Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.

“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).

“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.

The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.

All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.

The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.

Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.

Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).

“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”

[email protected]

Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.

“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).

“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.

The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.

All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.

The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.

Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.

Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).

“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”

[email protected]

Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.

“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).

“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.

The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.

All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.

The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.

Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.

Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).

“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”

[email protected]

Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.

A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.

Wikimedia Commons/Saltanat/Creative Commons

[email protected]

Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.

A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.

Wikimedia Commons/Saltanat/Creative Commons

[email protected]

Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.

A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.

Wikimedia Commons/Saltanat/Creative Commons

[email protected]

With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:

1. Lax enforcement of the individual mandate

Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.

As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.

2. Little advertising, outreach

The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.

In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added.

3. Highlight what’s “wrong” with the ACA

In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.

Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.

“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”

Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.

“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”

Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.

Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%.

4. Work for Medicaid recipients

Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.

On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”

Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.

Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.

5. Withhold cost sharing reduction payments

For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”

Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.

Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.

President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.

“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”

While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.

Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.

“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”

[email protected]

On Twitter @legal_med

With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:

1. Lax enforcement of the individual mandate

Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.

As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.

2. Little advertising, outreach

The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.

In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added.

3. Highlight what’s “wrong” with the ACA

In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.

Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.

“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”

Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.

“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”

Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.

Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%.

4. Work for Medicaid recipients

Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.

On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”

Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.

Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.

5. Withhold cost sharing reduction payments

For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”

Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.

Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.

President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.

“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”

While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.

Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.

“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”

[email protected]

On Twitter @legal_med

With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:

1. Lax enforcement of the individual mandate

Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.

As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.

2. Little advertising, outreach

The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.

In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added.

3. Highlight what’s “wrong” with the ACA

In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.

Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.

“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”

Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.

“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”

Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.

Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%.

4. Work for Medicaid recipients

Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.

On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”

Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.

Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.

5. Withhold cost sharing reduction payments

For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”

Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.

Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.

President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.

“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”

While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.

Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.

“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”

[email protected]

On Twitter @legal_med

From the University of Maryland School of Medicine, Baltimore, MD.

Abstract

• Objective: To review the current literature on menopause in HIV-infected women.
• Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
• Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
• Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.

Effect of HIV on the Menstrual Cycle

Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].

As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].

The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.

Age at Menopause

Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20].  These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].

As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].

Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].

There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].

In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.

HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm³ had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm³. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm³, 46.0 years in women with CD4 cell counts between 200 cells/mm³ and 500 cells/mm³, and 46.5 years in women with CD4 cell counts > 500 cells/mm³ [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm³ to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm³ [41]. De Pommerol et al  studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm³ were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm³ [37].

Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].

Menopause-Associated Symptoms

The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].

It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.

Vasomotor Symptoms

In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].

Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].

Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm³ were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.

Genitourinary Symptoms

With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.

Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].

Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia

Psychiatric Symptoms

Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].

In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].

Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].

Other Symptoms

Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].

Treatment

For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].

Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].

Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].

Cardiovascular Risk

Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].

HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.

Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.

Osteoporosis

Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].

Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].

Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].

Cognition

The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].

Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].

Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].

Cervical Dysplasia

As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.

In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].

Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.

HIV Acquisition and Transmission

The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.

In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.

In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].

HIV Progression

Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.

Conclusion

As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.

There still remain significant gaps in our understanding of menopause in HIV-infected women.  As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.

Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

From the University of Maryland School of Medicine, Baltimore, MD.

Abstract

• Objective: To review the current literature on menopause in HIV-infected women.
• Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
• Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
• Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.

Effect of HIV on the Menstrual Cycle

Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].

As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].

The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.

Age at Menopause

Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20].  These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].

As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].

Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].

There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].

In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.

HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm³ had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm³. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm³, 46.0 years in women with CD4 cell counts between 200 cells/mm³ and 500 cells/mm³, and 46.5 years in women with CD4 cell counts > 500 cells/mm³ [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm³ to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm³ [41]. De Pommerol et al  studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm³ were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm³ [37].

Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].

Menopause-Associated Symptoms

The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].

It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.

Vasomotor Symptoms

In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].

Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].

Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm³ were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.

Genitourinary Symptoms

With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.

Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].

Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia

Psychiatric Symptoms

Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].

In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].

Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].

Other Symptoms

Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].

Treatment

For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].

Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].

Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].

Cardiovascular Risk

Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].

HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.

Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.

Osteoporosis

Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].

Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].

Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].

Cognition

The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].

Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].

Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].

Cervical Dysplasia

As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.

In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].

Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.

HIV Acquisition and Transmission

The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.

In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.

In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].

HIV Progression

Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.

Conclusion

As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.

There still remain significant gaps in our understanding of menopause in HIV-infected women.  As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.

Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

From the University of Maryland School of Medicine, Baltimore, MD.

Abstract

• Objective: To review the current literature on menopause in HIV-infected women.
• Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
• Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
• Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.

Effect of HIV on the Menstrual Cycle

Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].

As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].

The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.

Age at Menopause

Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20].  These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].

As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].

Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].

There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].

In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.

HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm³ had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm³. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm³, 46.0 years in women with CD4 cell counts between 200 cells/mm³ and 500 cells/mm³, and 46.5 years in women with CD4 cell counts > 500 cells/mm³ [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm³ to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm³ [41]. De Pommerol et al  studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm³ were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm³ [37].

Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].

Menopause-Associated Symptoms

The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].

It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.

Vasomotor Symptoms

In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].

Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].

Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm³ were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.

Genitourinary Symptoms

With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.

Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].

Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia

Psychiatric Symptoms

Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].

In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].

Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].

Other Symptoms

Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].

Treatment

For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].

Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].

Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].

Cardiovascular Risk

Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].

HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.

Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.

Osteoporosis

Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].

Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].

Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].

Cognition

The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].

Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].

Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].

Cervical Dysplasia

As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.

In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].

Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.

HIV Acquisition and Transmission

The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.

In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.

In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].

HIV Progression

Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.

Conclusion

As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.

There still remain significant gaps in our understanding of menopause in HIV-infected women.  As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.

Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.

The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.

Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).

A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.

Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.

The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
 

[email protected]

Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.

The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.

Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).

A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.

Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.

The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
 

[email protected]

Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.

The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.

Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).

A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.

Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.

The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
 

[email protected]

A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.

The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.

copyright Dlumen/Thinkstock

The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.

[email protected]

A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.

The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.

copyright Dlumen/Thinkstock

The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.

[email protected]

A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.

The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.

copyright Dlumen/Thinkstock

The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.

[email protected]

Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.

Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).

For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.

Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).

“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.

The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.

Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.

Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.

Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).

For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.

Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).

“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.

The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.

Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.

Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.

Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).

For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.

Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).

“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.

The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.

Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.

For many years, pediatric patients undergoing procedures in the ED have received inadequate pain management and sedation. Children’s (and parents’) anxieties and distress leading up to and during a potentially painful or anxiety-inducing procedure are now more easily mitigated by the appropriate use of a variety of pediatric-appropriate analgesics, sedatives, and anxiolytics. The ability to provide adequate, minimally invasive sedation and analgesia is critically important to performing successful procedures in children, and is a hallmark of excellent pediatric emergency care.

The following case vignettes, based on actual cases, illustrate the range and routes of medications available to provide appropriate analgesia, sedation, and anxiolysis.

Cases

Case 1

A 4-year-old boy presented to the ED for evaluation of a fractured wrist sustained after he fell off his bed during a temper tantrum. At presentation, the patient’s vital signs were: blood pressure (BP), 110/70 mm Hg; heart rate (HR), 100 beats/min; respiratory rate (RR), 28 breaths/min; and temperature (T), 99.5°F. Oxygen saturation on room air was within normal limits. The patient’s weight was within normal range for his age and height at 15 kg (33 lb).

Upon examination, the child appeared agitated and in significant distress; his anxiety increased after an initial attempt at placing an intravenous (IV) line in his uninjured arm failed.

The emergency physician (EP) considered several options to ameliorate the child’s anxiety and facilitate evaluation and treatment.

Case 2

After accidentally running into a pole, a 6-year-old girl presented to the ED for evaluation and suturing of a large laceration to her forehead. At presentation, the patient’s vital signs were: BP, 115/70 mm Hg; HR, 95 beats/min; RR, 24 breaths/min; and T, 98.6°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 20 kg (44 lb).

On examination, the patient was awake, alert, and in no acute distress. However, she immediately became tearful and visibly upset when she learned that an IV line was about to be placed in her arm.

The physician instead decided to employ an IV/needle-free strategy for this wound repair, as well as anxiolysis.

Case 3

A 5-year-old girl was brought to a community hospital ED by emergency medical services after falling from a balance beam and landing headfirst on the ground during a gymnastics class. Prior to presentation, emergency medical technicians had placed the patient in a cervical collar. At presentation, the patient’s vital signs were: BP, 105/75 mm Hg; HR, 115 beats/min; RR, 28 breaths/min; and T, 99.1°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 18 kg (39.6 lb).

Although the neurological examination was normal, the patient had persistent midline cervical tenderness as well as hemotympanum. The EP ordered a head and neck computed tomography (CT) scan, but shortly after the patient arrived at radiology, the CT technician informed the EP that she was unable to perform the scan because the patient kept moving and would not stay still.

The EP considered several sedatives to facilitate the CT study.

Case 4

A febrile, but nontoxic-appearing 3-week-old girl was referred to the ED by her pediatrician for a lumbar puncture (LP) to diagnose or exclude meningitis. However, the mother’s own recent negative experience with an epidural analgesia during the patient’s delivery, made the neonate’s mother extremely anxious that the procedure might be too painful for her daughter.

The EP considered the best choice of medication to provide analgesia and allay the mother’s concerns prior to performing the LP in this neonatal patient.

Overview and Definitions

Analgesia describes the alleviation of pain without intentional sedation. However, pediatric patients typically receive sedative hypnotics (anxiolytics) both for analgesia and for anxiolysis to modify behavior (eg, enhance immobility) and to allow for the safe completion of a procedure.¹ The ultimate goal of procedural sedation and analgesia is to provide a depressed level of consciousness and pain relief while the patient maintains a patent airway and spontaneous ventilation.²

Sedation Continuum

The American Society of Anesthesiologists (ASA) classifies procedural sedation and analgesia based on a sedation continuum that affects overall responsiveness, airway, ventilation, and cardiovascular (CV) function.³ Procedural sedation is subcategorized into minimal, moderate, and deep sedation.

Minimal Sedation. Formally referred to as anxiolysis, minimal sedation is a state in which the patient is responsive but somewhat cognitively impaired, while maintaining all other functions rated in the sedation continuum.

Moderate Sedation. Previously referred to as “conscious sedation,” moderate sedation is a state of drug-induced depression of consciousness that still enables the patient to maintain purposeful responses to age-appropriate verbal commands and tactile stimulation, spontaneous ventilation, and CV integrity.

Deep Sedation. Deep sedation causes a drug-induced depression of consciousness that may potentially impair spontaneous ventilation and independent airway patency, while maintaining CV function. A deeply sedated patient is usually arousable with repeated painful stimulation.

Dissociative Sedation. This level of sedation induces a unique, trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability. The dissociative state can facilitate the performance of moderate-to-severe painful procedures, as well as procedures requiring immobilization in uncooperative patients.⁴

Contraindications to Procedural Sedation

Though there are no absolute contraindications to procedural sedation in children, its use is generally determined based on ASA’s patient physical status classification system. In this grading system, procedural sedation is appropriate for pediatric patients with a physical status of Class I (normally healthy patient) or Class II (a patient with mild systemic disease—eg, mild asthma).⁵ The EP should consult with a pediatric anesthesiologist prior to sedating a patient with an ASA status of Class II or higher, or a patient with a known laryngotracheal pathology.¹

Pre- and Postsedation Considerations

History and Physical Examination

Prior to patient sedation, the EP should perform a focused history, including a determination of the patient’s last meal and/or drink, and a physical examination. The history should also include known allergies and past or current medication use—specifically any history of adverse events associated with prior sedation. Pregnancy status should be determined in every postpubertal female patient.

The physical examination should focus on the cardiac and respiratory systems, with particular attention to any airway abnormalities or possible sources of obstruction.^1,3

Fasting

A need for fasting prior to procedural sedation remains controversial: Current ASA guidelines for fasting call for fasting times of 2 hours for clear liquids, 4 hours after breastfeeding, 6 hours for nonhuman milk or formula feeding, and 8 hours for solids.⁶

Fasting prior to general anesthesia has become a common requirement because of the risk of adverse respiratory events, including apnea, stridor, bronchospasm, emesis, and pulmonary aspiration of gastric contents. However, these events rarely occur during pediatric procedural sedation in the ED, and it is important to note that the American College of Emergency Physicians’ standards do not require delaying procedural sedation based on fasting times. There is no strong evidence that the duration of preprocedural sedation-fasting reduces or prevents emesis or aspiration.⁷

Equipment

In 2016, the American Academy of Pediatrics (AAP) updated its “Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures,”¹ including the essential equipment required for the safe administration of sedation, which can be remembered using the following “SOAPME” mnemonic:

Size: appropriate suction catheters and a functioning suction apparatus (eg, Yankauer-type suction);

Oxygen: An adequate oxygen supply and functioning flow meters or other devices to allow its delivery;

Airway: Size-appropriate equipment (eg, bag-valve-mask or equivalent device [functioning]), nasopharyngeal and oropharyngeal airways, laryngeal mask airway, laryngoscope blades (checked and functioning), endotracheal tubes, stylets, face mask;

Pharmacy: All the basic drugs needed to support life during an emergency, including antagonists as indicated;

Monitors: Functioning pulse oximeter with size-appropriate oximeter probes, end-tidal carbon dioxide monitor, and other monitors as appropriate for the procedure (eg, noninvasive blood pressure, electrocardiogram, stethoscope); and

Equipment: Special equipment or drugs for a particular case (eg, defibrillator).¹

Personnel

The 2016 AAP guidelines¹ also indicate the number and type of personnel needed for sedation—in addition to the physician performing the procedure—which is primarily determined by the intended level of sedation as follows:

Minimal Sedation. Though there are no set guidelines for minimal sedation, all providers must be capable of caring for a child who progresses to moderate sedation.

Moderate Sedation. Intentional moderate sedation necessitates two practitioners: one practitioner to oversee the sedation and monitor the patient’s vital signs, who is capable of rescuing the patient from deep sedation if it occurs; and a second provider proficient at least in basic life support to monitor vital signs and assist in a resuscitation as needed.

Deep Sedation. For patients requiring deep sedation, the practitioner administering or supervising sedative drug administration should have no other responsibilities other than observing the patient. Moreover, there must be at least one other individual present who is certified in advanced life support and airway management.¹

Discharge Criteria

Prior to discharge, pediatric patients must meet predetermined criteria that include easy arousability, a return to baseline mental status, stable age-appropriate vital signs, and the ability to remain hydrated.^1,3 In addition, while late postsedation complications are rare, caregivers should be provided with specific symptoms that would warrant immediate return to the ED.

Available Options for Analgesia and Sedation

Several different methods of providing analgesia and pediatric procedural sedation are available, ranging from nonpharmacological methods to topical and parenteral medication administration.

Nonpharmacological Options: Child-Life Specialists

Child-life specialists can be particularly helpful with pediatric emergency patients. With a background in normal child development, child-life specialists utilize myriad distraction techniques and coping strategies to help patients within the stressful environment of an ED. Studies have shown that the presence of a child-life specialist may reduce the depth of sedation needed for certain procedures.¹

Sucrose

Several studies have identified the benefits of sucrose as a pain reliever in neonates. Available as a 12% to 25% solution, sucrose decreases noxious stimuli and is a useful analgesic for such common neonatal procedures as venipuncture, circumcision, heel sticks, Foley catheter insertion, and LP. Efficacy of sucrose for these procedures is greatest in newborns, and decreases gradually after 6 months of age. The effectiveness of sucrose is enhanced when it is given in conjunction with nonnutritive sucking or maternal “skin-to-skin” techniques. There are no contraindications to the use of sucrose.⁸

Nonopioid Systemic Analgesia

Nonopioid oral analgesics (NOAs), such as acetaminophen and the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, are appropriate for mild-to-moderate procedural pain. The NOAs can be given alone or in conjunction with an opioid to enhance the analgesic effect for patients with severe pain.

Acetaminophen. Acetaminophen, which also has antipyretic properties, can be administered orally, rectally, or IV. Since acetaminophen is not an NSAID and does not affect platelet function, it is a good choice for treating patients with gastrointestinal (GI) pain.

