care is expanding, driven by the aging of the US population.³ Massive information technology investments, which promised efficiency for health care providers,⁴ have instead delivered a triple blow: They have diverted capital resources that might have been used to hire additional caregivers,⁵ diverted the time and attention of those already engaged in patient care,⁶ and done little to improve patient outcomes.⁷ Reimbursements are falling, and the only way for health systems to maintain their revenue is to increase the number of patients each clinician sees per day.⁸ As the resources of time and attention shrink, and as spending continues with no improvement in patient outcomes, clinician distress is on the rise.⁹ It will be important to understand exactly what the drivers of the problem are for federal clinicians so that solutions can be appropriately targeted. The first step in addressing the epidemic of physician distress is using the most accurate terminology to describe it.

Freudenberger defined burnout in 1975 as a constellation of symptoms—malaise, fatigue, frustration, cynicism, and inefficacy—that arise from “making excessive demands on energy, strength, or resources” in the workplace.¹⁰ The term was borrowed from other fields and applied to health care in the hopes of readily transferring the solutions that had worked in other industries to address a growing crisis among physicians. Unfortunately, the crisis in health care has proven resistant to solutions that have worked elsewhere, and many clinicians have resisted being characterized as burned out, citing a subtle, elusive disconnect between what they have experienced and what burnout encapsulates.

In July 2018, the conversation about clinician distress shifted with an article we wrote in STAT that described the moral injury of health care.¹¹ The concept of moral injury was first described in service members who returned from the Vietnam War with symptoms that loosely fit a diagnosis of posttraumatic stress disorder (PTSD), but which did not respond to standard PTSD treatment and contained symptoms outside the PTSD constellation.¹² On closer assessment, what these service members were experiencing had a different driver. Whereas those with PTSD experienced a real and imminent threat to their mortality and had come back deeply concerned for their individual, physical safety, those with this different presentation experienced repeated insults to their morality and had returned questioning whether they were still, at their core, moral beings. They had been forced, in some way, to act contrary to what their beliefs dictated was right by killing civilians on orders from their superiors, for example. This was a different category of psychological injury that required different treatment.

Moral injury occurs when we perpetrate, bear witness to, or fail to prevent an act that transgresses our deeply held moral beliefs. In the health care context, that deeply held moral belief is the oath each of us took when embarking on our paths as health care providers: Put the needs of patients first. That oath is the lynchpin of our working lives and our guiding principle when searching for the right course of action. But as clinicians, we are increasingly forced to consider the demands of other stakeholders—the electronic medical record (EMR), the insurers, the hospital, the health care system, even our own financial security—before the needs of our patients. Every time we are forced to make a decision that contravenes our patients’ best interests, we feel a sting of moral injustice. Over time, these repetitive insults amass into moral injury.

The difference between burnout and moral injury is important because using different terminology reframes the problem and the solutions. Burnout suggests that the problem resides within the individual, who is in some way deficient. It implies that the individual lacks the resources or resilience to withstand the work environment. Since the problem is in the individual, the solutions to burnout must be in the individual, too, and therefore, it is the individual’s responsibility to find and implement them. Many of the solutions to physician distress posited to date revolve around this conception; hence, the focus on yoga, mindfulness, wellness retreats, and meditation.¹³ While there is nothing inherently wrong with any of those practices, it is absurd to believe that yoga will solve the problems of treating a cancer patient with a declined preauthorization for chemotherapy, having no time to discuss a complex diagnosis, or relying on a computer system that places metrics ahead of communication. These problems are not the result of some failing on the part of the individual clinician.

Moral injury, on the other hand, describes the challenge of simultaneously knowing what care patients need but being unable to provide it due to constraints that are beyond our control. Moral injury is the consequence of the ever-present double binds in health care: Do we take care of our patient, the hospital, the insurer, the EMR, the health care system, or our productivity metrics first? There should be only 1 answer to that question, but the current business framework of medicine pressures us to serve all these masters at once. Moral injury locates the source of distress in a broken system, not a broken individual, and allows us to direct solutions at the causes of distress. And in the end, addressing the drivers of moral injury on a large scale may be the most effective preventive treatment for its cumulative effects among health care providers.

The long-term solutions to moral injury demand changes in the business framework of health care. The solutions reside not in promoting mindfulness or resilience among individual physicians, but in creating a health care environment that finally acknowledges the value of the time clinicians and patients spend together developing the trust, understanding, and compassion that accompany a true relationship. The long-term solutions to moral injury include a health care system that prioritizes healing over profit and that trusts its clinicians to always put their patients’ best interests first.

Treating moral injury will not be simple. It cannot happen quickly, and it will not happen without widespread clinician engagement. Change can begin when clinicians identify the double binds they face every day and convey those challenges to their administrators. If administrators and clinicians are willing to work together to resolve these double binds, health care will improve for everyone.

The following are our recommendations for how you can bring change both locally and on a broader scale.

Bring together the 2 sides of the health care house: administrators and clinicians. Invite administrators to join you on rounds, in clinic, or in the operating room. Ask them to follow you during a night of call or to spend an overnight shift with you in the emergency department. The majority of people, including health care administrators, have had only glancing encounters with the medical system. They see their primary care doctor, have regular screening procedures, and maybe get treated for a routine illness or injury. None of those encounters expose them to the depth of challenge in the system.

It takes exposure over a longer duration, or with greater intensity, to appreciate the tensions and double binds that patients and clinicians face regularly.^14,15 Whether or not the administrators accept your invitation, you must also ask to see the challenges from their side. Block out an afternoon, a day, or a week to follow them and learn where they struggle in their work. Only when we understand the other party’s perspective can we truly begin to empathize and communicate meaningfully. That profound understanding is the place where commonality and compromises are found.

Make clinician satisfaction a financial priority. Although care team well-being is now part of the quadruple aim (patient experience, population health, reducing costs, and provider experience), organizations must be held accountable to ensure it is a priority. If we choose to link patient satisfaction with clinician compensation, why not link clinician satisfaction with executive compensation?

Make sure every physician leader has and uses the cell phone number of his or her legislators. Hospitals and big pharma have nearly bottomless lobbying budgets, which makes competing with them for lawmakers’ attention a formidable prospect. Despite this, physician leaders (ie, chief wellness officer, department chairperson, medical society president, etc) have a responsibility to communicate with legislators about the needs of patients (their constituents) and what role our legislators can play in fulfilling those needs. We must understand how policy, regulation, and legislation work, and we need to find seats at every table where the decisions that impact clinical care are made. The first step is opening lines of communication with those who have the power to enact large-scale change.

Reestablish a sense of community among clinicians. Too often clinicians are pitted against one another as resources shrink. Doctors compete with each other for referrals, advanced practitioners and nurses compete with doctors, and everyone feels overstressed. What we tend to forget is that we are all working toward the same goal: To give patients the best care possible. It’s time to view each other with the presumption of charity and to have each other’s backs. Uniting for support, camaraderie, mentorship, and activism is a necessary step in making change.

*This version has been corrected. In the original version the first sentence incorrectly referred to moral injury instead of burnout.

For more than a decade, the term burnout has been used to describe clinician distress.^1,2 Although some clinicians in federal health care systems may be protected from some of the drivers of burnout, other federal practitioners suffer from rule-driven health care practices and distant, top-down administration. The demand for health care is expanding, driven by the aging of the US population.³ Massive information technology investments, which promised efficiency for health care providers,⁴ have instead delivered a triple blow: They have diverted capital resources that might have been used to hire additional caregivers,⁵ diverted the time and attention of those already engaged in patient care,⁶ and done little to improve patient outcomes.⁷ Reimbursements are falling, and the only way for health systems to maintain their revenue is to increase the number of patients each clinician sees per day.⁸ As the resources of time and attention shrink, and as spending continues with no improvement in patient outcomes, clinician distress is on the rise.⁹ It will be important to understand exactly what the drivers of the problem are for federal clinicians so that solutions can be appropriately targeted. The first step in addressing the epidemic of physician distress is using the most accurate terminology to describe it.