Adverse effects of acetaminophen, which is metabolized by the liver, include hepatotoxicity in toxic doses. The suggested oral dose for infants and children weighing less than 60 kg (132 lb) is 10 to 15 mg/kg per dose every 4 to 6 hours as needed, with a maximum dose of 75 mg/kg/d for infants and 100 mg/kg/d for children. Rectal dosing for infants and children weighing less than 60 kg (132 lb) is 10 to 20 mg/kg every 6 hours as needed, with a maximum daily dose of 75 mg/kg/d in infants, and 100 mg/kg/d in children.

Ibuprofen. Ibuprofen, an NSAID with both antipyretic and anti-inflammatory properties, acts as a prostaglandin inhibitor and is indicated for use in patients over 6 months of age. Since ibuprofen inhibits platelet function, it can cause GI bleeding with chronic use. The suggested pediatric dose for ibuprofen is 5 to 10 mg/kg per dose every 6 to 8 hours orally, with a maximum dose of 40 mg/kg/d.⁹

Local Anesthesia

Local anesthetics administered via the topical or subcutaneous (SC) route provide anesthesia by temporarily blocking peripheral or central nerve conduction at the sodium channel.

LET Gel. This topical anesthetic combination composed of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine (LET gel) is commonly used on patients prior to repair of a skin laceration. Its peak onset of action occurs in 30 minutes, with an anesthetic duration of 45 minutes. The epinephrine component of LET reduces blood flow to the anesthetized area, which increases duration of action but also creates a small risk of vasoconstriction in the areas supplied by end arteries, such as in the penis, nose, digits, and pinna.⁹

EMLA and LMX4. Topical lidocaine anesthetics are extremely useful in the ED because their application can help reduce the pain of minor procedures, when they are applied in adequate time prior to initiating the procedure to reach peak effect. Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) and liposomal 4% lidocaine (LMX4) are the most commonly used topical lidocaine anesthetics. The peak analgesic effect of EMLA occurs within 60 minutes, with a duration of 90 minutes; LMX4 reaches its analgesic peak after 30 minutes with duration of up to 60 minutes.

Because of the slight delay of the time-to-peak effect, these topical anesthetics are not useful for emergent procedures. Further, neither EMLA nor LMX4 is approved for nonintact skin injuries such as lacerations.⁹ Both LMX4 and EMLA are approved for use in intact skin, providing effective analgesia for procedures such as venipuncture, circumcision, LP, and abscess drainage.

Subcutaneous Lidocaine. When SC injection of lidocaine is preferred, a useful technique to reduce the pain of administration is to warm the lidocaine, alkalinize the solution with 1 mL (1 mEq) sodium bicarbonate to 9 mL lidocaine,⁶ prior to injecting it slowly with a small-gauge needle.⁸Vapocoolant Lidocaine. Vapocoolant sprays produce an immediate cold sensation that is effective in reducing localized pain in adults. Studies looking at its efficacy in children are not as convincing, with some studies suggesting the cold sensation is quite distressing for many children.⁸

Opioids

Opioids are commonly chosen for pediatric procedural sedation because of their short onset of action and ability to produce significant analgesia with varying amounts of sedation. Fentanyl and morphine are the most widely used opioid analgesics to manage moderate-to-severe procedural pain in children.

Morphine. Morphine remains the gold standard for pediatric opioid analgesia, partly because it can be administered SC, IV, intramuscularly (IM), and orally. Its properties are more quickly achieved via the IV route, as the onset of action is 4 to 6 minutes. The standard IV dose of morphine is 0.1 mg/kg per dose, and can provide analgesia for up to 4 hours.

Adverse effects of morphine include dependence (though not an issue with a single emergency dose), respiratory depression, nausea, vomiting, constipation, urinary retention, hypotension, and bradycardia. Naloxone can rapidly reverse these adverse effects.

Fentanyl. Fentanyl, which is 100 times more potent than morphine, can be administered IV, transdermally, or transmucosally. When given IV, the onset of action of fentanyl is 2 to 3 minutes, and duration of action of 30 to 60 minutes. For sedation and analgesia, the suggested IV dose of fentanyl in neonates and young infants is 1 to 4 mcg/kg every 2 to 4 hours as needed, and for older infants and children, 1 to 2 mcg/kg every 30 to 60 minutes as needed.

Adverse effects of fentanyl are respiratory depression and chest wall rigidity,⁹ which can be rapidly reversed with naloxone (the dose of naloxone by patient weight is the same as that given to reverse adverse effects of morphine and fentanyl).

Codeine. A weaker opioid analgesic, codeine is not recommended for routine pediatric use because of its significant potential to hypermetabolize to morphine in some children, leading to overdose.⁶

Benzodiazepines: Midazolam

Benzodiazepines, which act on the type A gamma-aminobutyric acid receptor, causing muscle relaxation, anxiolysis, and anterograde amnesia, are useful for pediatric procedural sedation. Due to its short half-life, midazolam is the most common benzodiazepine used in pediatric patients. Midazolam can be delivered via different routes of administration, including orally, IM, IV, and transmucosally.

Intramuscular Route. Intramuscular midazolam has been shown to cause deep sedation at doses of 0.3 mg/kg, with maximum sedation occurring at 45 minutes, recovery beginning by 60 minutes, and the most common side effect being euphoria.¹⁰

Intravenous Route. Intravenous midazolam is used extensively in pediatric procedural sedation and is usually given at a dose of 0.05 to 0.1 mg/kg, with a maximum dose of 2 mg.

Even among small children, midazolam is usually quite safe when given alone, but because it does not provide effective analgesia, it often requires combination with an opioid for effective procedural sedation. Flumazenil may be given for rapid reversal of known benzodiazepine-induced respiratory depression, but it should be avoided in children with seizure disorders.

Propofol

Propofol is now frequently employed for pediatric sedation outside of the operating room. Propofol has excellent sedation properties but, like midazolam, does not provide analgesia and necessitates a second agent such as ketamine or an opioid for successful completion of more painful procedures. However, for children in whom sedation is required to facilitate simple neuroimaging of the head or spine, propofol is a very useful agent given the child’s quick return to his/her baseline mental status following the procedure.

Regarding contraindications, since propofol contains egg lecithin and soybean oil, it was once considered inappropriate for use in patients with an egg or soy allergy. Recent data, however, have refuted this belief, and while the package insert for propofol still lists patient allergy to egg, egg products, soy, or soybeans as a contraindication to use,¹¹ the American Academy of Allergy, Asthma and Immunology recently concluded that patients with soy allergy or egg allergy can receive propofol without any special precautions.¹²

Since propofol is a powerful sedative and can cause a greater depth of sedation than that intended, providers must be comfortable with both monitoring and managing the pediatric airway. The induction dose of propofol is 1 mg/kg with repeated doses of 0.5 mg/kg to achieve the desired level of sedation. One emergency medicine-specific study by Jasiak et al¹³ found a mean cumulative propofol dose of 2.1 mg/kg for pediatric procedures given in a median of three boluses, with younger children requiring an overall higher mg/kg induction dose. Another study by Young et al¹⁴ showed an induction dose of 2 mg/kg to be well tolerated and without increased adverse events for pediatric procedural sedation.

When used properly, propofol has been shown to be safe and effective in pediatric patients. A recent review by Mallory et al¹⁵ looking at 25,433 cases of EP administration of propofol to pediatric patients noted serious complications in only 2% of patients, including one unplanned intubation, one cardiac arrest, and two aspirations.

Ketamine

Dissociative procedural sedation is frequently utilized in pediatric patients, for which ketamine is usually the agent of choice given its fast onset of action, multiple modes of administration, and robust pediatric safety data. Ketamine is a unique agent because of its sedative, analgesic, and paralytic-like properties. A phencyclidine derivative, ketamine exerts its effect by binding to the N-methyl-D-aspartate receptor, and may be given IM or IV, with usual dosing of 1 to 1.5 mg/kg IV, or 2 to 4 mg/kg IM. Unlike other sedatives, there is a “dissociation threshold” for ketamine, and further dosing does not increase its effects.¹⁶

Because of multiple observations and reported cases of airway complications in infants younger than 3 months of age, it is not recommended for routine use in this age group. While ketamine-associated infant airway events are thought by some experts to not be specific to ketamine (and more representative of infant differences in airway anatomy and laryngeal excitability), risks seem to outweigh benefits for routine use in this cohort.¹⁶

Ketamine is known to exaggerate protective airway reflexes and can cause laryngospasm, so it is best avoided during procedures that cause a large amount of pharyngeal stimulation. The overall rate of ketamine-induced pediatric laryngospasm is low in the general population (0.3%), and when it does occur, can usually be treated easily with assisted ventilation and oxygenation.¹⁷

Prior concerns of ketamine increasing intracranial pressure (ICP) have been shown not to be the case by recent data, which in fact demonstrate that ketamine may instead actually lower ICP.¹⁸

For many pediatric centers, including the authors’, ketamine is a first-line agent to facilitate head and/or neck CT in otherwise uncooperative children. Emesis is the most common side effect of ketamine, but the incidence can be significantly reduced by pretreating the patient with ondansetron.¹⁹ Though ketamine may also be combined with propofol, there is no robust pediatric-specific evidence showing any benefits of this practice.

Nitrous Oxide

Nitrous oxide (N₂O), the most commonly used inhaled anesthetic agent used in the pediatric ED, provides analgesia, sedation, anterograde amnesia, and anxiolysis. It can be given in mixtures of 30% to 70% N₂O with oxygen, has a rapid onset of action (<1 minute), and there is rapid recovery after cessation. In patients older than 5 years of age, N₂O is usually given via a demand valve system, which will fall off the patient’s face if he or she becomes overly sedated.

Nitrous oxide is usually very well tolerated with few serious events, the most common being emesis.²⁰ Absolute contraindications to its use are few and include pneumothorax, pulmonary blebs, bowel obstruction, air embolus, and a recent history of intracranial or middle ear surgery.

Intranasal Analgesia

Intranasal (IN) analgesics are becoming increasingly popular for pediatric procedures because of their rapid onset of action compared with oral medications, without the need for IV or “needle” access prior to administration.

Intranasal Fentanyl. The EP should use a mucosal atomizer when administering midazolam or fentanyl via the IN route. The atomizer transforms these liquid drugs into a fine spray, which increases surface area, improving mucosal absorption and central nervous system concentrations when compared with IN administration via dropper.²¹

In a study by Klein et al,²² IN midazolam effectively provided sedation, with more effective diminution of activity and better overall patient satisfaction than with either oral or buccal midazolam. Intranasal midazolam causes a slight burning sensation, and some patients report initial discomfort after administration. The half-lives of IN and IV midazolam are very similar (2.2 vs 2.4 hours).²³Intranasal Fentanyl. IN fentanyl is an excellent alternative to IV pain medications for patients in whom there is no IV access. When given at a dose of 1.7 mcg/kg, IN fentanyl produces analgesic effects similar to that of morphine 0.1 mg/kg.

The only reported adverse effect associated with IN fentanyl has been a bad taste in the mouth.²⁴ Another study of children aged 1 to 3 years showed a significant decrease in pain in 93% of children at 10 minutes, and 98% of children at 30 minutes, with no significant side effects.²⁵

Intranasal fentanyl is a great choice for initial and immediate pain control in children with suspected long bone fractures, and is especially useful in facilitating their comfort during radiographic imaging.

Managing a Child for Radiographic Imaging

To facilitate a relatively rapid procedure such as obtaining plain films or a CT scan, anxiolysis, rather than analgesia, is required. Given its quick and predictable onset of action, IN midazolam is an excellent choice for pediatric patients requiring imaging studies. If, however, a mucosal atomizer is not available for IN drug delivery and the patient is already in radiology and requires emergent imaging studies, oral midazolam should not be given as an alternative because of its delayed onset of action. In such cases, placing an IV line and administering IV propofol offers the best chance of achieving quick and effective anxiolysis to obtain the images required to exclude clinically important injuries.

In hospitals that restrict the use of propofol in young children outside of the operating room—and when there are no findings suggestive of impending cerebral herniation—a safe and effective alternative is IV ketamine at a dose of 1.5 mg/kg.

Cases Continued

Case 1

[The 4-year-old boy with the fractured wrist.]

Recognizing that repeated attempts at IV placement in a child with a contralateral extremity fracture often leads to escalating distress and anxiety, the EP decided against further attempts to place an IV line. Instead, he gave the child fentanyl via the IN route, which immediately relieved the patient’s pain and facilitated radiographic evaluation. After administrating the fentanyl IN, the EP instructed a member of the ED staff to apply LMX4 cream to several potential IV sites and then cover each site with occlusive dressings. Afterward, the patient was taken to radiology, and X-ray images of the fracture were easily obtained. When the patient returned from imaging, the ED nurse was able to place an IV line at one of the sites that had been previously anesthetized with LMX4 cream.

The EP consulted with the orthopedist, who determined that the child’s distal radius fracture necessitated closed reduction. To facilitate the procedure, the patient was given 1.5 mg/kg of ketamine. After a successful closed reduction, the orthopedic chief resident recommended the EP discharge the 15-kg (33-lb) patient home in the care of his parents, with a prescription for 5 mL oral acetaminophen and codeine suspension four times a day as needed for pain (5 mL = acetaminophen 120 mg/codeine 12 mg, and codeine dosed at 0.5-1 mg/kg per dose). Prior to discharge, the EP counseled the patient’s parents on the risks of codeine hypermetabolism in children. However, based on the parents’ expressed concerns, the EP instead discharged the patient home with a prescription for 4 cc oral acetaminophen-hydrocodone elixir every 4 to 6 hours as needed for pain instead (dosing is 0.27 mL/kg; elixir is hydrocodone bitartrate 7.5 mg/acetaminophen 325 mg/15 mL).

Case 2

[The 6-year-old girl with a large laceration to her forehead.]

The type of laceration sustained by this patient was appropriate for treatment with a local anesthetic combined with an agent for non-IV anxiolysis. Thirty minutes prior to suturing, LET gel was applied over the open wound site, and 5 minutes prior to initiating closure of the wound, the patient received IN midazolam. Since the LET cream was placed on the wound 30 minutes prior to the procedure, the site was well anesthetized for both irrigation and closure. The anxiolytic effects of the IN midazolam resulted in a calm patient, who was happy and playful throughout the procedure.

After successfully closing the wound, the physician discharged the patient home in the care of her parents, with instructions to apply bacitracin ointment to the wound site three times a day for the next 3 days, and give the patient over-the-counter acetaminophen elixir for any mild discomfort.

Case 3

[The 5-year-old boy who suffered cervical spine injuries after falling head-first off of a balance beam during gymnastics.]

Since no mucosal atomizer was available for IN drug delivery, and hospital policy restricted the use of propofol in young children outside of the operating room, the patient was given 1.5 mg/kg of IV ketamine. Within 45 seconds of ketamine administration, the child had adequate dissociative sedation, which allowed for high-quality CT scans of both the head and neck without incident. 

Case 4

[The febrile 3-week-old female neonate referred by her pediatrician for evaluation and LP.]

Since this neonate did not appear toxic, the EP delayed the LP by 30 minutes to allow time for application of a topical anesthetic to minimize associated procedural pain. Thirty minutes prior to the LP, LMX4 cream was applied to the patient’s L4 spinal interspace, and just prior to the procedure, the patient was given a pacifier that had been dipped in a solution of 4% sucrose. The neonate was then positioned appropriately for the LP and barely squirmed when the spinal needle was introduced, allowing the EP to obtain a nontraumatic cerebrospinal fluid sample on the first attempt.

Conclusion

Addressing pediatric pain and anxiety, especially preceding and during procedures and radiographic imaging, is a serious challenge in the ED. Several means are now available to provide safe and effective sedation, analgesia, and anxiolysis in the ED, with or without IV access. Many of the medications utilized, however, can cause significant respiratory and CV depression, making proper patient selection and monitoring, and training of involved personnel imperative to ensure safe use in the ED. Appropriate use of the agents and strategies discussed above will allow EPs to reduce both procedural pain and anxiety for our youngest patients—and their parents.

For many years, pediatric patients undergoing procedures in the ED have received inadequate pain management and sedation. Children’s (and parents’) anxieties and distress leading up to and during a potentially painful or anxiety-inducing procedure are now more easily mitigated by the appropriate use of a variety of pediatric-appropriate analgesics, sedatives, and anxiolytics. The ability to provide adequate, minimally invasive sedation and analgesia is critically important to performing successful procedures in children, and is a hallmark of excellent pediatric emergency care.

The following case vignettes, based on actual cases, illustrate the range and routes of medications available to provide appropriate analgesia, sedation, and anxiolysis.