Freudenberger defined burnout in 1975 as a constellation of symptoms—malaise, fatigue, frustration, cynicism, and inefficacy—that arise from “making excessive demands on energy, strength, or resources” in the workplace.¹⁰ The term was borrowed from other fields and applied to health care in the hopes of readily transferring the solutions that had worked in other industries to address a growing crisis among physicians. Unfortunately, the crisis in health care has proven resistant to solutions that have worked elsewhere, and many clinicians have resisted being characterized as burned out, citing a subtle, elusive disconnect between what they have experienced and what burnout encapsulates.

In July 2018, the conversation about clinician distress shifted with an article we wrote in STAT that described the moral injury of health care.¹¹ The concept of moral injury was first described in service members who returned from the Vietnam War with symptoms that loosely fit a diagnosis of posttraumatic stress disorder (PTSD), but which did not respond to standard PTSD treatment and contained symptoms outside the PTSD constellation.¹² On closer assessment, what these service members were experiencing had a different driver. Whereas those with PTSD experienced a real and imminent threat to their mortality and had come back deeply concerned for their individual, physical safety, those with this different presentation experienced repeated insults to their morality and had returned questioning whether they were still, at their core, moral beings. They had been forced, in some way, to act contrary to what their beliefs dictated was right by killing civilians on orders from their superiors, for example. This was a different category of psychological injury that required different treatment.

Moral injury occurs when we perpetrate, bear witness to, or fail to prevent an act that transgresses our deeply held moral beliefs. In the health care context, that deeply held moral belief is the oath each of us took when embarking on our paths as health care providers: Put the needs of patients first. That oath is the lynchpin of our working lives and our guiding principle when searching for the right course of action. But as clinicians, we are increasingly forced to consider the demands of other stakeholders—the electronic medical record (EMR), the insurers, the hospital, the health care system, even our own financial security—before the needs of our patients. Every time we are forced to make a decision that contravenes our patients’ best interests, we feel a sting of moral injustice. Over time, these repetitive insults amass into moral injury.

The difference between burnout and moral injury is important because using different terminology reframes the problem and the solutions. Burnout suggests that the problem resides within the individual, who is in some way deficient. It implies that the individual lacks the resources or resilience to withstand the work environment. Since the problem is in the individual, the solutions to burnout must be in the individual, too, and therefore, it is the individual’s responsibility to find and implement them. Many of the solutions to physician distress posited to date revolve around this conception; hence, the focus on yoga, mindfulness, wellness retreats, and meditation.¹³ While there is nothing inherently wrong with any of those practices, it is absurd to believe that yoga will solve the problems of treating a cancer patient with a declined preauthorization for chemotherapy, having no time to discuss a complex diagnosis, or relying on a computer system that places metrics ahead of communication. These problems are not the result of some failing on the part of the individual clinician.

Moral injury, on the other hand, describes the challenge of simultaneously knowing what care patients need but being unable to provide it due to constraints that are beyond our control. Moral injury is the consequence of the ever-present double binds in health care: Do we take care of our patient, the hospital, the insurer, the EMR, the health care system, or our productivity metrics first? There should be only 1 answer to that question, but the current business framework of medicine pressures us to serve all these masters at once. Moral injury locates the source of distress in a broken system, not a broken individual, and allows us to direct solutions at the causes of distress. And in the end, addressing the drivers of moral injury on a large scale may be the most effective preventive treatment for its cumulative effects among health care providers.

The long-term solutions to moral injury demand changes in the business framework of health care. The solutions reside not in promoting mindfulness or resilience among individual physicians, but in creating a health care environment that finally acknowledges the value of the time clinicians and patients spend together developing the trust, understanding, and compassion that accompany a true relationship. The long-term solutions to moral injury include a health care system that prioritizes healing over profit and that trusts its clinicians to always put their patients’ best interests first.

Treating moral injury will not be simple. It cannot happen quickly, and it will not happen without widespread clinician engagement. Change can begin when clinicians identify the double binds they face every day and convey those challenges to their administrators. If administrators and clinicians are willing to work together to resolve these double binds, health care will improve for everyone.

The following are our recommendations for how you can bring change both locally and on a broader scale.

Bring together the 2 sides of the health care house: administrators and clinicians. Invite administrators to join you on rounds, in clinic, or in the operating room. Ask them to follow you during a night of call or to spend an overnight shift with you in the emergency department. The majority of people, including health care administrators, have had only glancing encounters with the medical system. They see their primary care doctor, have regular screening procedures, and maybe get treated for a routine illness or injury. None of those encounters expose them to the depth of challenge in the system.

It takes exposure over a longer duration, or with greater intensity, to appreciate the tensions and double binds that patients and clinicians face regularly.^14,15 Whether or not the administrators accept your invitation, you must also ask to see the challenges from their side. Block out an afternoon, a day, or a week to follow them and learn where they struggle in their work. Only when we understand the other party’s perspective can we truly begin to empathize and communicate meaningfully. That profound understanding is the place where commonality and compromises are found.

Make clinician satisfaction a financial priority. Although care team well-being is now part of the quadruple aim (patient experience, population health, reducing costs, and provider experience), organizations must be held accountable to ensure it is a priority. If we choose to link patient satisfaction with clinician compensation, why not link clinician satisfaction with executive compensation?

Make sure every physician leader has and uses the cell phone number of his or her legislators. Hospitals and big pharma have nearly bottomless lobbying budgets, which makes competing with them for lawmakers’ attention a formidable prospect. Despite this, physician leaders (ie, chief wellness officer, department chairperson, medical society president, etc) have a responsibility to communicate with legislators about the needs of patients (their constituents) and what role our legislators can play in fulfilling those needs. We must understand how policy, regulation, and legislation work, and we need to find seats at every table where the decisions that impact clinical care are made. The first step is opening lines of communication with those who have the power to enact large-scale change.

Reestablish a sense of community among clinicians. Too often clinicians are pitted against one another as resources shrink. Doctors compete with each other for referrals, advanced practitioners and nurses compete with doctors, and everyone feels overstressed. What we tend to forget is that we are all working toward the same goal: To give patients the best care possible. It’s time to view each other with the presumption of charity and to have each other’s backs. Uniting for support, camaraderie, mentorship, and activism is a necessary step in making change.

*This version has been corrected. In the original version the first sentence incorrectly referred to moral injury instead of burnout.

For more than a decade, the term burnout has been used to describe clinician distress.^1,2 Although some clinicians in federal health care systems may be protected from some of the drivers of burnout, other federal practitioners suffer from rule-driven health care practices and distant, top-down administration. The demand for health care is expanding, driven by the aging of the US population.³ Massive information technology investments, which promised efficiency for health care providers,⁴ have instead delivered a triple blow: They have diverted capital resources that might have been used to hire additional caregivers,⁵ diverted the time and attention of those already engaged in patient care,⁶ and done little to improve patient outcomes.⁷ Reimbursements are falling, and the only way for health systems to maintain their revenue is to increase the number of patients each clinician sees per day.⁸ As the resources of time and attention shrink, and as spending continues with no improvement in patient outcomes, clinician distress is on the rise.⁹ It will be important to understand exactly what the drivers of the problem are for federal clinicians so that solutions can be appropriately targeted. The first step in addressing the epidemic of physician distress is using the most accurate terminology to describe it.