Cases

Case 1

A 4-year-old boy presented to the ED for evaluation of a fractured wrist sustained after he fell off his bed during a temper tantrum. At presentation, the patient’s vital signs were: blood pressure (BP), 110/70 mm Hg; heart rate (HR), 100 beats/min; respiratory rate (RR), 28 breaths/min; and temperature (T), 99.5°F. Oxygen saturation on room air was within normal limits. The patient’s weight was within normal range for his age and height at 15 kg (33 lb).

Upon examination, the child appeared agitated and in significant distress; his anxiety increased after an initial attempt at placing an intravenous (IV) line in his uninjured arm failed.

The emergency physician (EP) considered several options to ameliorate the child’s anxiety and facilitate evaluation and treatment.

Case 2

After accidentally running into a pole, a 6-year-old girl presented to the ED for evaluation and suturing of a large laceration to her forehead. At presentation, the patient’s vital signs were: BP, 115/70 mm Hg; HR, 95 beats/min; RR, 24 breaths/min; and T, 98.6°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 20 kg (44 lb).

On examination, the patient was awake, alert, and in no acute distress. However, she immediately became tearful and visibly upset when she learned that an IV line was about to be placed in her arm.

The physician instead decided to employ an IV/needle-free strategy for this wound repair, as well as anxiolysis.

Case 3

A 5-year-old girl was brought to a community hospital ED by emergency medical services after falling from a balance beam and landing headfirst on the ground during a gymnastics class. Prior to presentation, emergency medical technicians had placed the patient in a cervical collar. At presentation, the patient’s vital signs were: BP, 105/75 mm Hg; HR, 115 beats/min; RR, 28 breaths/min; and T, 99.1°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 18 kg (39.6 lb).

Although the neurological examination was normal, the patient had persistent midline cervical tenderness as well as hemotympanum. The EP ordered a head and neck computed tomography (CT) scan, but shortly after the patient arrived at radiology, the CT technician informed the EP that she was unable to perform the scan because the patient kept moving and would not stay still.

The EP considered several sedatives to facilitate the CT study.

Case 4

A febrile, but nontoxic-appearing 3-week-old girl was referred to the ED by her pediatrician for a lumbar puncture (LP) to diagnose or exclude meningitis. However, the mother’s own recent negative experience with an epidural analgesia during the patient’s delivery, made the neonate’s mother extremely anxious that the procedure might be too painful for her daughter.

The EP considered the best choice of medication to provide analgesia and allay the mother’s concerns prior to performing the LP in this neonatal patient.

Overview and Definitions

Analgesia describes the alleviation of pain without intentional sedation. However, pediatric patients typically receive sedative hypnotics (anxiolytics) both for analgesia and for anxiolysis to modify behavior (eg, enhance immobility) and to allow for the safe completion of a procedure.¹ The ultimate goal of procedural sedation and analgesia is to provide a depressed level of consciousness and pain relief while the patient maintains a patent airway and spontaneous ventilation.²

Sedation Continuum

The American Society of Anesthesiologists (ASA) classifies procedural sedation and analgesia based on a sedation continuum that affects overall responsiveness, airway, ventilation, and cardiovascular (CV) function.³ Procedural sedation is subcategorized into minimal, moderate, and deep sedation.

Minimal Sedation. Formally referred to as anxiolysis, minimal sedation is a state in which the patient is responsive but somewhat cognitively impaired, while maintaining all other functions rated in the sedation continuum.

Moderate Sedation. Previously referred to as “conscious sedation,” moderate sedation is a state of drug-induced depression of consciousness that still enables the patient to maintain purposeful responses to age-appropriate verbal commands and tactile stimulation, spontaneous ventilation, and CV integrity.

Deep Sedation. Deep sedation causes a drug-induced depression of consciousness that may potentially impair spontaneous ventilation and independent airway patency, while maintaining CV function. A deeply sedated patient is usually arousable with repeated painful stimulation.

Dissociative Sedation. This level of sedation induces a unique, trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability. The dissociative state can facilitate the performance of moderate-to-severe painful procedures, as well as procedures requiring immobilization in uncooperative patients.⁴

Contraindications to Procedural Sedation

Though there are no absolute contraindications to procedural sedation in children, its use is generally determined based on ASA’s patient physical status classification system. In this grading system, procedural sedation is appropriate for pediatric patients with a physical status of Class I (normally healthy patient) or Class II (a patient with mild systemic disease—eg, mild asthma).⁵ The EP should consult with a pediatric anesthesiologist prior to sedating a patient with an ASA status of Class II or higher, or a patient with a known laryngotracheal pathology.¹

Pre- and Postsedation Considerations

History and Physical Examination

Prior to patient sedation, the EP should perform a focused history, including a determination of the patient’s last meal and/or drink, and a physical examination. The history should also include known allergies and past or current medication use—specifically any history of adverse events associated with prior sedation. Pregnancy status should be determined in every postpubertal female patient.

The physical examination should focus on the cardiac and respiratory systems, with particular attention to any airway abnormalities or possible sources of obstruction.^1,3

Fasting

A need for fasting prior to procedural sedation remains controversial: Current ASA guidelines for fasting call for fasting times of 2 hours for clear liquids, 4 hours after breastfeeding, 6 hours for nonhuman milk or formula feeding, and 8 hours for solids.⁶

Fasting prior to general anesthesia has become a common requirement because of the risk of adverse respiratory events, including apnea, stridor, bronchospasm, emesis, and pulmonary aspiration of gastric contents. However, these events rarely occur during pediatric procedural sedation in the ED, and it is important to note that the American College of Emergency Physicians’ standards do not require delaying procedural sedation based on fasting times. There is no strong evidence that the duration of preprocedural sedation-fasting reduces or prevents emesis or aspiration.⁷

Equipment

In 2016, the American Academy of Pediatrics (AAP) updated its “Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures,”¹ including the essential equipment required for the safe administration of sedation, which can be remembered using the following “SOAPME” mnemonic:

Size: appropriate suction catheters and a functioning suction apparatus (eg, Yankauer-type suction);

Oxygen: An adequate oxygen supply and functioning flow meters or other devices to allow its delivery;

Airway: Size-appropriate equipment (eg, bag-valve-mask or equivalent device [functioning]), nasopharyngeal and oropharyngeal airways, laryngeal mask airway, laryngoscope blades (checked and functioning), endotracheal tubes, stylets, face mask;

Pharmacy: All the basic drugs needed to support life during an emergency, including antagonists as indicated;

Monitors: Functioning pulse oximeter with size-appropriate oximeter probes, end-tidal carbon dioxide monitor, and other monitors as appropriate for the procedure (eg, noninvasive blood pressure, electrocardiogram, stethoscope); and

Equipment: Special equipment or drugs for a particular case (eg, defibrillator).¹

Personnel

The 2016 AAP guidelines¹ also indicate the number and type of personnel needed for sedation—in addition to the physician performing the procedure—which is primarily determined by the intended level of sedation as follows:

Minimal Sedation. Though there are no set guidelines for minimal sedation, all providers must be capable of caring for a child who progresses to moderate sedation.

Moderate Sedation. Intentional moderate sedation necessitates two practitioners: one practitioner to oversee the sedation and monitor the patient’s vital signs, who is capable of rescuing the patient from deep sedation if it occurs; and a second provider proficient at least in basic life support to monitor vital signs and assist in a resuscitation as needed.

Deep Sedation. For patients requiring deep sedation, the practitioner administering or supervising sedative drug administration should have no other responsibilities other than observing the patient. Moreover, there must be at least one other individual present who is certified in advanced life support and airway management.¹

Discharge Criteria

Prior to discharge, pediatric patients must meet predetermined criteria that include easy arousability, a return to baseline mental status, stable age-appropriate vital signs, and the ability to remain hydrated.^1,3 In addition, while late postsedation complications are rare, caregivers should be provided with specific symptoms that would warrant immediate return to the ED.

Available Options for Analgesia and Sedation

Several different methods of providing analgesia and pediatric procedural sedation are available, ranging from nonpharmacological methods to topical and parenteral medication administration.

Nonpharmacological Options: Child-Life Specialists

Child-life specialists can be particularly helpful with pediatric emergency patients. With a background in normal child development, child-life specialists utilize myriad distraction techniques and coping strategies to help patients within the stressful environment of an ED. Studies have shown that the presence of a child-life specialist may reduce the depth of sedation needed for certain procedures.¹

Sucrose

Several studies have identified the benefits of sucrose as a pain reliever in neonates. Available as a 12% to 25% solution, sucrose decreases noxious stimuli and is a useful analgesic for such common neonatal procedures as venipuncture, circumcision, heel sticks, Foley catheter insertion, and LP. Efficacy of sucrose for these procedures is greatest in newborns, and decreases gradually after 6 months of age. The effectiveness of sucrose is enhanced when it is given in conjunction with nonnutritive sucking or maternal “skin-to-skin” techniques. There are no contraindications to the use of sucrose.⁸

Nonopioid Systemic Analgesia

Nonopioid oral analgesics (NOAs), such as acetaminophen and the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, are appropriate for mild-to-moderate procedural pain. The NOAs can be given alone or in conjunction with an opioid to enhance the analgesic effect for patients with severe pain.

Acetaminophen. Acetaminophen, which also has antipyretic properties, can be administered orally, rectally, or IV. Since acetaminophen is not an NSAID and does not affect platelet function, it is a good choice for treating patients with gastrointestinal (GI) pain.

Adverse effects of acetaminophen, which is metabolized by the liver, include hepatotoxicity in toxic doses. The suggested oral dose for infants and children weighing less than 60 kg (132 lb) is 10 to 15 mg/kg per dose every 4 to 6 hours as needed, with a maximum dose of 75 mg/kg/d for infants and 100 mg/kg/d for children. Rectal dosing for infants and children weighing less than 60 kg (132 lb) is 10 to 20 mg/kg every 6 hours as needed, with a maximum daily dose of 75 mg/kg/d in infants, and 100 mg/kg/d in children.

Ibuprofen. Ibuprofen, an NSAID with both antipyretic and anti-inflammatory properties, acts as a prostaglandin inhibitor and is indicated for use in patients over 6 months of age. Since ibuprofen inhibits platelet function, it can cause GI bleeding with chronic use. The suggested pediatric dose for ibuprofen is 5 to 10 mg/kg per dose every 6 to 8 hours orally, with a maximum dose of 40 mg/kg/d.⁹

Local Anesthesia

Local anesthetics administered via the topical or subcutaneous (SC) route provide anesthesia by temporarily blocking peripheral or central nerve conduction at the sodium channel.

LET Gel. This topical anesthetic combination composed of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine (LET gel) is commonly used on patients prior to repair of a skin laceration. Its peak onset of action occurs in 30 minutes, with an anesthetic duration of 45 minutes. The epinephrine component of LET reduces blood flow to the anesthetized area, which increases duration of action but also creates a small risk of vasoconstriction in the areas supplied by end arteries, such as in the penis, nose, digits, and pinna.⁹

EMLA and LMX4. Topical lidocaine anesthetics are extremely useful in the ED because their application can help reduce the pain of minor procedures, when they are applied in adequate time prior to initiating the procedure to reach peak effect. Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) and liposomal 4% lidocaine (LMX4) are the most commonly used topical lidocaine anesthetics. The peak analgesic effect of EMLA occurs within 60 minutes, with a duration of 90 minutes; LMX4 reaches its analgesic peak after 30 minutes with duration of up to 60 minutes.

Because of the slight delay of the time-to-peak effect, these topical anesthetics are not useful for emergent procedures. Further, neither EMLA nor LMX4 is approved for nonintact skin injuries such as lacerations.⁹ Both LMX4 and EMLA are approved for use in intact skin, providing effective analgesia for procedures such as venipuncture, circumcision, LP, and abscess drainage.

Subcutaneous Lidocaine. When SC injection of lidocaine is preferred, a useful technique to reduce the pain of administration is to warm the lidocaine, alkalinize the solution with 1 mL (1 mEq) sodium bicarbonate to 9 mL lidocaine,⁶ prior to injecting it slowly with a small-gauge needle.⁸Vapocoolant Lidocaine. Vapocoolant sprays produce an immediate cold sensation that is effective in reducing localized pain in adults. Studies looking at its efficacy in children are not as convincing, with some studies suggesting the cold sensation is quite distressing for many children.⁸

Opioids

Opioids are commonly chosen for pediatric procedural sedation because of their short onset of action and ability to produce significant analgesia with varying amounts of sedation. Fentanyl and morphine are the most widely used opioid analgesics to manage moderate-to-severe procedural pain in children.

Morphine. Morphine remains the gold standard for pediatric opioid analgesia, partly because it can be administered SC, IV, intramuscularly (IM), and orally. Its properties are more quickly achieved via the IV route, as the onset of action is 4 to 6 minutes. The standard IV dose of morphine is 0.1 mg/kg per dose, and can provide analgesia for up to 4 hours.

Adverse effects of morphine include dependence (though not an issue with a single emergency dose), respiratory depression, nausea, vomiting, constipation, urinary retention, hypotension, and bradycardia. Naloxone can rapidly reverse these adverse effects.

Fentanyl. Fentanyl, which is 100 times more potent than morphine, can be administered IV, transdermally, or transmucosally. When given IV, the onset of action of fentanyl is 2 to 3 minutes, and duration of action of 30 to 60 minutes. For sedation and analgesia, the suggested IV dose of fentanyl in neonates and young infants is 1 to 4 mcg/kg every 2 to 4 hours as needed, and for older infants and children, 1 to 2 mcg/kg every 30 to 60 minutes as needed.

Adverse effects of fentanyl are respiratory depression and chest wall rigidity,⁹ which can be rapidly reversed with naloxone (the dose of naloxone by patient weight is the same as that given to reverse adverse effects of morphine and fentanyl).

Codeine. A weaker opioid analgesic, codeine is not recommended for routine pediatric use because of its significant potential to hypermetabolize to morphine in some children, leading to overdose.⁶

Benzodiazepines: Midazolam

Benzodiazepines, which act on the type A gamma-aminobutyric acid receptor, causing muscle relaxation, anxiolysis, and anterograde amnesia, are useful for pediatric procedural sedation. Due to its short half-life, midazolam is the most common benzodiazepine used in pediatric patients. Midazolam can be delivered via different routes of administration, including orally, IM, IV, and transmucosally.

Intramuscular Route. Intramuscular midazolam has been shown to cause deep sedation at doses of 0.3 mg/kg, with maximum sedation occurring at 45 minutes, recovery beginning by 60 minutes, and the most common side effect being euphoria.¹⁰

Intravenous Route. Intravenous midazolam is used extensively in pediatric procedural sedation and is usually given at a dose of 0.05 to 0.1 mg/kg, with a maximum dose of 2 mg.

Even among small children, midazolam is usually quite safe when given alone, but because it does not provide effective analgesia, it often requires combination with an opioid for effective procedural sedation. Flumazenil may be given for rapid reversal of known benzodiazepine-induced respiratory depression, but it should be avoided in children with seizure disorders.

Propofol

Propofol is now frequently employed for pediatric sedation outside of the operating room. Propofol has excellent sedation properties but, like midazolam, does not provide analgesia and necessitates a second agent such as ketamine or an opioid for successful completion of more painful procedures. However, for children in whom sedation is required to facilitate simple neuroimaging of the head or spine, propofol is a very useful agent given the child’s quick return to his/her baseline mental status following the procedure.

Regarding contraindications, since propofol contains egg lecithin and soybean oil, it was once considered inappropriate for use in patients with an egg or soy allergy. Recent data, however, have refuted this belief, and while the package insert for propofol still lists patient allergy to egg, egg products, soy, or soybeans as a contraindication to use,¹¹ the American Academy of Allergy, Asthma and Immunology recently concluded that patients with soy allergy or egg allergy can receive propofol without any special precautions.¹²

Since propofol is a powerful sedative and can cause a greater depth of sedation than that intended, providers must be comfortable with both monitoring and managing the pediatric airway. The induction dose of propofol is 1 mg/kg with repeated doses of 0.5 mg/kg to achieve the desired level of sedation. One emergency medicine-specific study by Jasiak et al¹³ found a mean cumulative propofol dose of 2.1 mg/kg for pediatric procedures given in a median of three boluses, with younger children requiring an overall higher mg/kg induction dose. Another study by Young et al¹⁴ showed an induction dose of 2 mg/kg to be well tolerated and without increased adverse events for pediatric procedural sedation.

When used properly, propofol has been shown to be safe and effective in pediatric patients. A recent review by Mallory et al¹⁵ looking at 25,433 cases of EP administration of propofol to pediatric patients noted serious complications in only 2% of patients, including one unplanned intubation, one cardiac arrest, and two aspirations.

Ketamine

Dissociative procedural sedation is frequently utilized in pediatric patients, for which ketamine is usually the agent of choice given its fast onset of action, multiple modes of administration, and robust pediatric safety data. Ketamine is a unique agent because of its sedative, analgesic, and paralytic-like properties. A phencyclidine derivative, ketamine exerts its effect by binding to the N-methyl-D-aspartate receptor, and may be given IM or IV, with usual dosing of 1 to 1.5 mg/kg IV, or 2 to 4 mg/kg IM. Unlike other sedatives, there is a “dissociation threshold” for ketamine, and further dosing does not increase its effects.¹⁶

Because of multiple observations and reported cases of airway complications in infants younger than 3 months of age, it is not recommended for routine use in this age group. While ketamine-associated infant airway events are thought by some experts to not be specific to ketamine (and more representative of infant differences in airway anatomy and laryngeal excitability), risks seem to outweigh benefits for routine use in this cohort.¹⁶

Ketamine is known to exaggerate protective airway reflexes and can cause laryngospasm, so it is best avoided during procedures that cause a large amount of pharyngeal stimulation. The overall rate of ketamine-induced pediatric laryngospasm is low in the general population (0.3%), and when it does occur, can usually be treated easily with assisted ventilation and oxygenation.¹⁷

Prior concerns of ketamine increasing intracranial pressure (ICP) have been shown not to be the case by recent data, which in fact demonstrate that ketamine may instead actually lower ICP.¹⁸

For many pediatric centers, including the authors’, ketamine is a first-line agent to facilitate head and/or neck CT in otherwise uncooperative children. Emesis is the most common side effect of ketamine, but the incidence can be significantly reduced by pretreating the patient with ondansetron.¹⁹ Though ketamine may also be combined with propofol, there is no robust pediatric-specific evidence showing any benefits of this practice.

Nitrous Oxide

Nitrous oxide (N₂O), the most commonly used inhaled anesthetic agent used in the pediatric ED, provides analgesia, sedation, anterograde amnesia, and anxiolysis. It can be given in mixtures of 30% to 70% N₂O with oxygen, has a rapid onset of action (<1 minute), and there is rapid recovery after cessation. In patients older than 5 years of age, N₂O is usually given via a demand valve system, which will fall off the patient’s face if he or she becomes overly sedated.

Nitrous oxide is usually very well tolerated with few serious events, the most common being emesis.²⁰ Absolute contraindications to its use are few and include pneumothorax, pulmonary blebs, bowel obstruction, air embolus, and a recent history of intracranial or middle ear surgery.

Intranasal Analgesia

Intranasal (IN) analgesics are becoming increasingly popular for pediatric procedures because of their rapid onset of action compared with oral medications, without the need for IV or “needle” access prior to administration.

Intranasal Fentanyl. The EP should use a mucosal atomizer when administering midazolam or fentanyl via the IN route. The atomizer transforms these liquid drugs into a fine spray, which increases surface area, improving mucosal absorption and central nervous system concentrations when compared with IN administration via dropper.²¹

In a study by Klein et al,²² IN midazolam effectively provided sedation, with more effective diminution of activity and better overall patient satisfaction than with either oral or buccal midazolam. Intranasal midazolam causes a slight burning sensation, and some patients report initial discomfort after administration. The half-lives of IN and IV midazolam are very similar (2.2 vs 2.4 hours).²³Intranasal Fentanyl. IN fentanyl is an excellent alternative to IV pain medications for patients in whom there is no IV access. When given at a dose of 1.7 mcg/kg, IN fentanyl produces analgesic effects similar to that of morphine 0.1 mg/kg.

The only reported adverse effect associated with IN fentanyl has been a bad taste in the mouth.²⁴ Another study of children aged 1 to 3 years showed a significant decrease in pain in 93% of children at 10 minutes, and 98% of children at 30 minutes, with no significant side effects.²⁵

Intranasal fentanyl is a great choice for initial and immediate pain control in children with suspected long bone fractures, and is especially useful in facilitating their comfort during radiographic imaging.

Managing a Child for Radiographic Imaging

To facilitate a relatively rapid procedure such as obtaining plain films or a CT scan, anxiolysis, rather than analgesia, is required. Given its quick and predictable onset of action, IN midazolam is an excellent choice for pediatric patients requiring imaging studies. If, however, a mucosal atomizer is not available for IN drug delivery and the patient is already in radiology and requires emergent imaging studies, oral midazolam should not be given as an alternative because of its delayed onset of action. In such cases, placing an IV line and administering IV propofol offers the best chance of achieving quick and effective anxiolysis to obtain the images required to exclude clinically important injuries.

In hospitals that restrict the use of propofol in young children outside of the operating room—and when there are no findings suggestive of impending cerebral herniation—a safe and effective alternative is IV ketamine at a dose of 1.5 mg/kg.

Cases Continued

Case 1

[The 4-year-old boy with the fractured wrist.]

Recognizing that repeated attempts at IV placement in a child with a contralateral extremity fracture often leads to escalating distress and anxiety, the EP decided against further attempts to place an IV line. Instead, he gave the child fentanyl via the IN route, which immediately relieved the patient’s pain and facilitated radiographic evaluation. After administrating the fentanyl IN, the EP instructed a member of the ED staff to apply LMX4 cream to several potential IV sites and then cover each site with occlusive dressings. Afterward, the patient was taken to radiology, and X-ray images of the fracture were easily obtained. When the patient returned from imaging, the ED nurse was able to place an IV line at one of the sites that had been previously anesthetized with LMX4 cream.

The EP consulted with the orthopedist, who determined that the child’s distal radius fracture necessitated closed reduction. To facilitate the procedure, the patient was given 1.5 mg/kg of ketamine. After a successful closed reduction, the orthopedic chief resident recommended the EP discharge the 15-kg (33-lb) patient home in the care of his parents, with a prescription for 5 mL oral acetaminophen and codeine suspension four times a day as needed for pain (5 mL = acetaminophen 120 mg/codeine 12 mg, and codeine dosed at 0.5-1 mg/kg per dose). Prior to discharge, the EP counseled the patient’s parents on the risks of codeine hypermetabolism in children. However, based on the parents’ expressed concerns, the EP instead discharged the patient home with a prescription for 4 cc oral acetaminophen-hydrocodone elixir every 4 to 6 hours as needed for pain instead (dosing is 0.27 mL/kg; elixir is hydrocodone bitartrate 7.5 mg/acetaminophen 325 mg/15 mL).

Case 2

[The 6-year-old girl with a large laceration to her forehead.]

The type of laceration sustained by this patient was appropriate for treatment with a local anesthetic combined with an agent for non-IV anxiolysis. Thirty minutes prior to suturing, LET gel was applied over the open wound site, and 5 minutes prior to initiating closure of the wound, the patient received IN midazolam. Since the LET cream was placed on the wound 30 minutes prior to the procedure, the site was well anesthetized for both irrigation and closure. The anxiolytic effects of the IN midazolam resulted in a calm patient, who was happy and playful throughout the procedure.

After successfully closing the wound, the physician discharged the patient home in the care of her parents, with instructions to apply bacitracin ointment to the wound site three times a day for the next 3 days, and give the patient over-the-counter acetaminophen elixir for any mild discomfort.

Case 3

[The 5-year-old boy who suffered cervical spine injuries after falling head-first off of a balance beam during gymnastics.]

Since no mucosal atomizer was available for IN drug delivery, and hospital policy restricted the use of propofol in young children outside of the operating room, the patient was given 1.5 mg/kg of IV ketamine. Within 45 seconds of ketamine administration, the child had adequate dissociative sedation, which allowed for high-quality CT scans of both the head and neck without incident. 

Case 4

[The febrile 3-week-old female neonate referred by her pediatrician for evaluation and LP.]

Since this neonate did not appear toxic, the EP delayed the LP by 30 minutes to allow time for application of a topical anesthetic to minimize associated procedural pain. Thirty minutes prior to the LP, LMX4 cream was applied to the patient’s L4 spinal interspace, and just prior to the procedure, the patient was given a pacifier that had been dipped in a solution of 4% sucrose. The neonate was then positioned appropriately for the LP and barely squirmed when the spinal needle was introduced, allowing the EP to obtain a nontraumatic cerebrospinal fluid sample on the first attempt.

Conclusion

Addressing pediatric pain and anxiety, especially preceding and during procedures and radiographic imaging, is a serious challenge in the ED. Several means are now available to provide safe and effective sedation, analgesia, and anxiolysis in the ED, with or without IV access. Many of the medications utilized, however, can cause significant respiratory and CV depression, making proper patient selection and monitoring, and training of involved personnel imperative to ensure safe use in the ED. Appropriate use of the agents and strategies discussed above will allow EPs to reduce both procedural pain and anxiety for our youngest patients—and their parents.

For many years, pediatric patients undergoing procedures in the ED have received inadequate pain management and sedation. Children’s (and parents’) anxieties and distress leading up to and during a potentially painful or anxiety-inducing procedure are now more easily mitigated by the appropriate use of a variety of pediatric-appropriate analgesics, sedatives, and anxiolytics. The ability to provide adequate, minimally invasive sedation and analgesia is critically important to performing successful procedures in children, and is a hallmark of excellent pediatric emergency care.

The following case vignettes, based on actual cases, illustrate the range and routes of medications available to provide appropriate analgesia, sedation, and anxiolysis.

Cases

Case 1

A 4-year-old boy presented to the ED for evaluation of a fractured wrist sustained after he fell off his bed during a temper tantrum. At presentation, the patient’s vital signs were: blood pressure (BP), 110/70 mm Hg; heart rate (HR), 100 beats/min; respiratory rate (RR), 28 breaths/min; and temperature (T), 99.5°F. Oxygen saturation on room air was within normal limits. The patient’s weight was within normal range for his age and height at 15 kg (33 lb).

Upon examination, the child appeared agitated and in significant distress; his anxiety increased after an initial attempt at placing an intravenous (IV) line in his uninjured arm failed.

The emergency physician (EP) considered several options to ameliorate the child’s anxiety and facilitate evaluation and treatment.

Case 2

After accidentally running into a pole, a 6-year-old girl presented to the ED for evaluation and suturing of a large laceration to her forehead. At presentation, the patient’s vital signs were: BP, 115/70 mm Hg; HR, 95 beats/min; RR, 24 breaths/min; and T, 98.6°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 20 kg (44 lb).

On examination, the patient was awake, alert, and in no acute distress. However, she immediately became tearful and visibly upset when she learned that an IV line was about to be placed in her arm.

The physician instead decided to employ an IV/needle-free strategy for this wound repair, as well as anxiolysis.

Case 3

A 5-year-old girl was brought to a community hospital ED by emergency medical services after falling from a balance beam and landing headfirst on the ground during a gymnastics class. Prior to presentation, emergency medical technicians had placed the patient in a cervical collar. At presentation, the patient’s vital signs were: BP, 105/75 mm Hg; HR, 115 beats/min; RR, 28 breaths/min; and T, 99.1°F. Oxygen saturation on room air was within normal limits. The patient’s body weight was normal for her age and height at 18 kg (39.6 lb).

Although the neurological examination was normal, the patient had persistent midline cervical tenderness as well as hemotympanum. The EP ordered a head and neck computed tomography (CT) scan, but shortly after the patient arrived at radiology, the CT technician informed the EP that she was unable to perform the scan because the patient kept moving and would not stay still.

The EP considered several sedatives to facilitate the CT study.

Case 4

A febrile, but nontoxic-appearing 3-week-old girl was referred to the ED by her pediatrician for a lumbar puncture (LP) to diagnose or exclude meningitis. However, the mother’s own recent negative experience with an epidural analgesia during the patient’s delivery, made the neonate’s mother extremely anxious that the procedure might be too painful for her daughter.

The EP considered the best choice of medication to provide analgesia and allay the mother’s concerns prior to performing the LP in this neonatal patient.

Overview and Definitions

Analgesia describes the alleviation of pain without intentional sedation. However, pediatric patients typically receive sedative hypnotics (anxiolytics) both for analgesia and for anxiolysis to modify behavior (eg, enhance immobility) and to allow for the safe completion of a procedure.¹ The ultimate goal of procedural sedation and analgesia is to provide a depressed level of consciousness and pain relief while the patient maintains a patent airway and spontaneous ventilation.²

Sedation Continuum

The American Society of Anesthesiologists (ASA) classifies procedural sedation and analgesia based on a sedation continuum that affects overall responsiveness, airway, ventilation, and cardiovascular (CV) function.³ Procedural sedation is subcategorized into minimal, moderate, and deep sedation.

Minimal Sedation. Formally referred to as anxiolysis, minimal sedation is a state in which the patient is responsive but somewhat cognitively impaired, while maintaining all other functions rated in the sedation continuum.

Moderate Sedation. Previously referred to as “conscious sedation,” moderate sedation is a state of drug-induced depression of consciousness that still enables the patient to maintain purposeful responses to age-appropriate verbal commands and tactile stimulation, spontaneous ventilation, and CV integrity.

Deep Sedation. Deep sedation causes a drug-induced depression of consciousness that may potentially impair spontaneous ventilation and independent airway patency, while maintaining CV function. A deeply sedated patient is usually arousable with repeated painful stimulation.

Dissociative Sedation. This level of sedation induces a unique, trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability. The dissociative state can facilitate the performance of moderate-to-severe painful procedures, as well as procedures requiring immobilization in uncooperative patients.⁴

Contraindications to Procedural Sedation

Though there are no absolute contraindications to procedural sedation in children, its use is generally determined based on ASA’s patient physical status classification system. In this grading system, procedural sedation is appropriate for pediatric patients with a physical status of Class I (normally healthy patient) or Class II (a patient with mild systemic disease—eg, mild asthma).⁵ The EP should consult with a pediatric anesthesiologist prior to sedating a patient with an ASA status of Class II or higher, or a patient with a known laryngotracheal pathology.¹

Pre- and Postsedation Considerations

History and Physical Examination

Prior to patient sedation, the EP should perform a focused history, including a determination of the patient’s last meal and/or drink, and a physical examination. The history should also include known allergies and past or current medication use—specifically any history of adverse events associated with prior sedation. Pregnancy status should be determined in every postpubertal female patient.

The physical examination should focus on the cardiac and respiratory systems, with particular attention to any airway abnormalities or possible sources of obstruction.^1,3

Fasting

A need for fasting prior to procedural sedation remains controversial: Current ASA guidelines for fasting call for fasting times of 2 hours for clear liquids, 4 hours after breastfeeding, 6 hours for nonhuman milk or formula feeding, and 8 hours for solids.⁶

Fasting prior to general anesthesia has become a common requirement because of the risk of adverse respiratory events, including apnea, stridor, bronchospasm, emesis, and pulmonary aspiration of gastric contents. However, these events rarely occur during pediatric procedural sedation in the ED, and it is important to note that the American College of Emergency Physicians’ standards do not require delaying procedural sedation based on fasting times. There is no strong evidence that the duration of preprocedural sedation-fasting reduces or prevents emesis or aspiration.⁷

Equipment

In 2016, the American Academy of Pediatrics (AAP) updated its “Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures,”¹ including the essential equipment required for the safe administration of sedation, which can be remembered using the following “SOAPME” mnemonic:

Size: appropriate suction catheters and a functioning suction apparatus (eg, Yankauer-type suction);

Oxygen: An adequate oxygen supply and functioning flow meters or other devices to allow its delivery;

Airway: Size-appropriate equipment (eg, bag-valve-mask or equivalent device [functioning]), nasopharyngeal and oropharyngeal airways, laryngeal mask airway, laryngoscope blades (checked and functioning), endotracheal tubes, stylets, face mask;

Pharmacy: All the basic drugs needed to support life during an emergency, including antagonists as indicated;

Monitors: Functioning pulse oximeter with size-appropriate oximeter probes, end-tidal carbon dioxide monitor, and other monitors as appropriate for the procedure (eg, noninvasive blood pressure, electrocardiogram, stethoscope); and

Equipment: Special equipment or drugs for a particular case (eg, defibrillator).¹

Personnel

The 2016 AAP guidelines¹ also indicate the number and type of personnel needed for sedation—in addition to the physician performing the procedure—which is primarily determined by the intended level of sedation as follows:

Minimal Sedation. Though there are no set guidelines for minimal sedation, all providers must be capable of caring for a child who progresses to moderate sedation.