Freudenberger defined burnout in 1975 as a constellation of symptoms—malaise, fatigue, frustration, cynicism, and inefficacy—that arise from “making excessive demands on energy, strength, or resources” in the workplace.¹⁰ The term was borrowed from other fields and applied to health care in the hopes of readily transferring the solutions that had worked in other industries to address a growing crisis among physicians. Unfortunately, the crisis in health care has proven resistant to solutions that have worked elsewhere, and many clinicians have resisted being characterized as burned out, citing a subtle, elusive disconnect between what they have experienced and what burnout encapsulates.

In July 2018, the conversation about clinician distress shifted with an article we wrote in STAT that described the moral injury of health care.¹¹ The concept of moral injury was first described in service members who returned from the Vietnam War with symptoms that loosely fit a diagnosis of posttraumatic stress disorder (PTSD), but which did not respond to standard PTSD treatment and contained symptoms outside the PTSD constellation.¹² On closer assessment, what these service members were experiencing had a different driver. Whereas those with PTSD experienced a real and imminent threat to their mortality and had come back deeply concerned for their individual, physical safety, those with this different presentation experienced repeated insults to their morality and had returned questioning whether they were still, at their core, moral beings. They had been forced, in some way, to act contrary to what their beliefs dictated was right by killing civilians on orders from their superiors, for example. This was a different category of psychological injury that required different treatment.

Moral injury occurs when we perpetrate, bear witness to, or fail to prevent an act that transgresses our deeply held moral beliefs. In the health care context, that deeply held moral belief is the oath each of us took when embarking on our paths as health care providers: Put the needs of patients first. That oath is the lynchpin of our working lives and our guiding principle when searching for the right course of action. But as clinicians, we are increasingly forced to consider the demands of other stakeholders—the electronic medical record (EMR), the insurers, the hospital, the health care system, even our own financial security—before the needs of our patients. Every time we are forced to make a decision that contravenes our patients’ best interests, we feel a sting of moral injustice. Over time, these repetitive insults amass into moral injury.

The difference between burnout and moral injury is important because using different terminology reframes the problem and the solutions. Burnout suggests that the problem resides within the individual, who is in some way deficient. It implies that the individual lacks the resources or resilience to withstand the work environment. Since the problem is in the individual, the solutions to burnout must be in the individual, too, and therefore, it is the individual’s responsibility to find and implement them. Many of the solutions to physician distress posited to date revolve around this conception; hence, the focus on yoga, mindfulness, wellness retreats, and meditation.¹³ While there is nothing inherently wrong with any of those practices, it is absurd to believe that yoga will solve the problems of treating a cancer patient with a declined preauthorization for chemotherapy, having no time to discuss a complex diagnosis, or relying on a computer system that places metrics ahead of communication. These problems are not the result of some failing on the part of the individual clinician.

Moral injury, on the other hand, describes the challenge of simultaneously knowing what care patients need but being unable to provide it due to constraints that are beyond our control. Moral injury is the consequence of the ever-present double binds in health care: Do we take care of our patient, the hospital, the insurer, the EMR, the health care system, or our productivity metrics first? There should be only 1 answer to that question, but the current business framework of medicine pressures us to serve all these masters at once. Moral injury locates the source of distress in a broken system, not a broken individual, and allows us to direct solutions at the causes of distress. And in the end, addressing the drivers of moral injury on a large scale may be the most effective preventive treatment for its cumulative effects among health care providers.

The long-term solutions to moral injury demand changes in the business framework of health care. The solutions reside not in promoting mindfulness or resilience among individual physicians, but in creating a health care environment that finally acknowledges the value of the time clinicians and patients spend together developing the trust, understanding, and compassion that accompany a true relationship. The long-term solutions to moral injury include a health care system that prioritizes healing over profit and that trusts its clinicians to always put their patients’ best interests first.

Treating moral injury will not be simple. It cannot happen quickly, and it will not happen without widespread clinician engagement. Change can begin when clinicians identify the double binds they face every day and convey those challenges to their administrators. If administrators and clinicians are willing to work together to resolve these double binds, health care will improve for everyone.

The following are our recommendations for how you can bring change both locally and on a broader scale.

Bring together the 2 sides of the health care house: administrators and clinicians. Invite administrators to join you on rounds, in clinic, or in the operating room. Ask them to follow you during a night of call or to spend an overnight shift with you in the emergency department. The majority of people, including health care administrators, have had only glancing encounters with the medical system. They see their primary care doctor, have regular screening procedures, and maybe get treated for a routine illness or injury. None of those encounters expose them to the depth of challenge in the system.

It takes exposure over a longer duration, or with greater intensity, to appreciate the tensions and double binds that patients and clinicians face regularly.^14,15 Whether or not the administrators accept your invitation, you must also ask to see the challenges from their side. Block out an afternoon, a day, or a week to follow them and learn where they struggle in their work. Only when we understand the other party’s perspective can we truly begin to empathize and communicate meaningfully. That profound understanding is the place where commonality and compromises are found.

Make clinician satisfaction a financial priority. Although care team well-being is now part of the quadruple aim (patient experience, population health, reducing costs, and provider experience), organizations must be held accountable to ensure it is a priority. If we choose to link patient satisfaction with clinician compensation, why not link clinician satisfaction with executive compensation?

Make sure every physician leader has and uses the cell phone number of his or her legislators. Hospitals and big pharma have nearly bottomless lobbying budgets, which makes competing with them for lawmakers’ attention a formidable prospect. Despite this, physician leaders (ie, chief wellness officer, department chairperson, medical society president, etc) have a responsibility to communicate with legislators about the needs of patients (their constituents) and what role our legislators can play in fulfilling those needs. We must understand how policy, regulation, and legislation work, and we need to find seats at every table where the decisions that impact clinical care are made. The first step is opening lines of communication with those who have the power to enact large-scale change.

Reestablish a sense of community among clinicians. Too often clinicians are pitted against one another as resources shrink. Doctors compete with each other for referrals, advanced practitioners and nurses compete with doctors, and everyone feels overstressed. What we tend to forget is that we are all working toward the same goal: To give patients the best care possible. It’s time to view each other with the presumption of charity and to have each other’s backs. Uniting for support, camaraderie, mentorship, and activism is a necessary step in making change.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

Though exposure to the obesogen bisphenol A (BPA) is decreasing, a new study has linked substitute chemicals bisphenol S (BPS) and bisphenol F (BPF) to obesity as well.

“The potential health effects of BPS and other BPA replacement compounds should be monitored going forward, given that human exposure to these compounds is likely to continue to increase in the future,” wrote Melanie H. Jacobson, PhD, of New York University, and coauthors. Their report is in the Journal of the Endocrine Society.

BPA is one of the best known synthetic chemical obesogens, the authors noted. “It enlarges adipocytes and enhances differentiation from mesenchymal cells to adipocytes, inhibits adiponectin function, and is a synthetic estrogen and thereby can have sex-specific effects on body mass,” they explained.

To determine if the BPA analogues, BPS and BPF, could also induce obesity, the researchers analyzed data from 1,831 children and adolescents gathered through the U.S. National Health and Nutrition Examination Surveys from 2013 to 2016. Concentrations of BPA, BPS, and BPF were measured in spot urine samples and they were detected in 97.5%, 87.8%, and 55.2% of samples, respectively.

Log-transformed BPS concentrations were associated with an increased prevalence of general obesity (odds ratio, 1.16; 95% confidence interval, 1.02-1.32), which was defined as being greater than or equal to the 95th percentile of standardized body mass index z scores. BPS concentrations were also associated with an increased prevalence of abdominal obesity (OR, 1.13; 95% CI, 1.02-1.27), as was BPF detection (OR, 1.29; 95% CI, 1.01-1.64).

BPA and total bisphenols were not significantly associated with general or abdominal obesity.

“Though tissue and animal studies of the replacements are lacking, [BPS and BPF] have shown estrogenic activity. Further, BPS has been shown to promote preadipocyte differentiation, raising the possibility that these BPA replacements may induce the same obesogenic effects in humans,” the authors wrote.

They acknowledged that their results should be interpreted cautiously, because they were not able to determine if exposure to bisphenols influences weight gain or if obese children are merely more exposed to those compounds. In addition, because BPS and BPF are metabolized rapidly, spot urine samples cannot accurately reflect long-term exposure levels. Finally, because a good deal of food and beverage packaging contains bisphenols, “those who consume more of these products are more likely to have higher exposure levels,” they wrote.

The study was funded by grants from the National Institutes of Environmental Health Sciences. The authors reported no conflicts of interest.

SOURCE: Jacobson MH et al. J Endocr Soc. 2019 Jul 25. doi: 10.1210/js.2019-00201.

Though exposure to the obesogen bisphenol A (BPA) is decreasing, a new study has linked substitute chemicals bisphenol S (BPS) and bisphenol F (BPF) to obesity as well.

“The potential health effects of BPS and other BPA replacement compounds should be monitored going forward, given that human exposure to these compounds is likely to continue to increase in the future,” wrote Melanie H. Jacobson, PhD, of New York University, and coauthors. Their report is in the Journal of the Endocrine Society.

BPA is one of the best known synthetic chemical obesogens, the authors noted. “It enlarges adipocytes and enhances differentiation from mesenchymal cells to adipocytes, inhibits adiponectin function, and is a synthetic estrogen and thereby can have sex-specific effects on body mass,” they explained.

To determine if the BPA analogues, BPS and BPF, could also induce obesity, the researchers analyzed data from 1,831 children and adolescents gathered through the U.S. National Health and Nutrition Examination Surveys from 2013 to 2016. Concentrations of BPA, BPS, and BPF were measured in spot urine samples and they were detected in 97.5%, 87.8%, and 55.2% of samples, respectively.

Log-transformed BPS concentrations were associated with an increased prevalence of general obesity (odds ratio, 1.16; 95% confidence interval, 1.02-1.32), which was defined as being greater than or equal to the 95th percentile of standardized body mass index z scores. BPS concentrations were also associated with an increased prevalence of abdominal obesity (OR, 1.13; 95% CI, 1.02-1.27), as was BPF detection (OR, 1.29; 95% CI, 1.01-1.64).

BPA and total bisphenols were not significantly associated with general or abdominal obesity.

“Though tissue and animal studies of the replacements are lacking, [BPS and BPF] have shown estrogenic activity. Further, BPS has been shown to promote preadipocyte differentiation, raising the possibility that these BPA replacements may induce the same obesogenic effects in humans,” the authors wrote.

They acknowledged that their results should be interpreted cautiously, because they were not able to determine if exposure to bisphenols influences weight gain or if obese children are merely more exposed to those compounds. In addition, because BPS and BPF are metabolized rapidly, spot urine samples cannot accurately reflect long-term exposure levels. Finally, because a good deal of food and beverage packaging contains bisphenols, “those who consume more of these products are more likely to have higher exposure levels,” they wrote.

The study was funded by grants from the National Institutes of Environmental Health Sciences. The authors reported no conflicts of interest.

SOURCE: Jacobson MH et al. J Endocr Soc. 2019 Jul 25. doi: 10.1210/js.2019-00201.

Though exposure to the obesogen bisphenol A (BPA) is decreasing, a new study has linked substitute chemicals bisphenol S (BPS) and bisphenol F (BPF) to obesity as well.

“The potential health effects of BPS and other BPA replacement compounds should be monitored going forward, given that human exposure to these compounds is likely to continue to increase in the future,” wrote Melanie H. Jacobson, PhD, of New York University, and coauthors. Their report is in the Journal of the Endocrine Society.

BPA is one of the best known synthetic chemical obesogens, the authors noted. “It enlarges adipocytes and enhances differentiation from mesenchymal cells to adipocytes, inhibits adiponectin function, and is a synthetic estrogen and thereby can have sex-specific effects on body mass,” they explained.

To determine if the BPA analogues, BPS and BPF, could also induce obesity, the researchers analyzed data from 1,831 children and adolescents gathered through the U.S. National Health and Nutrition Examination Surveys from 2013 to 2016. Concentrations of BPA, BPS, and BPF were measured in spot urine samples and they were detected in 97.5%, 87.8%, and 55.2% of samples, respectively.

Log-transformed BPS concentrations were associated with an increased prevalence of general obesity (odds ratio, 1.16; 95% confidence interval, 1.02-1.32), which was defined as being greater than or equal to the 95th percentile of standardized body mass index z scores. BPS concentrations were also associated with an increased prevalence of abdominal obesity (OR, 1.13; 95% CI, 1.02-1.27), as was BPF detection (OR, 1.29; 95% CI, 1.01-1.64).

BPA and total bisphenols were not significantly associated with general or abdominal obesity.

“Though tissue and animal studies of the replacements are lacking, [BPS and BPF] have shown estrogenic activity. Further, BPS has been shown to promote preadipocyte differentiation, raising the possibility that these BPA replacements may induce the same obesogenic effects in humans,” the authors wrote.

They acknowledged that their results should be interpreted cautiously, because they were not able to determine if exposure to bisphenols influences weight gain or if obese children are merely more exposed to those compounds. In addition, because BPS and BPF are metabolized rapidly, spot urine samples cannot accurately reflect long-term exposure levels. Finally, because a good deal of food and beverage packaging contains bisphenols, “those who consume more of these products are more likely to have higher exposure levels,” they wrote.

The study was funded by grants from the National Institutes of Environmental Health Sciences. The authors reported no conflicts of interest.

SOURCE: Jacobson MH et al. J Endocr Soc. 2019 Jul 25. doi: 10.1210/js.2019-00201.

The “opioid epidemic” has become, perhaps, the most talked-about health crisis of the 21st century. It is a pervasive topic of discussion in the health literature and beyond, written about on the front pages of national newspapers and even mentioned in presidential state-of-the-union addresses.

As practicing physicians, we are all too familiar with the ills of chronic opioid use and have dealt with the implications of the crisis long before the issue attracted the public’s attention. In many ways, we have felt alone in bearing the burdens of caring for patients on chronic controlled substances. Until this point it has been our sacred duty to determine which patients are truly in need of those medications, and which are merely dependent on or – even worse – abusing them.

Health care providers have been largely blamed for the creation of this crisis, but we are not alone. Responsibility must also be shared by the pharmaceutical industry, health insurers, and even the government. Marketing practices, inadequate coverage of pain-relieving procedures and rehabilitation, and poorly-conceived drug policies have created an environment where it has been far too difficult to provide appropriate care for patients with chronic pain. As a result, patients who may have had an alternative to opioids were still started on these medications, and we – their physicians – have been left alone to manage the outcome.

Recently, however, health policy and public awareness have signaled a dramatic shift in the management of long-term pain medication. Suddenly, prevention of opioid use and abuse has become a national priority. Significant legislation has been enacted on national, state, and local levels, and parties who are perceived to be responsible for the crisis are being held to task. For example, in August a landmark legal case was decided in an Oklahoma district court. Johnson & Johnson Pharmaceuticals was found guilty of promoting drug addiction through false and misleading marketing and was thus ordered to pay $572 million to the state to fund drug rehabilitation programs. This is likely a harbinger of many more such decisions to come, and the industry as a whole is bracing for the worst.