Moderate Sedation. Intentional moderate sedation necessitates two practitioners: one practitioner to oversee the sedation and monitor the patient’s vital signs, who is capable of rescuing the patient from deep sedation if it occurs; and a second provider proficient at least in basic life support to monitor vital signs and assist in a resuscitation as needed.

Deep Sedation. For patients requiring deep sedation, the practitioner administering or supervising sedative drug administration should have no other responsibilities other than observing the patient. Moreover, there must be at least one other individual present who is certified in advanced life support and airway management.¹

Discharge Criteria

Prior to discharge, pediatric patients must meet predetermined criteria that include easy arousability, a return to baseline mental status, stable age-appropriate vital signs, and the ability to remain hydrated.^1,3 In addition, while late postsedation complications are rare, caregivers should be provided with specific symptoms that would warrant immediate return to the ED.

Available Options for Analgesia and Sedation

Several different methods of providing analgesia and pediatric procedural sedation are available, ranging from nonpharmacological methods to topical and parenteral medication administration.

Nonpharmacological Options: Child-Life Specialists

Child-life specialists can be particularly helpful with pediatric emergency patients. With a background in normal child development, child-life specialists utilize myriad distraction techniques and coping strategies to help patients within the stressful environment of an ED. Studies have shown that the presence of a child-life specialist may reduce the depth of sedation needed for certain procedures.¹

Sucrose

Several studies have identified the benefits of sucrose as a pain reliever in neonates. Available as a 12% to 25% solution, sucrose decreases noxious stimuli and is a useful analgesic for such common neonatal procedures as venipuncture, circumcision, heel sticks, Foley catheter insertion, and LP. Efficacy of sucrose for these procedures is greatest in newborns, and decreases gradually after 6 months of age. The effectiveness of sucrose is enhanced when it is given in conjunction with nonnutritive sucking or maternal “skin-to-skin” techniques. There are no contraindications to the use of sucrose.⁸

Nonopioid Systemic Analgesia

Nonopioid oral analgesics (NOAs), such as acetaminophen and the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, are appropriate for mild-to-moderate procedural pain. The NOAs can be given alone or in conjunction with an opioid to enhance the analgesic effect for patients with severe pain.

Acetaminophen. Acetaminophen, which also has antipyretic properties, can be administered orally, rectally, or IV. Since acetaminophen is not an NSAID and does not affect platelet function, it is a good choice for treating patients with gastrointestinal (GI) pain.

Adverse effects of acetaminophen, which is metabolized by the liver, include hepatotoxicity in toxic doses. The suggested oral dose for infants and children weighing less than 60 kg (132 lb) is 10 to 15 mg/kg per dose every 4 to 6 hours as needed, with a maximum dose of 75 mg/kg/d for infants and 100 mg/kg/d for children. Rectal dosing for infants and children weighing less than 60 kg (132 lb) is 10 to 20 mg/kg every 6 hours as needed, with a maximum daily dose of 75 mg/kg/d in infants, and 100 mg/kg/d in children.

Ibuprofen. Ibuprofen, an NSAID with both antipyretic and anti-inflammatory properties, acts as a prostaglandin inhibitor and is indicated for use in patients over 6 months of age. Since ibuprofen inhibits platelet function, it can cause GI bleeding with chronic use. The suggested pediatric dose for ibuprofen is 5 to 10 mg/kg per dose every 6 to 8 hours orally, with a maximum dose of 40 mg/kg/d.⁹

Local Anesthesia

Local anesthetics administered via the topical or subcutaneous (SC) route provide anesthesia by temporarily blocking peripheral or central nerve conduction at the sodium channel.

LET Gel. This topical anesthetic combination composed of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine (LET gel) is commonly used on patients prior to repair of a skin laceration. Its peak onset of action occurs in 30 minutes, with an anesthetic duration of 45 minutes. The epinephrine component of LET reduces blood flow to the anesthetized area, which increases duration of action but also creates a small risk of vasoconstriction in the areas supplied by end arteries, such as in the penis, nose, digits, and pinna.⁹

EMLA and LMX4. Topical lidocaine anesthetics are extremely useful in the ED because their application can help reduce the pain of minor procedures, when they are applied in adequate time prior to initiating the procedure to reach peak effect. Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) and liposomal 4% lidocaine (LMX4) are the most commonly used topical lidocaine anesthetics. The peak analgesic effect of EMLA occurs within 60 minutes, with a duration of 90 minutes; LMX4 reaches its analgesic peak after 30 minutes with duration of up to 60 minutes.

Because of the slight delay of the time-to-peak effect, these topical anesthetics are not useful for emergent procedures. Further, neither EMLA nor LMX4 is approved for nonintact skin injuries such as lacerations.⁹ Both LMX4 and EMLA are approved for use in intact skin, providing effective analgesia for procedures such as venipuncture, circumcision, LP, and abscess drainage.

Subcutaneous Lidocaine. When SC injection of lidocaine is preferred, a useful technique to reduce the pain of administration is to warm the lidocaine, alkalinize the solution with 1 mL (1 mEq) sodium bicarbonate to 9 mL lidocaine,⁶ prior to injecting it slowly with a small-gauge needle.⁸Vapocoolant Lidocaine. Vapocoolant sprays produce an immediate cold sensation that is effective in reducing localized pain in adults. Studies looking at its efficacy in children are not as convincing, with some studies suggesting the cold sensation is quite distressing for many children.⁸

Opioids

Opioids are commonly chosen for pediatric procedural sedation because of their short onset of action and ability to produce significant analgesia with varying amounts of sedation. Fentanyl and morphine are the most widely used opioid analgesics to manage moderate-to-severe procedural pain in children.

Morphine. Morphine remains the gold standard for pediatric opioid analgesia, partly because it can be administered SC, IV, intramuscularly (IM), and orally. Its properties are more quickly achieved via the IV route, as the onset of action is 4 to 6 minutes. The standard IV dose of morphine is 0.1 mg/kg per dose, and can provide analgesia for up to 4 hours.

Adverse effects of morphine include dependence (though not an issue with a single emergency dose), respiratory depression, nausea, vomiting, constipation, urinary retention, hypotension, and bradycardia. Naloxone can rapidly reverse these adverse effects.

Fentanyl. Fentanyl, which is 100 times more potent than morphine, can be administered IV, transdermally, or transmucosally. When given IV, the onset of action of fentanyl is 2 to 3 minutes, and duration of action of 30 to 60 minutes. For sedation and analgesia, the suggested IV dose of fentanyl in neonates and young infants is 1 to 4 mcg/kg every 2 to 4 hours as needed, and for older infants and children, 1 to 2 mcg/kg every 30 to 60 minutes as needed.

Adverse effects of fentanyl are respiratory depression and chest wall rigidity,⁹ which can be rapidly reversed with naloxone (the dose of naloxone by patient weight is the same as that given to reverse adverse effects of morphine and fentanyl).

Codeine. A weaker opioid analgesic, codeine is not recommended for routine pediatric use because of its significant potential to hypermetabolize to morphine in some children, leading to overdose.⁶

Benzodiazepines: Midazolam

Benzodiazepines, which act on the type A gamma-aminobutyric acid receptor, causing muscle relaxation, anxiolysis, and anterograde amnesia, are useful for pediatric procedural sedation. Due to its short half-life, midazolam is the most common benzodiazepine used in pediatric patients. Midazolam can be delivered via different routes of administration, including orally, IM, IV, and transmucosally.

Intramuscular Route. Intramuscular midazolam has been shown to cause deep sedation at doses of 0.3 mg/kg, with maximum sedation occurring at 45 minutes, recovery beginning by 60 minutes, and the most common side effect being euphoria.¹⁰

Intravenous Route. Intravenous midazolam is used extensively in pediatric procedural sedation and is usually given at a dose of 0.05 to 0.1 mg/kg, with a maximum dose of 2 mg.

Even among small children, midazolam is usually quite safe when given alone, but because it does not provide effective analgesia, it often requires combination with an opioid for effective procedural sedation. Flumazenil may be given for rapid reversal of known benzodiazepine-induced respiratory depression, but it should be avoided in children with seizure disorders.

Propofol

Propofol is now frequently employed for pediatric sedation outside of the operating room. Propofol has excellent sedation properties but, like midazolam, does not provide analgesia and necessitates a second agent such as ketamine or an opioid for successful completion of more painful procedures. However, for children in whom sedation is required to facilitate simple neuroimaging of the head or spine, propofol is a very useful agent given the child’s quick return to his/her baseline mental status following the procedure.

Regarding contraindications, since propofol contains egg lecithin and soybean oil, it was once considered inappropriate for use in patients with an egg or soy allergy. Recent data, however, have refuted this belief, and while the package insert for propofol still lists patient allergy to egg, egg products, soy, or soybeans as a contraindication to use,¹¹ the American Academy of Allergy, Asthma and Immunology recently concluded that patients with soy allergy or egg allergy can receive propofol without any special precautions.¹²

Since propofol is a powerful sedative and can cause a greater depth of sedation than that intended, providers must be comfortable with both monitoring and managing the pediatric airway. The induction dose of propofol is 1 mg/kg with repeated doses of 0.5 mg/kg to achieve the desired level of sedation. One emergency medicine-specific study by Jasiak et al¹³ found a mean cumulative propofol dose of 2.1 mg/kg for pediatric procedures given in a median of three boluses, with younger children requiring an overall higher mg/kg induction dose. Another study by Young et al¹⁴ showed an induction dose of 2 mg/kg to be well tolerated and without increased adverse events for pediatric procedural sedation.

When used properly, propofol has been shown to be safe and effective in pediatric patients. A recent review by Mallory et al¹⁵ looking at 25,433 cases of EP administration of propofol to pediatric patients noted serious complications in only 2% of patients, including one unplanned intubation, one cardiac arrest, and two aspirations.

Ketamine

Dissociative procedural sedation is frequently utilized in pediatric patients, for which ketamine is usually the agent of choice given its fast onset of action, multiple modes of administration, and robust pediatric safety data. Ketamine is a unique agent because of its sedative, analgesic, and paralytic-like properties. A phencyclidine derivative, ketamine exerts its effect by binding to the N-methyl-D-aspartate receptor, and may be given IM or IV, with usual dosing of 1 to 1.5 mg/kg IV, or 2 to 4 mg/kg IM. Unlike other sedatives, there is a “dissociation threshold” for ketamine, and further dosing does not increase its effects.¹⁶

Because of multiple observations and reported cases of airway complications in infants younger than 3 months of age, it is not recommended for routine use in this age group. While ketamine-associated infant airway events are thought by some experts to not be specific to ketamine (and more representative of infant differences in airway anatomy and laryngeal excitability), risks seem to outweigh benefits for routine use in this cohort.¹⁶

Ketamine is known to exaggerate protective airway reflexes and can cause laryngospasm, so it is best avoided during procedures that cause a large amount of pharyngeal stimulation. The overall rate of ketamine-induced pediatric laryngospasm is low in the general population (0.3%), and when it does occur, can usually be treated easily with assisted ventilation and oxygenation.¹⁷

Prior concerns of ketamine increasing intracranial pressure (ICP) have been shown not to be the case by recent data, which in fact demonstrate that ketamine may instead actually lower ICP.¹⁸

For many pediatric centers, including the authors’, ketamine is a first-line agent to facilitate head and/or neck CT in otherwise uncooperative children. Emesis is the most common side effect of ketamine, but the incidence can be significantly reduced by pretreating the patient with ondansetron.¹⁹ Though ketamine may also be combined with propofol, there is no robust pediatric-specific evidence showing any benefits of this practice.

Nitrous Oxide

Nitrous oxide (N₂O), the most commonly used inhaled anesthetic agent used in the pediatric ED, provides analgesia, sedation, anterograde amnesia, and anxiolysis. It can be given in mixtures of 30% to 70% N₂O with oxygen, has a rapid onset of action (<1 minute), and there is rapid recovery after cessation. In patients older than 5 years of age, N₂O is usually given via a demand valve system, which will fall off the patient’s face if he or she becomes overly sedated.

Nitrous oxide is usually very well tolerated with few serious events, the most common being emesis.²⁰ Absolute contraindications to its use are few and include pneumothorax, pulmonary blebs, bowel obstruction, air embolus, and a recent history of intracranial or middle ear surgery.

Intranasal Analgesia

Intranasal (IN) analgesics are becoming increasingly popular for pediatric procedures because of their rapid onset of action compared with oral medications, without the need for IV or “needle” access prior to administration.

Intranasal Fentanyl. The EP should use a mucosal atomizer when administering midazolam or fentanyl via the IN route. The atomizer transforms these liquid drugs into a fine spray, which increases surface area, improving mucosal absorption and central nervous system concentrations when compared with IN administration via dropper.²¹

In a study by Klein et al,²² IN midazolam effectively provided sedation, with more effective diminution of activity and better overall patient satisfaction than with either oral or buccal midazolam. Intranasal midazolam causes a slight burning sensation, and some patients report initial discomfort after administration. The half-lives of IN and IV midazolam are very similar (2.2 vs 2.4 hours).²³Intranasal Fentanyl. IN fentanyl is an excellent alternative to IV pain medications for patients in whom there is no IV access. When given at a dose of 1.7 mcg/kg, IN fentanyl produces analgesic effects similar to that of morphine 0.1 mg/kg.

The only reported adverse effect associated with IN fentanyl has been a bad taste in the mouth.²⁴ Another study of children aged 1 to 3 years showed a significant decrease in pain in 93% of children at 10 minutes, and 98% of children at 30 minutes, with no significant side effects.²⁵

Intranasal fentanyl is a great choice for initial and immediate pain control in children with suspected long bone fractures, and is especially useful in facilitating their comfort during radiographic imaging.

Managing a Child for Radiographic Imaging

To facilitate a relatively rapid procedure such as obtaining plain films or a CT scan, anxiolysis, rather than analgesia, is required. Given its quick and predictable onset of action, IN midazolam is an excellent choice for pediatric patients requiring imaging studies. If, however, a mucosal atomizer is not available for IN drug delivery and the patient is already in radiology and requires emergent imaging studies, oral midazolam should not be given as an alternative because of its delayed onset of action. In such cases, placing an IV line and administering IV propofol offers the best chance of achieving quick and effective anxiolysis to obtain the images required to exclude clinically important injuries.

In hospitals that restrict the use of propofol in young children outside of the operating room—and when there are no findings suggestive of impending cerebral herniation—a safe and effective alternative is IV ketamine at a dose of 1.5 mg/kg.

Cases Continued

Case 1

[The 4-year-old boy with the fractured wrist.]

Recognizing that repeated attempts at IV placement in a child with a contralateral extremity fracture often leads to escalating distress and anxiety, the EP decided against further attempts to place an IV line. Instead, he gave the child fentanyl via the IN route, which immediately relieved the patient’s pain and facilitated radiographic evaluation. After administrating the fentanyl IN, the EP instructed a member of the ED staff to apply LMX4 cream to several potential IV sites and then cover each site with occlusive dressings. Afterward, the patient was taken to radiology, and X-ray images of the fracture were easily obtained. When the patient returned from imaging, the ED nurse was able to place an IV line at one of the sites that had been previously anesthetized with LMX4 cream.

The EP consulted with the orthopedist, who determined that the child’s distal radius fracture necessitated closed reduction. To facilitate the procedure, the patient was given 1.5 mg/kg of ketamine. After a successful closed reduction, the orthopedic chief resident recommended the EP discharge the 15-kg (33-lb) patient home in the care of his parents, with a prescription for 5 mL oral acetaminophen and codeine suspension four times a day as needed for pain (5 mL = acetaminophen 120 mg/codeine 12 mg, and codeine dosed at 0.5-1 mg/kg per dose). Prior to discharge, the EP counseled the patient’s parents on the risks of codeine hypermetabolism in children. However, based on the parents’ expressed concerns, the EP instead discharged the patient home with a prescription for 4 cc oral acetaminophen-hydrocodone elixir every 4 to 6 hours as needed for pain instead (dosing is 0.27 mL/kg; elixir is hydrocodone bitartrate 7.5 mg/acetaminophen 325 mg/15 mL).

Case 2

[The 6-year-old girl with a large laceration to her forehead.]

The type of laceration sustained by this patient was appropriate for treatment with a local anesthetic combined with an agent for non-IV anxiolysis. Thirty minutes prior to suturing, LET gel was applied over the open wound site, and 5 minutes prior to initiating closure of the wound, the patient received IN midazolam. Since the LET cream was placed on the wound 30 minutes prior to the procedure, the site was well anesthetized for both irrigation and closure. The anxiolytic effects of the IN midazolam resulted in a calm patient, who was happy and playful throughout the procedure.