Physician prescribing practices are also being carefully scrutinized by the DEA, and a significant number of new “checks and balances” have been put in place to address dependence and addiction concerns. Unfortunately, as with all sweeping reform programs, there are good – and not-so-good – aspects to these changes. In many ways, the new tools at our disposal are a powerful way of mitigating drug dependence and diversion while protecting the sanctity of our “prescription pads.” Yet, as with so many other government mandates, we are burdened with the onus of complying with the new mandates for each and every opioid prescription, while our EHRs provide little help. This means more “clicks” for us, which can feel quite burdensome. It doesn’t need to be this way. Below are two straightforward things that can and should occur in order for providers to feel unburdened and to fully embrace the changes.
 

PDMP integration

One of the major ways of controlling prescription opioid abuse is through effective monitoring. Forty-nine of the 50 U.S. states have developed Prescription Drug Monitoring Programs (PDMPs), with Missouri being the only holdout (due to the politics of individual privacy concerns and conflation with gun control legislation). Most – though not all – of the states with a PDMP also mandate that physicians query a database prior to prescribing controlled substances. While noble and helpful in principle, querying a PDMP can be cumbersome, and the process is rarely integrated into the EHR workflow. Instead, physicians typically need to login to a separate website and manually transpose patient data to search the database. While most states have offered to subsidize PDMP integration with electronic records, EHR vendors have been very slow to develop the capability, leaving most physicians with no choice but to continue the aforementioned workflow. That is, if they comply at all; many well-meaning physicians have told us that they find themselves too harried to use the PDMP consistently. This reduces the value of these databases and places the physicians at significant risk. In some states, failure to query the database can lead to loss of a doctor’s medical license. It is high time that EHR vendors step up and integrate with every state’s prescription drug database.

Electronic prescribing of controlled substances

The other major milestone in prescription opioid management is the electronic prescribing of controlled substances (EPCS). This received national priority when the SUPPORT for Patients and Communities Act was signed into federal law in October of 2018. Included in this act is a requirement that, by January of 2021, all controlled substance prescriptions covered under Medicare Part D be sent electronically. Taking this as inspiration, many states and private companies have adopted more aggressive policies, choosing to implement electronic prescription requirements prior to the 2021 deadline. In Pennsylvania, where we practice, an EPCS requirement goes into effect in October of this year (2019). National pharmacy chains have also taken a more proactive approach. Walmart, for example, has decided that it will require EPCS nationwide in all of its stores beginning in January of 2020.

Essentially physicians have no choice – if they plan to continue to prescribe controlled substances, they will need to begin doing so electronically. Unfortunately, this may not be a straightforward process. While most EHRs offer some sort of EPCS solution, it is typically far from user friendly. Setting up EPCS can be costly and incredibly time consuming, and the procedure of actually submitting controlled prescriptions can be onerous and add many extra clicks. If vendors are serious about assisting in solving the opioid crisis, they need to make streamlining the steps of EPCS a high priority.
 

A prescription for success

As with so many other topics we’ve written about, we face an ever-increasing burden to provide quality patient care while complying with cumbersome and often unfunded external mandates. In the case of the opioid crisis, we believe we can do better. Our prescription for success? Streamlined workflow, smarter EHRs, and fewer clicks. There is no question that physicians and patients will benefit from effective implementation of the new tools at our disposal, but we need EHR vendors to step up and help carry the load.

Dr. Notte is a family physician and associate chief medical information officer for Abington (Pa.) Jefferson Health. Follow him on Twitter @doctornotte. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

The “opioid epidemic” has become, perhaps, the most talked-about health crisis of the 21st century. It is a pervasive topic of discussion in the health literature and beyond, written about on the front pages of national newspapers and even mentioned in presidential state-of-the-union addresses.

As practicing physicians, we are all too familiar with the ills of chronic opioid use and have dealt with the implications of the crisis long before the issue attracted the public’s attention. In many ways, we have felt alone in bearing the burdens of caring for patients on chronic controlled substances. Until this point it has been our sacred duty to determine which patients are truly in need of those medications, and which are merely dependent on or – even worse – abusing them.

Health care providers have been largely blamed for the creation of this crisis, but we are not alone. Responsibility must also be shared by the pharmaceutical industry, health insurers, and even the government. Marketing practices, inadequate coverage of pain-relieving procedures and rehabilitation, and poorly-conceived drug policies have created an environment where it has been far too difficult to provide appropriate care for patients with chronic pain. As a result, patients who may have had an alternative to opioids were still started on these medications, and we – their physicians – have been left alone to manage the outcome.

Recently, however, health policy and public awareness have signaled a dramatic shift in the management of long-term pain medication. Suddenly, prevention of opioid use and abuse has become a national priority. Significant legislation has been enacted on national, state, and local levels, and parties who are perceived to be responsible for the crisis are being held to task. For example, in August a landmark legal case was decided in an Oklahoma district court. Johnson & Johnson Pharmaceuticals was found guilty of promoting drug addiction through false and misleading marketing and was thus ordered to pay $572 million to the state to fund drug rehabilitation programs. This is likely a harbinger of many more such decisions to come, and the industry as a whole is bracing for the worst.

Physician prescribing practices are also being carefully scrutinized by the DEA, and a significant number of new “checks and balances” have been put in place to address dependence and addiction concerns. Unfortunately, as with all sweeping reform programs, there are good – and not-so-good – aspects to these changes. In many ways, the new tools at our disposal are a powerful way of mitigating drug dependence and diversion while protecting the sanctity of our “prescription pads.” Yet, as with so many other government mandates, we are burdened with the onus of complying with the new mandates for each and every opioid prescription, while our EHRs provide little help. This means more “clicks” for us, which can feel quite burdensome. It doesn’t need to be this way. Below are two straightforward things that can and should occur in order for providers to feel unburdened and to fully embrace the changes.
 

PDMP integration

One of the major ways of controlling prescription opioid abuse is through effective monitoring. Forty-nine of the 50 U.S. states have developed Prescription Drug Monitoring Programs (PDMPs), with Missouri being the only holdout (due to the politics of individual privacy concerns and conflation with gun control legislation). Most – though not all – of the states with a PDMP also mandate that physicians query a database prior to prescribing controlled substances. While noble and helpful in principle, querying a PDMP can be cumbersome, and the process is rarely integrated into the EHR workflow. Instead, physicians typically need to login to a separate website and manually transpose patient data to search the database. While most states have offered to subsidize PDMP integration with electronic records, EHR vendors have been very slow to develop the capability, leaving most physicians with no choice but to continue the aforementioned workflow. That is, if they comply at all; many well-meaning physicians have told us that they find themselves too harried to use the PDMP consistently. This reduces the value of these databases and places the physicians at significant risk. In some states, failure to query the database can lead to loss of a doctor’s medical license. It is high time that EHR vendors step up and integrate with every state’s prescription drug database.

Electronic prescribing of controlled substances

The other major milestone in prescription opioid management is the electronic prescribing of controlled substances (EPCS). This received national priority when the SUPPORT for Patients and Communities Act was signed into federal law in October of 2018. Included in this act is a requirement that, by January of 2021, all controlled substance prescriptions covered under Medicare Part D be sent electronically. Taking this as inspiration, many states and private companies have adopted more aggressive policies, choosing to implement electronic prescription requirements prior to the 2021 deadline. In Pennsylvania, where we practice, an EPCS requirement goes into effect in October of this year (2019). National pharmacy chains have also taken a more proactive approach. Walmart, for example, has decided that it will require EPCS nationwide in all of its stores beginning in January of 2020.

Essentially physicians have no choice – if they plan to continue to prescribe controlled substances, they will need to begin doing so electronically. Unfortunately, this may not be a straightforward process. While most EHRs offer some sort of EPCS solution, it is typically far from user friendly. Setting up EPCS can be costly and incredibly time consuming, and the procedure of actually submitting controlled prescriptions can be onerous and add many extra clicks. If vendors are serious about assisting in solving the opioid crisis, they need to make streamlining the steps of EPCS a high priority.
 

A prescription for success

As with so many other topics we’ve written about, we face an ever-increasing burden to provide quality patient care while complying with cumbersome and often unfunded external mandates. In the case of the opioid crisis, we believe we can do better. Our prescription for success? Streamlined workflow, smarter EHRs, and fewer clicks. There is no question that physicians and patients will benefit from effective implementation of the new tools at our disposal, but we need EHR vendors to step up and help carry the load.

Dr. Notte is a family physician and associate chief medical information officer for Abington (Pa.) Jefferson Health. Follow him on Twitter @doctornotte. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

The “opioid epidemic” has become, perhaps, the most talked-about health crisis of the 21st century. It is a pervasive topic of discussion in the health literature and beyond, written about on the front pages of national newspapers and even mentioned in presidential state-of-the-union addresses.

As practicing physicians, we are all too familiar with the ills of chronic opioid use and have dealt with the implications of the crisis long before the issue attracted the public’s attention. In many ways, we have felt alone in bearing the burdens of caring for patients on chronic controlled substances. Until this point it has been our sacred duty to determine which patients are truly in need of those medications, and which are merely dependent on or – even worse – abusing them.

Health care providers have been largely blamed for the creation of this crisis, but we are not alone. Responsibility must also be shared by the pharmaceutical industry, health insurers, and even the government. Marketing practices, inadequate coverage of pain-relieving procedures and rehabilitation, and poorly-conceived drug policies have created an environment where it has been far too difficult to provide appropriate care for patients with chronic pain. As a result, patients who may have had an alternative to opioids were still started on these medications, and we – their physicians – have been left alone to manage the outcome.

Recently, however, health policy and public awareness have signaled a dramatic shift in the management of long-term pain medication. Suddenly, prevention of opioid use and abuse has become a national priority. Significant legislation has been enacted on national, state, and local levels, and parties who are perceived to be responsible for the crisis are being held to task. For example, in August a landmark legal case was decided in an Oklahoma district court. Johnson & Johnson Pharmaceuticals was found guilty of promoting drug addiction through false and misleading marketing and was thus ordered to pay $572 million to the state to fund drug rehabilitation programs. This is likely a harbinger of many more such decisions to come, and the industry as a whole is bracing for the worst.

Physician prescribing practices are also being carefully scrutinized by the DEA, and a significant number of new “checks and balances” have been put in place to address dependence and addiction concerns. Unfortunately, as with all sweeping reform programs, there are good – and not-so-good – aspects to these changes. In many ways, the new tools at our disposal are a powerful way of mitigating drug dependence and diversion while protecting the sanctity of our “prescription pads.” Yet, as with so many other government mandates, we are burdened with the onus of complying with the new mandates for each and every opioid prescription, while our EHRs provide little help. This means more “clicks” for us, which can feel quite burdensome. It doesn’t need to be this way. Below are two straightforward things that can and should occur in order for providers to feel unburdened and to fully embrace the changes.
 

PDMP integration

One of the major ways of controlling prescription opioid abuse is through effective monitoring. Forty-nine of the 50 U.S. states have developed Prescription Drug Monitoring Programs (PDMPs), with Missouri being the only holdout (due to the politics of individual privacy concerns and conflation with gun control legislation). Most – though not all – of the states with a PDMP also mandate that physicians query a database prior to prescribing controlled substances. While noble and helpful in principle, querying a PDMP can be cumbersome, and the process is rarely integrated into the EHR workflow. Instead, physicians typically need to login to a separate website and manually transpose patient data to search the database. While most states have offered to subsidize PDMP integration with electronic records, EHR vendors have been very slow to develop the capability, leaving most physicians with no choice but to continue the aforementioned workflow. That is, if they comply at all; many well-meaning physicians have told us that they find themselves too harried to use the PDMP consistently. This reduces the value of these databases and places the physicians at significant risk. In some states, failure to query the database can lead to loss of a doctor’s medical license. It is high time that EHR vendors step up and integrate with every state’s prescription drug database.

Electronic prescribing of controlled substances

The other major milestone in prescription opioid management is the electronic prescribing of controlled substances (EPCS). This received national priority when the SUPPORT for Patients and Communities Act was signed into federal law in October of 2018. Included in this act is a requirement that, by January of 2021, all controlled substance prescriptions covered under Medicare Part D be sent electronically. Taking this as inspiration, many states and private companies have adopted more aggressive policies, choosing to implement electronic prescription requirements prior to the 2021 deadline. In Pennsylvania, where we practice, an EPCS requirement goes into effect in October of this year (2019). National pharmacy chains have also taken a more proactive approach. Walmart, for example, has decided that it will require EPCS nationwide in all of its stores beginning in January of 2020.

Essentially physicians have no choice – if they plan to continue to prescribe controlled substances, they will need to begin doing so electronically. Unfortunately, this may not be a straightforward process. While most EHRs offer some sort of EPCS solution, it is typically far from user friendly. Setting up EPCS can be costly and incredibly time consuming, and the procedure of actually submitting controlled prescriptions can be onerous and add many extra clicks. If vendors are serious about assisting in solving the opioid crisis, they need to make streamlining the steps of EPCS a high priority.
 

A prescription for success

As with so many other topics we’ve written about, we face an ever-increasing burden to provide quality patient care while complying with cumbersome and often unfunded external mandates. In the case of the opioid crisis, we believe we can do better. Our prescription for success? Streamlined workflow, smarter EHRs, and fewer clicks. There is no question that physicians and patients will benefit from effective implementation of the new tools at our disposal, but we need EHR vendors to step up and help carry the load.

Dr. Notte is a family physician and associate chief medical information officer for Abington (Pa.) Jefferson Health. Follow him on Twitter @doctornotte. Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

Background: Inclusion of noninvasive ventilation in weaning among chronic obstructive pulmonary disease (COPD) patients has been shown to reduce total duration of ventilation and invasive ventilator days with an associated reduction in morbidity and mortality. It is not well studied whether these results apply to general ICU patients.

Not all secondary outcomes were powered to detect treatment differences. Hospitalists should consider noninvasive ventilation as an adjunct in weaning, especially in COPD patients, to reduce ventilator-associated complications and ICU resources when appropriate.

Bottom line: Protocolized early extubation to noninvasive ventilation was not associated with earlier liberation from all types of ventilation in the general ICU population.

Citation: Perkins GD et al. Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: The breathe randomized clinical trial. JAMA. 2018;320(18):1881-8.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: Inclusion of noninvasive ventilation in weaning among chronic obstructive pulmonary disease (COPD) patients has been shown to reduce total duration of ventilation and invasive ventilator days with an associated reduction in morbidity and mortality. It is not well studied whether these results apply to general ICU patients.

Not all secondary outcomes were powered to detect treatment differences. Hospitalists should consider noninvasive ventilation as an adjunct in weaning, especially in COPD patients, to reduce ventilator-associated complications and ICU resources when appropriate.

Bottom line: Protocolized early extubation to noninvasive ventilation was not associated with earlier liberation from all types of ventilation in the general ICU population.

Citation: Perkins GD et al. Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: The breathe randomized clinical trial. JAMA. 2018;320(18):1881-8.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: Inclusion of noninvasive ventilation in weaning among chronic obstructive pulmonary disease (COPD) patients has been shown to reduce total duration of ventilation and invasive ventilator days with an associated reduction in morbidity and mortality. It is not well studied whether these results apply to general ICU patients.

Not all secondary outcomes were powered to detect treatment differences. Hospitalists should consider noninvasive ventilation as an adjunct in weaning, especially in COPD patients, to reduce ventilator-associated complications and ICU resources when appropriate.

Bottom line: Protocolized early extubation to noninvasive ventilation was not associated with earlier liberation from all types of ventilation in the general ICU population.