After successfully closing the wound, the physician discharged the patient home in the care of her parents, with instructions to apply bacitracin ointment to the wound site three times a day for the next 3 days, and give the patient over-the-counter acetaminophen elixir for any mild discomfort.

Case 3

[The 5-year-old boy who suffered cervical spine injuries after falling head-first off of a balance beam during gymnastics.]

Since no mucosal atomizer was available for IN drug delivery, and hospital policy restricted the use of propofol in young children outside of the operating room, the patient was given 1.5 mg/kg of IV ketamine. Within 45 seconds of ketamine administration, the child had adequate dissociative sedation, which allowed for high-quality CT scans of both the head and neck without incident. 

Case 4

[The febrile 3-week-old female neonate referred by her pediatrician for evaluation and LP.]

Since this neonate did not appear toxic, the EP delayed the LP by 30 minutes to allow time for application of a topical anesthetic to minimize associated procedural pain. Thirty minutes prior to the LP, LMX4 cream was applied to the patient’s L4 spinal interspace, and just prior to the procedure, the patient was given a pacifier that had been dipped in a solution of 4% sucrose. The neonate was then positioned appropriately for the LP and barely squirmed when the spinal needle was introduced, allowing the EP to obtain a nontraumatic cerebrospinal fluid sample on the first attempt.

Conclusion

Addressing pediatric pain and anxiety, especially preceding and during procedures and radiographic imaging, is a serious challenge in the ED. Several means are now available to provide safe and effective sedation, analgesia, and anxiolysis in the ED, with or without IV access. Many of the medications utilized, however, can cause significant respiratory and CV depression, making proper patient selection and monitoring, and training of involved personnel imperative to ensure safe use in the ED. Appropriate use of the agents and strategies discussed above will allow EPs to reduce both procedural pain and anxiety for our youngest patients—and their parents.

Introduction

For decades, virtually all injury was treated with open operative surgery. Resuscitation was based on the belief that large-volume crystalloid infusion to raise blood pressure (BP) to normal was the optimal therapy. Advanced trauma life support teaching was that 2 L of crystalloid fluid should be the initial resuscitation for all trauma patients, and those who failed to respond should receive additional crystalloid fluid. Patients did not receive a blood transfusion until later in treatment, and fresh frozen plasma (FFP) and platelets were not given until 10 U of blood had been administered. Regardless of the fluid infused, the goal of initial resuscitation was to raise BP to a normal level. During the time I (TS) was chair of the emergency medicine department at the State University of New York’s Kings County Hospital, I remember administering liters of crystalloid fluid preoperatively, believing it was not safe to operate until the patient had been what we termed “adequately resuscitated.”

However, as early as 1918, Walter B. Cannon, MD, correctly observed that fluid therapy without hemostasis was not wise, and numerous animal studies since then also raised serious questions about this approach. This article points out the revolutionary changes in the thinking and practice of resuscitation that have occurred in the last 20 years. We now realize that raising BP to normal only perpetuates hemorrhage. Hypotension treated with additional volume resuscitation without surgical control of hemorrhage creates a cycle leading to dilution of clotting factors and red blood cells (RBCs), recurrent hypotension, and ultimately death.

The realization that early blood transfusion is probably the wisest course is a concept that has only been in clinical practice for less than 15 years. Major trauma centers now routinely keep type O negative blood in the ED refrigerators so that it is instantly available.

Our understanding of trauma coagulopathy also has changed dramatically. Once thought to be simply a consequence of hypotension and hypothermia, we now realize that coagulopathy following trauma is far more complicated and likely occurs in concert with the inflammatory response to serious injury. Regardless of its etiology, we have recognized that earlier administration of plasma and platelets following trauma prevents coagulopathy, and this approach is more beneficial than treating coagulopathy after it develops. There has been much debate about the optimal ratios of RBCs, plasma, and platelets, and the ideal ratio has yet to be determined. The idea that “one-size-fits-all” is almost certainly not the case: Different patients require different and more precise treatment strategies.

For years, we have relied on laboratory measurements of coagulation to guide transfusion therapy, but standard laboratory values often take over 30 minutes to obtain. In an extremely dynamic situation involving large-volume blood loss, this interval is too lax. A more personalized approach using rapidly available technology, such as thromboelastography (TEG), allows for real-time assessment of a multiplicity of coagulation dynamics and rapid correction of any abnormalities. Procoagulants such as factor 7A, prothrombin complex concentrate (PCC), and tranexamic acid (TXA) have a role. However, the data to support the use of these expensive agents is lacking. While they certainly can be life-saving, each of these components brings with it a risk of causing indiscriminate coagulation—even in areas of the body that are not injured. Moreover, their availability in nontrauma centers is either limited or not an option.

There is little question that our rapid advances in understanding resuscitation and transfusion practice has saved lives. Twenty years ago, intensive care units were populated by trauma patients who had received many liters of crystalloid fluid, and at least partly a consequence of the resuscitation experience, many had severe respiratory failure. Open abdomens were common and also a likely consequence of large-volume crystalloid use. While these problems have not entirely disappeared, they now occur much less frequently.

Standardizing trauma care has also helped enhance patient care a great deal. Most major trauma centers have a “massive transfusion” protocol which allows the blood bank to prepare coolers containing not only blood, but also plasma, platelets, and procoagulants. This practice obviates the need to order the components individually. Rapid access to technology such as TEG allows emergency physicians (EPs) and other trauma care professionals to precisely guide transfusion therapy, but this remains an area of intensely debated investigation. Hopefully, our understanding will continue to mature over the next few years.

Another area of trauma care that has rapidly evolved is the use of endovascular techniques for trauma hemostasis. The realization that we can obtain control of vascular injury without the need for a large open operation has revolutionized care. While endovascular techniques have been used for pelvic hemostasis since 1972, we now use it regularly in every body cavity. Splenic artery embolization was developed by our (TS) group in Brooklyn, New York in 1995, and its use has now expanded to other abdominal solid organ injuries.

Injuries to the thoracic aorta once required a thoracotomy, cardiopulmonary bypass, and open repair. Stent grafting is now the treatment of choice for these injuries, allowing for a minimally invasive solution, and permitting those with both aortic and many other injuries to receive care for all of these wounds much sooner than was possible in the past, when multiply injured patients were simply not considered candidates for early open repair.

Thoracotomy in the ED has been widely practiced for a variety of indications. While it is still the only available solution for injury to the heart and/or proximal pulmonary vasculature in a patient who is hemodynamically unstable and/or in extremis, other options now exist to obtain vascular inflow for patients bleeding in the abdomen or pelvis. The use of transfemoral balloons for aortic occlusion allows clinicians to temporize hemorrhage without a huge open operation, and resuscitative endovascular balloon occlusion of the aorta (REBOA), has only been available for the last several years. The exact indications, wisest strategy, length of time the balloon can be inflated, rate of complications, and who is the appropriate physician (eg, EP, intensivist, vascular surgeon) to insert it, all remain questions requiring resolution. Much more work is necessary to pursue the role that REBOA can have in the care of desperately injured trauma patients.

There has been a revolution in the care of severely injured patients. After 50 years of thinking that we knew the answers, we have come to realize that those answers were wrong. Newer resuscitation strategies, as well as new treatment strategies continue to evolve, allowing us to refine care of severely injured patients. Perhaps the one thing we have really learned is that we do not have all of the answers and that the discussion must continue if we are to do better at serving more trauma victims.

Damage Control Resuscitation

In the United States, trauma is the leading cause of death in patients younger than age 45 years and ranks as the fifth leading cause of death among all age groups. Hemorrhage remains the leading cause of preventable death in the trauma population,¹ and one of the most important recent changes in our care of the injured patient is the manner in which we manage hemorrhage. As noted earlier, there has been a paradigm shift away from large-volume crystalloid resuscitation and toward what has been termed “damage control resuscitation” (DCR).^2,3

The principles of the DCR strategy are aimed at preemptively treating the lethal triad of hypothermia, acidosis, and coagulopathy in conjunction with control of surgical bleeding using damage control surgery. The main principles of DCR include “permissive hypotension,” prevention of heat loss and/or active warming, minimizing the use of crystalloid infusions, and initiating resuscitation with blood products in a ratio that more closely resembles whole blood.²

Permissive Hypotension

Permissive hypotension, also referred to as hypotensive resuscitation, is not considered a goal or an endpoint, but rather a “bridge” to definitive surgical control of hemorrhage. The body’s initial response to injury involves vasoconstriction and early clot formation, a process facilitated by hypotension. The rationale for permissive hypotension is that attempting to drive the BP up to normal ranges may interfere with vasoconstriction, as well as physically disrupting this early clot, leading to increased bleeding and further hypotension.

This concept has been corroborated by many animal and human studies.³ In 1994, the landmark study by Bickell et al⁴ randomized patients with penetrating torso trauma and a systolic BP (SBP) of 90 mm Hg or lower to either immediate or delayed fluid resuscitation. Their study demonstrated that patients whose fluid resuscitation was delayed until they reached the operating room had improved outcomes. The study supported the long-time prehospital practice of the “scoop-and-run” strategy, especially in penetrating torso trauma.

In 2003, Sondeen et al⁵ used a swine model of aortic injury to find an inflection point for clot disruption and re-bleeding during volume resuscitation. They found the inflection point to be a mean arterial pressure (MAP) of 64 mm Hg and an SBP of 94 mm Hg, regardless of the size of the aortotomy. Using an animal model of hemorrhagic shock, Li et al⁶ demonstrated in 2011 that resuscitation to a MAP of 50 mm Hg was associated with a decreased amount of blood loss as well as with improved survival compared to patients who were resuscitated to a MAP of 80 mm Hg. However, they also showed that after a time period of more than 90 to 120 minutes, the lower MAP group had increased end organ damage and worse outcomes, emphasizing the importance of prompt surgical control of bleeding—regardless of preoperative resuscitation strategy.

Other studies, though, have not shown a clear benefit to permissive hypotension. A 2002 study by Dutton et al⁷ showed that titration of initial fluid to a lower SBP (70 mm Hg) did not affect mortality when compared to a target resuscitation MAP of more than 100 mm Hg. Further, in 2014, a plenary paper presented to the American Association for the Surgery of Trauma demonstrated that controlled resuscitation (CR) strategy was safe and feasible,⁸ but did not demonstrate a mortality benefit in the overall cohort, though patients with blunt trauma who received CR had improved survival at 24 hours.

The group at Ben Taub General Hospital in Houston, Texas recently performed a randomized controlled trial evaluating intraoperative hypotensive resuscitation strategies. Patients in hemorrhagic shock were randomized to either an intraoperative MAP goal of 50 mm Hg or 65 mm Hg.^9,10 Preliminary results suggested that targeting a lower MAP resulted in fewer blood product transfusions, less fluid administration, less coagulopathy, and lower mortality in the early postoperative period. Additionally, they demonstrated a nonsignificant trend toward improved 30-day mortality in the lower MAP group.⁹ Moreover, in this study there was no increased morbidity associated with the hypotensive strategy,¹⁰ suggesting that the approach was safe. Unfortunately, the trial was stopped early due to slow enrollment.

Despite the overall promising results with permissive hypotension, it is important to remember that it is contraindicated in patients with known or suspected traumatic brain injury, as hypotension has been shown to be detrimental in this population.¹¹

Hemostatic Resuscitation and Coagulopathy

Avoiding Aggressive Crystalloid Resuscitation. While the ideal MAP to target during DCR remains unclear, the potential harm caused by aggressive crystalloid resuscitation has become more evident. Infusing excessive amounts of crystalloid has been shown to be associated with increased ventilator days, multisystem organ failure, abdominal compartment syndrome, and surgical-site infections¹²—all of which have also been associated with systemic consequences of increased inflammation, including increased release of tumor necrosis factor-alpha and other proinflammatory cytokines.¹³

Rodent studies have demonstrated large-volume crystalloid administration and breakdown or “thinning” of the endothelial glycocalyx, which leads to increased capillary leak, third-spacing, and ultimately intravascular volume depletion.^14,15 This mechanism has been linked to pulmonary complications, namely acute lung injury and acute respiratory distress syndrome. Enteric edema resulting from aggressive crystalloid resuscitation has also been associated with prolonged postoperative ileus, increased risk of anastomotic leak,¹³ and inability to achieve primary fascial closure.¹⁶ All of the aforementioned complications are reduced when employing a restrictive fluid resuscitation strategy.¹⁷

Aggressive crystalloid administration in hemorrhagic shock also leads to dilutional coagulopathy. Multiple animal and human studies have shown an association between increased crystalloid volumes in hemorrhaging patients and increasing coagulopathy, blood loss, and mortality. In 2004, Barak et al¹⁸ demonstrated that administration of a high volume of crystalloid fluid (>3 L) or colloid (500 mL) was associated with postoperative coagulopathy; whereas in 2017, Harada et al,¹⁹ at Cedars-Sinai Medical Center in New York, demonstrated over a 10-year period that decreased high-volume (>2 L) crystalloid resuscitation paralleled a decrease in mortality.

Massive Transfusion Protocols. Many trauma centers have shifted away from high-volume crystalloid resuscitation in favor of massive transfusion protocols (MTPs) utilizing standardized ratios that more closely mimic whole blood. The MTPs center on the principle of equal transfusion ratios of blood product as opposed to packed RBCs (PRBCs) alone. This means effecting a plasma-rich resuscitation and preemptive correction of coagulopathy with FFP and platelets in addition to PRBCs.

Data from a US Army combat support hospital have demonstrated improved survival with an FFP to PRBC ratio of more than 1:1.4,²⁰ and civilian studies have produced similar findings.^21-23 All of these studies also noted improved mortality with higher (>1:2) platelet to PRBC ratios.^22,23 Although, the ideal ratio remains unknown, many MTPs aim for 1:1:1 ratio (6 U FFP to 6 packed platelets to 6 U PRBC), which most closely mimics whole blood.

The Pragmatic Randomized Optimal Platelet and Plasma Ratios trial was a recent large multicenter randomized trial that compared transfusion ratios of 1:1:1 and 1:1:2. The trial was unable to demonstrate a difference in mortality at either 24 hours or 30 days, though more patients in the 1:1:1 ratio group achieved hemostasis and fewer patients in this group died from exsanguination in the first 24 hours.²⁴Prehospital PRBC Administration. A number of studies have looked at prehospital administration of PRBCs.^25-27 Holcomb et al²⁵ showed no overall survival advantage at 24 hours, but did demonstrate a negligible blood-product wastage. In 2015 Brown et al²⁶ found an increase probability of 24-hour survival, decreased shock, and lower 24-hour PRBC requirements with pretrauma-center PRBC transfusion. That same year Brown et al²⁷ demonstrated that prehospital PRBC transfusion in severely injured blunt trauma patients was associated with decreased 24-hour and 30-day mortality rates, and a lower risk of coagulopathy. Currently, the Prehospital Air Medical Plasma trial is enrolling patients to evaluate the prehospital administration of plasma.²⁸ The primary endpoint of the study is 30-day mortality; the tentative completion date for the study is January 2018.

Tranexamic Acid. Another important development in the treatment of hemorrhagic shock in recent years has been the use of TXA, an antifibrinolytic agent which inhibits the conversion of plasminogen to plasmin. It has been shown to decrease mortality in both civilian and military trauma populations.^29,30

The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 trial was a large multicenter randomized trial, which showed a survival benefit among those who received TXA. The generalizability of the study has been questioned in the setting of modern urban trauma centers, as most of those enrolled in the study were from hospitals with no formal MTPs and a limited availability of blood products. Additionally, no laboratory measures of fibrinolysis were available.³⁰

Most experts currently recommend TXA use as part of an MTP if there is evidence of hyperfibrinolysis on TEG or in severe hemorrhagic shock when the time from injury has been less than 3 hours, as studies have shown increased mortality when TXA was administered longer than 3 hours after injury.³⁰

Viscoelastic Assays

An alternative approach to standardized ratio MTPs involves goal-directed hemostatic resuscitation using viscoelastic assays to guide transfusion of blood-product components. Both TEG and rotational thromboelastometry (ROTEM) are point-of-care tools for assessment of coagulation parameters of whole blood. Although they are not new technology, their use in trauma resuscitation is a relatively new concept.

While ROTEM is more commonly used in Europe, TEG is more popular and commonly used in the United States, though not exclusively.^31,32

Thromboelastography

The TEG parameters most commonly used clinically are reaction time (R-time), kinetics time, angle, maximum amplitude (MA), and lysis at 30 minutes (LY30).