Citation: Perkins GD et al. Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: The breathe randomized clinical trial. JAMA. 2018;320(18):1881-8.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

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Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

---

Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

---

Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

CHICAGO – Physicians can recognize mast cell activation syndrome by learning its associated triggers and symptoms, which affect many organ systems. Patients have good outcomes when they receive the appropriate pharmaceutical and dietary therapies, according to an overview presented at Freston Conference 2019, sponsored by the American Gastroenterological Association.

Mast cells are immune cells that originate in bone marrow. They defend against pathogens and contribute to tissue homeostasis and repair, said Matthew J. Hamilton, MD, associate gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston.

Aberrant regulation, which may be perpetuated by persistent stimuli, can cause unwanted mast cell activation. Symptoms affect many systems simultaneously, such as the cutaneous (e.g., flushing, pruritis, and urticaria), digestive (e.g., abdominal cramping, diarrhea, reflux, and bloat), cardiovascular (e.g., hypotension, syncope, light-headedness, and tachycardia), and others. “These patients have a lot of morbidity due to these symptoms,” said Dr. Hamilton. Symptoms are episodic and result from predictable triggers. Their severity fluctuates. Alcohol, stress, heat, hot water, strong smells, medications, and foods are typical triggers for patients with mast cell activation syndrome. The foods that trigger symptoms vary greatly between patients, said Dr. Hamilton.
 

Patients have a typical presentation

On physical examination, patients often have flushing and dermatographia. Patients also may have tachycardia when at rest or when standing. Sites of abdominal pain or bloat and problems with concentration or memory also are common. Few biomarkers for mast cell activation syndrome have been identified. A blood test for mast cell tryptase and a 24-hour urine test for metabolites of histamine and prostaglandin should be ordered for every patient suspected of having the syndrome. “Ideally, you do baseline levels of these studies, and then repeat them when patients are symptomatic,” said Dr. Hamilton. “The tryptase really has to be done within hours of a reaction. That can be a challenge.” A subset of patients with mast cell activation syndrome have a baseline serum tryptase level greater than 11.4 ng/mL.

In 2010, Akin et al. proposed criteria for mast cell activation syndrome (J Allergy Clin Immunol. 2010;126[6]:1099-104). A patient must have typical signs and symptoms of mast cell activation that affect two or more organ systems, as well as laboratory evidence of mast cell activation. A patient also must respond to medications that block mast cell mediators, and no other diagnosis should better explain his or her clinical profile.

As in the workup for other gastroenterological disorders, an endoscopy or colonoscopy is warranted to rule out other conditions such as inflammatory bowel disease, celiac disease, or disorders associated with intestinal eosinophilia. These procedures also can evaluate patients for systemic mastocytosis, the clonal form of mast cell disorders. In general, endoscopy is normal and reveals no specific features in patients with mast cell activation syndrome, said Dr. Hamilton. Histopathology generally is normal, as well. One study indicated that the mean number of mast cells did not differ between patients with mast cell activation syndrome, patients with irritable bowel syndrome (IBS), and healthy controls. Current studies are evaluating subsets of patients with mast cell activation syndrome who have increased numbers of mast cells noted per high power field to determine the utility of quantifying mast cells on histology in patients suspected of having this disorder.
 

A multifaceted approach to treatment

The best treatment for mast cell activation syndrome is multifaceted, said Dr. Hamilton. The first step is to recommend medications that target mast cells, which are exceptionally effective. These medications include type 1 and type 2 antihistamines, cromolyn, ketotifen, and leukotriene antagonists. Medications to alleviate symptoms are another component of treatment. Dietary modification is beneficial, and social and psychological support may be needed, as well.

Patients often will ask which foods they can eat without triggering symptoms. In a survey of 420 patients with a mast cell disorder, half of respondents reported having an “allergy” to a food or beverage (J Allergy Clin Immunol Pract. 2014;2[1]:70-6). Although not all of these patients have true allergies, they have symptoms in response to certain foods, said Dr. Hamilton. Milk, dairy products, red meat, and wheat are common triggers for these patients. But for some patients, a food may not cause symptoms consistently. “It has more to do with [the patient’s] state of reactivity at the time of eating than the actual foods [that he or she] eats,” said Dr. Hamilton.

Dietary modifications can relieve symptoms for patients with mast cell activation syndrome. Food diaries can be beneficial because they prompt patients to observe what they eat and which foods cause symptoms. An important principle is to eliminate triggers, allergies, and food sensitivities.

One way for patients to take the initiative in their treatment is for them to prepare their own food as often as possible. They should avoid restaurants and strive to eat a balanced, nutritious diet, said Dr. Hamilton. A nutritionist can provide guidance in this regard. “In general, I tell [patients] to avoid sugars, chemicals, processed foods, preservatives, and alcohol,” said Dr. Hamilton. “These things in our Western diet can be toxic to a lot of patients.” A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can benefit patients with symptoms similar to those of IBS, he added.

Physicians who treat patients with mast cell activation syndrome still have unmet needs, however. Researchers need to identify additional objective biomarkers of the syndrome, said Dr. Hamilton. Research also should be directed toward recognizing disease subtypes such as familial hypertryptasemia, a subset of mast cell activation syndrome, he added. Finally, patients need more safe and effective therapies, as well as optimized diet therapy.

[email protected]

CHICAGO – Physicians can recognize mast cell activation syndrome by learning its associated triggers and symptoms, which affect many organ systems. Patients have good outcomes when they receive the appropriate pharmaceutical and dietary therapies, according to an overview presented at Freston Conference 2019, sponsored by the American Gastroenterological Association.

Mast cells are immune cells that originate in bone marrow. They defend against pathogens and contribute to tissue homeostasis and repair, said Matthew J. Hamilton, MD, associate gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston.

Aberrant regulation, which may be perpetuated by persistent stimuli, can cause unwanted mast cell activation. Symptoms affect many systems simultaneously, such as the cutaneous (e.g., flushing, pruritis, and urticaria), digestive (e.g., abdominal cramping, diarrhea, reflux, and bloat), cardiovascular (e.g., hypotension, syncope, light-headedness, and tachycardia), and others. “These patients have a lot of morbidity due to these symptoms,” said Dr. Hamilton. Symptoms are episodic and result from predictable triggers. Their severity fluctuates. Alcohol, stress, heat, hot water, strong smells, medications, and foods are typical triggers for patients with mast cell activation syndrome. The foods that trigger symptoms vary greatly between patients, said Dr. Hamilton.
 

Patients have a typical presentation

On physical examination, patients often have flushing and dermatographia. Patients also may have tachycardia when at rest or when standing. Sites of abdominal pain or bloat and problems with concentration or memory also are common. Few biomarkers for mast cell activation syndrome have been identified. A blood test for mast cell tryptase and a 24-hour urine test for metabolites of histamine and prostaglandin should be ordered for every patient suspected of having the syndrome. “Ideally, you do baseline levels of these studies, and then repeat them when patients are symptomatic,” said Dr. Hamilton. “The tryptase really has to be done within hours of a reaction. That can be a challenge.” A subset of patients with mast cell activation syndrome have a baseline serum tryptase level greater than 11.4 ng/mL.

In 2010, Akin et al. proposed criteria for mast cell activation syndrome (J Allergy Clin Immunol. 2010;126[6]:1099-104). A patient must have typical signs and symptoms of mast cell activation that affect two or more organ systems, as well as laboratory evidence of mast cell activation. A patient also must respond to medications that block mast cell mediators, and no other diagnosis should better explain his or her clinical profile.

As in the workup for other gastroenterological disorders, an endoscopy or colonoscopy is warranted to rule out other conditions such as inflammatory bowel disease, celiac disease, or disorders associated with intestinal eosinophilia. These procedures also can evaluate patients for systemic mastocytosis, the clonal form of mast cell disorders. In general, endoscopy is normal and reveals no specific features in patients with mast cell activation syndrome, said Dr. Hamilton. Histopathology generally is normal, as well. One study indicated that the mean number of mast cells did not differ between patients with mast cell activation syndrome, patients with irritable bowel syndrome (IBS), and healthy controls. Current studies are evaluating subsets of patients with mast cell activation syndrome who have increased numbers of mast cells noted per high power field to determine the utility of quantifying mast cells on histology in patients suspected of having this disorder.
 

A multifaceted approach to treatment

The best treatment for mast cell activation syndrome is multifaceted, said Dr. Hamilton. The first step is to recommend medications that target mast cells, which are exceptionally effective. These medications include type 1 and type 2 antihistamines, cromolyn, ketotifen, and leukotriene antagonists. Medications to alleviate symptoms are another component of treatment. Dietary modification is beneficial, and social and psychological support may be needed, as well.

Patients often will ask which foods they can eat without triggering symptoms. In a survey of 420 patients with a mast cell disorder, half of respondents reported having an “allergy” to a food or beverage (J Allergy Clin Immunol Pract. 2014;2[1]:70-6). Although not all of these patients have true allergies, they have symptoms in response to certain foods, said Dr. Hamilton. Milk, dairy products, red meat, and wheat are common triggers for these patients. But for some patients, a food may not cause symptoms consistently. “It has more to do with [the patient’s] state of reactivity at the time of eating than the actual foods [that he or she] eats,” said Dr. Hamilton.

Dietary modifications can relieve symptoms for patients with mast cell activation syndrome. Food diaries can be beneficial because they prompt patients to observe what they eat and which foods cause symptoms. An important principle is to eliminate triggers, allergies, and food sensitivities.

One way for patients to take the initiative in their treatment is for them to prepare their own food as often as possible. They should avoid restaurants and strive to eat a balanced, nutritious diet, said Dr. Hamilton. A nutritionist can provide guidance in this regard. “In general, I tell [patients] to avoid sugars, chemicals, processed foods, preservatives, and alcohol,” said Dr. Hamilton. “These things in our Western diet can be toxic to a lot of patients.” A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can benefit patients with symptoms similar to those of IBS, he added.

Physicians who treat patients with mast cell activation syndrome still have unmet needs, however. Researchers need to identify additional objective biomarkers of the syndrome, said Dr. Hamilton. Research also should be directed toward recognizing disease subtypes such as familial hypertryptasemia, a subset of mast cell activation syndrome, he added. Finally, patients need more safe and effective therapies, as well as optimized diet therapy.

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CHICAGO – Physicians can recognize mast cell activation syndrome by learning its associated triggers and symptoms, which affect many organ systems. Patients have good outcomes when they receive the appropriate pharmaceutical and dietary therapies, according to an overview presented at Freston Conference 2019, sponsored by the American Gastroenterological Association.

Mast cells are immune cells that originate in bone marrow. They defend against pathogens and contribute to tissue homeostasis and repair, said Matthew J. Hamilton, MD, associate gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston.

Aberrant regulation, which may be perpetuated by persistent stimuli, can cause unwanted mast cell activation. Symptoms affect many systems simultaneously, such as the cutaneous (e.g., flushing, pruritis, and urticaria), digestive (e.g., abdominal cramping, diarrhea, reflux, and bloat), cardiovascular (e.g., hypotension, syncope, light-headedness, and tachycardia), and others. “These patients have a lot of morbidity due to these symptoms,” said Dr. Hamilton. Symptoms are episodic and result from predictable triggers. Their severity fluctuates. Alcohol, stress, heat, hot water, strong smells, medications, and foods are typical triggers for patients with mast cell activation syndrome. The foods that trigger symptoms vary greatly between patients, said Dr. Hamilton.
 

Patients have a typical presentation

On physical examination, patients often have flushing and dermatographia. Patients also may have tachycardia when at rest or when standing. Sites of abdominal pain or bloat and problems with concentration or memory also are common. Few biomarkers for mast cell activation syndrome have been identified. A blood test for mast cell tryptase and a 24-hour urine test for metabolites of histamine and prostaglandin should be ordered for every patient suspected of having the syndrome. “Ideally, you do baseline levels of these studies, and then repeat them when patients are symptomatic,” said Dr. Hamilton. “The tryptase really has to be done within hours of a reaction. That can be a challenge.” A subset of patients with mast cell activation syndrome have a baseline serum tryptase level greater than 11.4 ng/mL.

In 2010, Akin et al. proposed criteria for mast cell activation syndrome (J Allergy Clin Immunol. 2010;126[6]:1099-104). A patient must have typical signs and symptoms of mast cell activation that affect two or more organ systems, as well as laboratory evidence of mast cell activation. A patient also must respond to medications that block mast cell mediators, and no other diagnosis should better explain his or her clinical profile.

As in the workup for other gastroenterological disorders, an endoscopy or colonoscopy is warranted to rule out other conditions such as inflammatory bowel disease, celiac disease, or disorders associated with intestinal eosinophilia. These procedures also can evaluate patients for systemic mastocytosis, the clonal form of mast cell disorders. In general, endoscopy is normal and reveals no specific features in patients with mast cell activation syndrome, said Dr. Hamilton. Histopathology generally is normal, as well. One study indicated that the mean number of mast cells did not differ between patients with mast cell activation syndrome, patients with irritable bowel syndrome (IBS), and healthy controls. Current studies are evaluating subsets of patients with mast cell activation syndrome who have increased numbers of mast cells noted per high power field to determine the utility of quantifying mast cells on histology in patients suspected of having this disorder.
 

A multifaceted approach to treatment

The best treatment for mast cell activation syndrome is multifaceted, said Dr. Hamilton. The first step is to recommend medications that target mast cells, which are exceptionally effective. These medications include type 1 and type 2 antihistamines, cromolyn, ketotifen, and leukotriene antagonists. Medications to alleviate symptoms are another component of treatment. Dietary modification is beneficial, and social and psychological support may be needed, as well.

Patients often will ask which foods they can eat without triggering symptoms. In a survey of 420 patients with a mast cell disorder, half of respondents reported having an “allergy” to a food or beverage (J Allergy Clin Immunol Pract. 2014;2[1]:70-6). Although not all of these patients have true allergies, they have symptoms in response to certain foods, said Dr. Hamilton. Milk, dairy products, red meat, and wheat are common triggers for these patients. But for some patients, a food may not cause symptoms consistently. “It has more to do with [the patient’s] state of reactivity at the time of eating than the actual foods [that he or she] eats,” said Dr. Hamilton.

Dietary modifications can relieve symptoms for patients with mast cell activation syndrome. Food diaries can be beneficial because they prompt patients to observe what they eat and which foods cause symptoms. An important principle is to eliminate triggers, allergies, and food sensitivities.

One way for patients to take the initiative in their treatment is for them to prepare their own food as often as possible. They should avoid restaurants and strive to eat a balanced, nutritious diet, said Dr. Hamilton. A nutritionist can provide guidance in this regard. “In general, I tell [patients] to avoid sugars, chemicals, processed foods, preservatives, and alcohol,” said Dr. Hamilton. “These things in our Western diet can be toxic to a lot of patients.” A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can benefit patients with symptoms similar to those of IBS, he added.

Physicians who treat patients with mast cell activation syndrome still have unmet needs, however. Researchers need to identify additional objective biomarkers of the syndrome, said Dr. Hamilton. Research also should be directed toward recognizing disease subtypes such as familial hypertryptasemia, a subset of mast cell activation syndrome, he added. Finally, patients need more safe and effective therapies, as well as optimized diet therapy.

[email protected]