Reaction Time. The R-time is measured in minutes and represents the time to clot initiation, reflecting activity of coagulation factors. It is used in TEG-guided MTPs to trigger transfusion of FFP.^31,32 The R-time is measured at the time the clot strength reaches an amplitude of 2 mm.³¹ The angle reflects the rate of rise of the amplitude of the TEG tracing, or the rate of increase in clot strength. Clinically, the angle represents fibrinogen concentration and function, and is used to trigger transfusion of cryoprecipitate or fibrinogen concentrate in MTPs.^31,32

Maximum Amplitude. The MA is reached by the TEG tracing, or the maximum clot strength achieved. Although the MA has been shown to correlate with platelet count, it actually represents platelet count and function as well as fibrinogen activity, all of which contribute to clot strength. Clinically, MA is used to trigger platelet transfusion and/or administration of desmopressin in MTPs.^31,32

Lysis at 30 Minutes. The LY30 is defined as the percent reduction in clot strength 30 minutes after reaching MA.^31,32 Normal LY30 values are between 0% and 7.5%; however, these values have been challenged in recent studies, which have reported that an LY30 greater than 3% (termed hyperfibrinolysis) confers a significant increase in mortality and an increased likelihood of requiring massive transfusion.^31,33 These findings have led to incorporation of this lower threshold as a trigger for administration of TXA during MTPs. Furthermore, an LY30 of less than 0.8% (described as fibrinolysis shutdown) has also been found to confer an increase in mortality,³⁴ which has led many to advocate for goal-directed administration of TXA, rather than empiric administration, as these patients are more likely to be harmed than helped by such an intervention.³¹

Rapid Thromboelastography

Rapid TEG employs tissue factor to accelerate clot initiation and reaction time, providing an additional parameter which reflects coagulation factor activity: the activated clotting time (ACT).³²

Activated Clotting Time. Historically used in cardiac surgery to measure anticoagulation during a cardiopulmonary bypass, ACT represents the same phase of coagulation as R-time, but is measured in seconds instead of minutes.³¹ The ACT has been found to correlate with prothrombin time/international normalized ratio (PT/INR), and accurately predicts the need for MTP.

Cotton et al³⁵ found that an ACT of more than 128 seconds predicted patients requiring MTP, and an ACT lower than 105 seconds predicted those who required no transfusions in the first 24 hours after injury.³⁵

The ACT can be used to trigger transfusion of FFP, but at certain thresholds, may also be used to trigger the early transfusion of cryoprecipitate and platelets.³⁶ Moore et al³⁶ found that an ACT over 140 seconds was able to predict an abnormal angle and MA. This had led to using this threshold as a trigger for early administration of cryoprecipitate and platelets, given this parameter is available within 5 minutes—long before the angle and MA have resulted.

Efficacy

The use of a TEG-guided strategy for MTP in trauma has shown great promise. In 2013, Tapia et al³⁷ compared a historical cohort who received 1:1:1 MTP to a TEG-guided MTP and demonstrated improved mortality.In 2016, Gonzalez et al³⁸ compared TEG-guided transfusion vs conventional coagulation tests (PT/INR, PTT, fibrinogen, platelets). The authors found a significant decrease in mortality and platelet and FFP transfusion when TEG-guided resuscitation is used.

Endovascular Techniques

The use of endovascular techniques in trauma continues to evolve. According to the National Trauma Data Bank, the use of endovascular therapies has increased from 1% of trauma cases in 2002 to 11% in 2008.³⁹

Thoracic Endovascular Aortic Repair

Thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury has essentially replaced open surgical repair. (See Figures 1a and 1b for an example of a blunt traumatic aortic injury prior to and post-TEVAR placement.)

Transarterial Catheter Embolization

Endovascular treatments have also been used successfully in the management of injuries to aortic branch vessels and extremity vessels.⁴² Transarterial catheter embolization with coils, plugs, or gel foam is being employed with increasing frequency to achieve hemostasis in the pelvis and spleen.⁴² It may also be used as an adjunct to laparotomy and perihepatic packing in high-grade liver injuries, though it is associated with significant morbidity related to hepatic necrosis, bile leaks, and abscesses.^43,44

Resuscitative Endovascular Balloon Occlusion of the Aorta

Most recently, REBOA has been used for noncompressible torso hemorrhage following trauma. This method involves percutaneous arterial cannulation of the common femoral artery and advancement of a balloon into the aorta, where it is then inflated at the desired level.

Once inflated, the balloon obstructs arterial inflow to the area of hemorrhage, curtailing blood loss, and increases proximal BP, improving coronary and cerebral perfusion. Multiple case reports and case series have described successful use of REBOA for hemorrhage control, including prehospital use by physicians in the United Kingdom. The largest series to date looked at 114 patients, of whom 46 had REBOA placement and 68 had open aortic occlusion through resuscitative thoracotomy.⁴⁵ Those treated with REBOA were significantly more likely to achieve hemodynamic stability (defined as SBP >90 mm Hg for >5 minutes). Furthermore, the authors noted minimal complications from REBOA and no difference in time to successful aortic occlusion, regardless of technique. There was also no difference in mortality between the two groups. Despite the small number of studies in trauma patients, REBOA has been established as a viable alternative to open aortic occlusion. The prospective Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry established by the American Association for the Surgery of Trauma is continuing to enroll patients and will hopefully answer many of the current uncertainties regarding the use of REBOA.

Conclusion

Strategies and techniques for the care of the injured patient have changed significantly in the past few years. Damage control resuscitation includes three elements: damage control surgery, permissive hypotension, and blood-product resuscitation.

The goals of lowering MAP in hemorrhagic shock appear to be safe and make sense physiologically, but have yet to show clear mortality benefit. Avoidance of excessive crystalloid resuscitation and trends toward more physiological ratios of blood product resuscitation have shown better outcomes. While the ideal ratio of blood products in transfusion remains unknown, the use of a massive transfusion strategy is preferable to crystalloid fluids. The use of viscoelastic assays (TEG and ROTEM) have allowed for goal-directed blood product resuscitation and may improve outcomes when compared with prescribed resuscitation ratios.

Finally, endovascular techniques in trauma have been increasingly utilized over the past 15 years, making nonoperative management with angiographic embolization for solid organ injury common practice now in most trauma centers worldwide. Temporary aortic balloon occlusion with REBOA appears promising in many cases of noncompressible truncal hemorrhage until definitive hemostasis can be achieved, but studies are needed to determine its ultimate place in the care of the trauma patient.

Introduction

For decades, virtually all injury was treated with open operative surgery. Resuscitation was based on the belief that large-volume crystalloid infusion to raise blood pressure (BP) to normal was the optimal therapy. Advanced trauma life support teaching was that 2 L of crystalloid fluid should be the initial resuscitation for all trauma patients, and those who failed to respond should receive additional crystalloid fluid. Patients did not receive a blood transfusion until later in treatment, and fresh frozen plasma (FFP) and platelets were not given until 10 U of blood had been administered. Regardless of the fluid infused, the goal of initial resuscitation was to raise BP to a normal level. During the time I (TS) was chair of the emergency medicine department at the State University of New York’s Kings County Hospital, I remember administering liters of crystalloid fluid preoperatively, believing it was not safe to operate until the patient had been what we termed “adequately resuscitated.”

However, as early as 1918, Walter B. Cannon, MD, correctly observed that fluid therapy without hemostasis was not wise, and numerous animal studies since then also raised serious questions about this approach. This article points out the revolutionary changes in the thinking and practice of resuscitation that have occurred in the last 20 years. We now realize that raising BP to normal only perpetuates hemorrhage. Hypotension treated with additional volume resuscitation without surgical control of hemorrhage creates a cycle leading to dilution of clotting factors and red blood cells (RBCs), recurrent hypotension, and ultimately death.

The realization that early blood transfusion is probably the wisest course is a concept that has only been in clinical practice for less than 15 years. Major trauma centers now routinely keep type O negative blood in the ED refrigerators so that it is instantly available.

Our understanding of trauma coagulopathy also has changed dramatically. Once thought to be simply a consequence of hypotension and hypothermia, we now realize that coagulopathy following trauma is far more complicated and likely occurs in concert with the inflammatory response to serious injury. Regardless of its etiology, we have recognized that earlier administration of plasma and platelets following trauma prevents coagulopathy, and this approach is more beneficial than treating coagulopathy after it develops. There has been much debate about the optimal ratios of RBCs, plasma, and platelets, and the ideal ratio has yet to be determined. The idea that “one-size-fits-all” is almost certainly not the case: Different patients require different and more precise treatment strategies.

For years, we have relied on laboratory measurements of coagulation to guide transfusion therapy, but standard laboratory values often take over 30 minutes to obtain. In an extremely dynamic situation involving large-volume blood loss, this interval is too lax. A more personalized approach using rapidly available technology, such as thromboelastography (TEG), allows for real-time assessment of a multiplicity of coagulation dynamics and rapid correction of any abnormalities. Procoagulants such as factor 7A, prothrombin complex concentrate (PCC), and tranexamic acid (TXA) have a role. However, the data to support the use of these expensive agents is lacking. While they certainly can be life-saving, each of these components brings with it a risk of causing indiscriminate coagulation—even in areas of the body that are not injured. Moreover, their availability in nontrauma centers is either limited or not an option.

There is little question that our rapid advances in understanding resuscitation and transfusion practice has saved lives. Twenty years ago, intensive care units were populated by trauma patients who had received many liters of crystalloid fluid, and at least partly a consequence of the resuscitation experience, many had severe respiratory failure. Open abdomens were common and also a likely consequence of large-volume crystalloid use. While these problems have not entirely disappeared, they now occur much less frequently.

Standardizing trauma care has also helped enhance patient care a great deal. Most major trauma centers have a “massive transfusion” protocol which allows the blood bank to prepare coolers containing not only blood, but also plasma, platelets, and procoagulants. This practice obviates the need to order the components individually. Rapid access to technology such as TEG allows emergency physicians (EPs) and other trauma care professionals to precisely guide transfusion therapy, but this remains an area of intensely debated investigation. Hopefully, our understanding will continue to mature over the next few years.

Another area of trauma care that has rapidly evolved is the use of endovascular techniques for trauma hemostasis. The realization that we can obtain control of vascular injury without the need for a large open operation has revolutionized care. While endovascular techniques have been used for pelvic hemostasis since 1972, we now use it regularly in every body cavity. Splenic artery embolization was developed by our (TS) group in Brooklyn, New York in 1995, and its use has now expanded to other abdominal solid organ injuries.

Injuries to the thoracic aorta once required a thoracotomy, cardiopulmonary bypass, and open repair. Stent grafting is now the treatment of choice for these injuries, allowing for a minimally invasive solution, and permitting those with both aortic and many other injuries to receive care for all of these wounds much sooner than was possible in the past, when multiply injured patients were simply not considered candidates for early open repair.

Thoracotomy in the ED has been widely practiced for a variety of indications. While it is still the only available solution for injury to the heart and/or proximal pulmonary vasculature in a patient who is hemodynamically unstable and/or in extremis, other options now exist to obtain vascular inflow for patients bleeding in the abdomen or pelvis. The use of transfemoral balloons for aortic occlusion allows clinicians to temporize hemorrhage without a huge open operation, and resuscitative endovascular balloon occlusion of the aorta (REBOA), has only been available for the last several years. The exact indications, wisest strategy, length of time the balloon can be inflated, rate of complications, and who is the appropriate physician (eg, EP, intensivist, vascular surgeon) to insert it, all remain questions requiring resolution. Much more work is necessary to pursue the role that REBOA can have in the care of desperately injured trauma patients.

There has been a revolution in the care of severely injured patients. After 50 years of thinking that we knew the answers, we have come to realize that those answers were wrong. Newer resuscitation strategies, as well as new treatment strategies continue to evolve, allowing us to refine care of severely injured patients. Perhaps the one thing we have really learned is that we do not have all of the answers and that the discussion must continue if we are to do better at serving more trauma victims.

Damage Control Resuscitation

In the United States, trauma is the leading cause of death in patients younger than age 45 years and ranks as the fifth leading cause of death among all age groups. Hemorrhage remains the leading cause of preventable death in the trauma population,¹ and one of the most important recent changes in our care of the injured patient is the manner in which we manage hemorrhage. As noted earlier, there has been a paradigm shift away from large-volume crystalloid resuscitation and toward what has been termed “damage control resuscitation” (DCR).^2,3

The principles of the DCR strategy are aimed at preemptively treating the lethal triad of hypothermia, acidosis, and coagulopathy in conjunction with control of surgical bleeding using damage control surgery. The main principles of DCR include “permissive hypotension,” prevention of heat loss and/or active warming, minimizing the use of crystalloid infusions, and initiating resuscitation with blood products in a ratio that more closely resembles whole blood.²

Permissive Hypotension

Permissive hypotension, also referred to as hypotensive resuscitation, is not considered a goal or an endpoint, but rather a “bridge” to definitive surgical control of hemorrhage. The body’s initial response to injury involves vasoconstriction and early clot formation, a process facilitated by hypotension. The rationale for permissive hypotension is that attempting to drive the BP up to normal ranges may interfere with vasoconstriction, as well as physically disrupting this early clot, leading to increased bleeding and further hypotension.

This concept has been corroborated by many animal and human studies.³ In 1994, the landmark study by Bickell et al⁴ randomized patients with penetrating torso trauma and a systolic BP (SBP) of 90 mm Hg or lower to either immediate or delayed fluid resuscitation. Their study demonstrated that patients whose fluid resuscitation was delayed until they reached the operating room had improved outcomes. The study supported the long-time prehospital practice of the “scoop-and-run” strategy, especially in penetrating torso trauma.

In 2003, Sondeen et al⁵ used a swine model of aortic injury to find an inflection point for clot disruption and re-bleeding during volume resuscitation. They found the inflection point to be a mean arterial pressure (MAP) of 64 mm Hg and an SBP of 94 mm Hg, regardless of the size of the aortotomy. Using an animal model of hemorrhagic shock, Li et al⁶ demonstrated in 2011 that resuscitation to a MAP of 50 mm Hg was associated with a decreased amount of blood loss as well as with improved survival compared to patients who were resuscitated to a MAP of 80 mm Hg. However, they also showed that after a time period of more than 90 to 120 minutes, the lower MAP group had increased end organ damage and worse outcomes, emphasizing the importance of prompt surgical control of bleeding—regardless of preoperative resuscitation strategy.

Other studies, though, have not shown a clear benefit to permissive hypotension. A 2002 study by Dutton et al⁷ showed that titration of initial fluid to a lower SBP (70 mm Hg) did not affect mortality when compared to a target resuscitation MAP of more than 100 mm Hg. Further, in 2014, a plenary paper presented to the American Association for the Surgery of Trauma demonstrated that controlled resuscitation (CR) strategy was safe and feasible,⁸ but did not demonstrate a mortality benefit in the overall cohort, though patients with blunt trauma who received CR had improved survival at 24 hours.

The group at Ben Taub General Hospital in Houston, Texas recently performed a randomized controlled trial evaluating intraoperative hypotensive resuscitation strategies. Patients in hemorrhagic shock were randomized to either an intraoperative MAP goal of 50 mm Hg or 65 mm Hg.^9,10 Preliminary results suggested that targeting a lower MAP resulted in fewer blood product transfusions, less fluid administration, less coagulopathy, and lower mortality in the early postoperative period. Additionally, they demonstrated a nonsignificant trend toward improved 30-day mortality in the lower MAP group.⁹ Moreover, in this study there was no increased morbidity associated with the hypotensive strategy,¹⁰ suggesting that the approach was safe. Unfortunately, the trial was stopped early due to slow enrollment.

Despite the overall promising results with permissive hypotension, it is important to remember that it is contraindicated in patients with known or suspected traumatic brain injury, as hypotension has been shown to be detrimental in this population.¹¹

Hemostatic Resuscitation and Coagulopathy

Avoiding Aggressive Crystalloid Resuscitation. While the ideal MAP to target during DCR remains unclear, the potential harm caused by aggressive crystalloid resuscitation has become more evident. Infusing excessive amounts of crystalloid has been shown to be associated with increased ventilator days, multisystem organ failure, abdominal compartment syndrome, and surgical-site infections¹²—all of which have also been associated with systemic consequences of increased inflammation, including increased release of tumor necrosis factor-alpha and other proinflammatory cytokines.¹³

Rodent studies have demonstrated large-volume crystalloid administration and breakdown or “thinning” of the endothelial glycocalyx, which leads to increased capillary leak, third-spacing, and ultimately intravascular volume depletion.^14,15 This mechanism has been linked to pulmonary complications, namely acute lung injury and acute respiratory distress syndrome. Enteric edema resulting from aggressive crystalloid resuscitation has also been associated with prolonged postoperative ileus, increased risk of anastomotic leak,¹³ and inability to achieve primary fascial closure.¹⁶ All of the aforementioned complications are reduced when employing a restrictive fluid resuscitation strategy.¹⁷

Aggressive crystalloid administration in hemorrhagic shock also leads to dilutional coagulopathy. Multiple animal and human studies have shown an association between increased crystalloid volumes in hemorrhaging patients and increasing coagulopathy, blood loss, and mortality. In 2004, Barak et al¹⁸ demonstrated that administration of a high volume of crystalloid fluid (>3 L) or colloid (500 mL) was associated with postoperative coagulopathy; whereas in 2017, Harada et al,¹⁹ at Cedars-Sinai Medical Center in New York, demonstrated over a 10-year period that decreased high-volume (>2 L) crystalloid resuscitation paralleled a decrease in mortality.

Massive Transfusion Protocols. Many trauma centers have shifted away from high-volume crystalloid resuscitation in favor of massive transfusion protocols (MTPs) utilizing standardized ratios that more closely mimic whole blood. The MTPs center on the principle of equal transfusion ratios of blood product as opposed to packed RBCs (PRBCs) alone. This means effecting a plasma-rich resuscitation and preemptive correction of coagulopathy with FFP and platelets in addition to PRBCs.

Data from a US Army combat support hospital have demonstrated improved survival with an FFP to PRBC ratio of more than 1:1.4,²⁰ and civilian studies have produced similar findings.^21-23 All of these studies also noted improved mortality with higher (>1:2) platelet to PRBC ratios.^22,23 Although, the ideal ratio remains unknown, many MTPs aim for 1:1:1 ratio (6 U FFP to 6 packed platelets to 6 U PRBC), which most closely mimics whole blood.

The Pragmatic Randomized Optimal Platelet and Plasma Ratios trial was a recent large multicenter randomized trial that compared transfusion ratios of 1:1:1 and 1:1:2. The trial was unable to demonstrate a difference in mortality at either 24 hours or 30 days, though more patients in the 1:1:1 ratio group achieved hemostasis and fewer patients in this group died from exsanguination in the first 24 hours.²⁴Prehospital PRBC Administration. A number of studies have looked at prehospital administration of PRBCs.^25-27 Holcomb et al²⁵ showed no overall survival advantage at 24 hours, but did demonstrate a negligible blood-product wastage. In 2015 Brown et al²⁶ found an increase probability of 24-hour survival, decreased shock, and lower 24-hour PRBC requirements with pretrauma-center PRBC transfusion. That same year Brown et al²⁷ demonstrated that prehospital PRBC transfusion in severely injured blunt trauma patients was associated with decreased 24-hour and 30-day mortality rates, and a lower risk of coagulopathy. Currently, the Prehospital Air Medical Plasma trial is enrolling patients to evaluate the prehospital administration of plasma.²⁸ The primary endpoint of the study is 30-day mortality; the tentative completion date for the study is January 2018.

Tranexamic Acid. Another important development in the treatment of hemorrhagic shock in recent years has been the use of TXA, an antifibrinolytic agent which inhibits the conversion of plasminogen to plasmin. It has been shown to decrease mortality in both civilian and military trauma populations.^29,30

The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 trial was a large multicenter randomized trial, which showed a survival benefit among those who received TXA. The generalizability of the study has been questioned in the setting of modern urban trauma centers, as most of those enrolled in the study were from hospitals with no formal MTPs and a limited availability of blood products. Additionally, no laboratory measures of fibrinolysis were available.³⁰

Most experts currently recommend TXA use as part of an MTP if there is evidence of hyperfibrinolysis on TEG or in severe hemorrhagic shock when the time from injury has been less than 3 hours, as studies have shown increased mortality when TXA was administered longer than 3 hours after injury.³⁰

Viscoelastic Assays

An alternative approach to standardized ratio MTPs involves goal-directed hemostatic resuscitation using viscoelastic assays to guide transfusion of blood-product components. Both TEG and rotational thromboelastometry (ROTEM) are point-of-care tools for assessment of coagulation parameters of whole blood. Although they are not new technology, their use in trauma resuscitation is a relatively new concept.

While ROTEM is more commonly used in Europe, TEG is more popular and commonly used in the United States, though not exclusively.^31,32

Thromboelastography

The TEG parameters most commonly used clinically are reaction time (R-time), kinetics time, angle, maximum amplitude (MA), and lysis at 30 minutes (LY30).

Reaction Time. The R-time is measured in minutes and represents the time to clot initiation, reflecting activity of coagulation factors. It is used in TEG-guided MTPs to trigger transfusion of FFP.^31,32 The R-time is measured at the time the clot strength reaches an amplitude of 2 mm.³¹ The angle reflects the rate of rise of the amplitude of the TEG tracing, or the rate of increase in clot strength. Clinically, the angle represents fibrinogen concentration and function, and is used to trigger transfusion of cryoprecipitate or fibrinogen concentrate in MTPs.^31,32

Maximum Amplitude. The MA is reached by the TEG tracing, or the maximum clot strength achieved. Although the MA has been shown to correlate with platelet count, it actually represents platelet count and function as well as fibrinogen activity, all of which contribute to clot strength. Clinically, MA is used to trigger platelet transfusion and/or administration of desmopressin in MTPs.^31,32

Lysis at 30 Minutes. The LY30 is defined as the percent reduction in clot strength 30 minutes after reaching MA.^31,32 Normal LY30 values are between 0% and 7.5%; however, these values have been challenged in recent studies, which have reported that an LY30 greater than 3% (termed hyperfibrinolysis) confers a significant increase in mortality and an increased likelihood of requiring massive transfusion.^31,33 These findings have led to incorporation of this lower threshold as a trigger for administration of TXA during MTPs. Furthermore, an LY30 of less than 0.8% (described as fibrinolysis shutdown) has also been found to confer an increase in mortality,³⁴ which has led many to advocate for goal-directed administration of TXA, rather than empiric administration, as these patients are more likely to be harmed than helped by such an intervention.³¹

Rapid Thromboelastography

Rapid TEG employs tissue factor to accelerate clot initiation and reaction time, providing an additional parameter which reflects coagulation factor activity: the activated clotting time (ACT).³²

Activated Clotting Time. Historically used in cardiac surgery to measure anticoagulation during a cardiopulmonary bypass, ACT represents the same phase of coagulation as R-time, but is measured in seconds instead of minutes.³¹ The ACT has been found to correlate with prothrombin time/international normalized ratio (PT/INR), and accurately predicts the need for MTP.

Cotton et al³⁵ found that an ACT of more than 128 seconds predicted patients requiring MTP, and an ACT lower than 105 seconds predicted those who required no transfusions in the first 24 hours after injury.³⁵

The ACT can be used to trigger transfusion of FFP, but at certain thresholds, may also be used to trigger the early transfusion of cryoprecipitate and platelets.³⁶ Moore et al³⁶ found that an ACT over 140 seconds was able to predict an abnormal angle and MA. This had led to using this threshold as a trigger for early administration of cryoprecipitate and platelets, given this parameter is available within 5 minutes—long before the angle and MA have resulted.

Efficacy

The use of a TEG-guided strategy for MTP in trauma has shown great promise. In 2013, Tapia et al³⁷ compared a historical cohort who received 1:1:1 MTP to a TEG-guided MTP and demonstrated improved mortality.In 2016, Gonzalez et al³⁸ compared TEG-guided transfusion vs conventional coagulation tests (PT/INR, PTT, fibrinogen, platelets). The authors found a significant decrease in mortality and platelet and FFP transfusion when TEG-guided resuscitation is used.

Endovascular Techniques

The use of endovascular techniques in trauma continues to evolve. According to the National Trauma Data Bank, the use of endovascular therapies has increased from 1% of trauma cases in 2002 to 11% in 2008.³⁹

Thoracic Endovascular Aortic Repair

Thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury has essentially replaced open surgical repair. (See Figures 1a and 1b for an example of a blunt traumatic aortic injury prior to and post-TEVAR placement.)

Transarterial Catheter Embolization

Endovascular treatments have also been used successfully in the management of injuries to aortic branch vessels and extremity vessels.⁴² Transarterial catheter embolization with coils, plugs, or gel foam is being employed with increasing frequency to achieve hemostasis in the pelvis and spleen.⁴² It may also be used as an adjunct to laparotomy and perihepatic packing in high-grade liver injuries, though it is associated with significant morbidity related to hepatic necrosis, bile leaks, and abscesses.^43,44

Resuscitative Endovascular Balloon Occlusion of the Aorta

Most recently, REBOA has been used for noncompressible torso hemorrhage following trauma. This method involves percutaneous arterial cannulation of the common femoral artery and advancement of a balloon into the aorta, where it is then inflated at the desired level.

Once inflated, the balloon obstructs arterial inflow to the area of hemorrhage, curtailing blood loss, and increases proximal BP, improving coronary and cerebral perfusion. Multiple case reports and case series have described successful use of REBOA for hemorrhage control, including prehospital use by physicians in the United Kingdom. The largest series to date looked at 114 patients, of whom 46 had REBOA placement and 68 had open aortic occlusion through resuscitative thoracotomy.⁴⁵ Those treated with REBOA were significantly more likely to achieve hemodynamic stability (defined as SBP >90 mm Hg for >5 minutes). Furthermore, the authors noted minimal complications from REBOA and no difference in time to successful aortic occlusion, regardless of technique. There was also no difference in mortality between the two groups. Despite the small number of studies in trauma patients, REBOA has been established as a viable alternative to open aortic occlusion. The prospective Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry established by the American Association for the Surgery of Trauma is continuing to enroll patients and will hopefully answer many of the current uncertainties regarding the use of REBOA.

Conclusion

Strategies and techniques for the care of the injured patient have changed significantly in the past few years. Damage control resuscitation includes three elements: damage control surgery, permissive hypotension, and blood-product resuscitation.

The goals of lowering MAP in hemorrhagic shock appear to be safe and make sense physiologically, but have yet to show clear mortality benefit. Avoidance of excessive crystalloid resuscitation and trends toward more physiological ratios of blood product resuscitation have shown better outcomes. While the ideal ratio of blood products in transfusion remains unknown, the use of a massive transfusion strategy is preferable to crystalloid fluids. The use of viscoelastic assays (TEG and ROTEM) have allowed for goal-directed blood product resuscitation and may improve outcomes when compared with prescribed resuscitation ratios.

Finally, endovascular techniques in trauma have been increasingly utilized over the past 15 years, making nonoperative management with angiographic embolization for solid organ injury common practice now in most trauma centers worldwide. Temporary aortic balloon occlusion with REBOA appears promising in many cases of noncompressible truncal hemorrhage until definitive hemostasis can be achieved, but studies are needed to determine its ultimate place in the care of the trauma patient.

Introduction

For decades, virtually all injury was treated with open operative surgery. Resuscitation was based on the belief that large-volume crystalloid infusion to raise blood pressure (BP) to normal was the optimal therapy. Advanced trauma life support teaching was that 2 L of crystalloid fluid should be the initial resuscitation for all trauma patients, and those who failed to respond should receive additional crystalloid fluid. Patients did not receive a blood transfusion until later in treatment, and fresh frozen plasma (FFP) and platelets were not given until 10 U of blood had been administered. Regardless of the fluid infused, the goal of initial resuscitation was to raise BP to a normal level. During the time I (TS) was chair of the emergency medicine department at the State University of New York’s Kings County Hospital, I remember administering liters of crystalloid fluid preoperatively, believing it was not safe to operate until the patient had been what we termed “adequately resuscitated.”

However, as early as 1918, Walter B. Cannon, MD, correctly observed that fluid therapy without hemostasis was not wise, and numerous animal studies since then also raised serious questions about this approach. This article points out the revolutionary changes in the thinking and practice of resuscitation that have occurred in the last 20 years. We now realize that raising BP to normal only perpetuates hemorrhage. Hypotension treated with additional volume resuscitation without surgical control of hemorrhage creates a cycle leading to dilution of clotting factors and red blood cells (RBCs), recurrent hypotension, and ultimately death.

The realization that early blood transfusion is probably the wisest course is a concept that has only been in clinical practice for less than 15 years. Major trauma centers now routinely keep type O negative blood in the ED refrigerators so that it is instantly available.

Our understanding of trauma coagulopathy also has changed dramatically. Once thought to be simply a consequence of hypotension and hypothermia, we now realize that coagulopathy following trauma is far more complicated and likely occurs in concert with the inflammatory response to serious injury. Regardless of its etiology, we have recognized that earlier administration of plasma and platelets following trauma prevents coagulopathy, and this approach is more beneficial than treating coagulopathy after it develops. There has been much debate about the optimal ratios of RBCs, plasma, and platelets, and the ideal ratio has yet to be determined. The idea that “one-size-fits-all” is almost certainly not the case: Different patients require different and more precise treatment strategies.

For years, we have relied on laboratory measurements of coagulation to guide transfusion therapy, but standard laboratory values often take over 30 minutes to obtain. In an extremely dynamic situation involving large-volume blood loss, this interval is too lax. A more personalized approach using rapidly available technology, such as thromboelastography (TEG), allows for real-time assessment of a multiplicity of coagulation dynamics and rapid correction of any abnormalities. Procoagulants such as factor 7A, prothrombin complex concentrate (PCC), and tranexamic acid (TXA) have a role. However, the data to support the use of these expensive agents is lacking. While they certainly can be life-saving, each of these components brings with it a risk of causing indiscriminate coagulation—even in areas of the body that are not injured. Moreover, their availability in nontrauma centers is either limited or not an option.

There is little question that our rapid advances in understanding resuscitation and transfusion practice has saved lives. Twenty years ago, intensive care units were populated by trauma patients who had received many liters of crystalloid fluid, and at least partly a consequence of the resuscitation experience, many had severe respiratory failure. Open abdomens were common and also a likely consequence of large-volume crystalloid use. While these problems have not entirely disappeared, they now occur much less frequently.

Standardizing trauma care has also helped enhance patient care a great deal. Most major trauma centers have a “massive transfusion” protocol which allows the blood bank to prepare coolers containing not only blood, but also plasma, platelets, and procoagulants. This practice obviates the need to order the components individually. Rapid access to technology such as TEG allows emergency physicians (EPs) and other trauma care professionals to precisely guide transfusion therapy, but this remains an area of intensely debated investigation. Hopefully, our understanding will continue to mature over the next few years.

Another area of trauma care that has rapidly evolved is the use of endovascular techniques for trauma hemostasis. The realization that we can obtain control of vascular injury without the need for a large open operation has revolutionized care. While endovascular techniques have been used for pelvic hemostasis since 1972, we now use it regularly in every body cavity. Splenic artery embolization was developed by our (TS) group in Brooklyn, New York in 1995, and its use has now expanded to other abdominal solid organ injuries.

Injuries to the thoracic aorta once required a thoracotomy, cardiopulmonary bypass, and open repair. Stent grafting is now the treatment of choice for these injuries, allowing for a minimally invasive solution, and permitting those with both aortic and many other injuries to receive care for all of these wounds much sooner than was possible in the past, when multiply injured patients were simply not considered candidates for early open repair.

Thoracotomy in the ED has been widely practiced for a variety of indications. While it is still the only available solution for injury to the heart and/or proximal pulmonary vasculature in a patient who is hemodynamically unstable and/or in extremis, other options now exist to obtain vascular inflow for patients bleeding in the abdomen or pelvis. The use of transfemoral balloons for aortic occlusion allows clinicians to temporize hemorrhage without a huge open operation, and resuscitative endovascular balloon occlusion of the aorta (REBOA), has only been available for the last several years. The exact indications, wisest strategy, length of time the balloon can be inflated, rate of complications, and who is the appropriate physician (eg, EP, intensivist, vascular surgeon) to insert it, all remain questions requiring resolution. Much more work is necessary to pursue the role that REBOA can have in the care of desperately injured trauma patients.

There has been a revolution in the care of severely injured patients. After 50 years of thinking that we knew the answers, we have come to realize that those answers were wrong. Newer resuscitation strategies, as well as new treatment strategies continue to evolve, allowing us to refine care of severely injured patients. Perhaps the one thing we have really learned is that we do not have all of the answers and that the discussion must continue if we are to do better at serving more trauma victims.

Damage Control Resuscitation

In the United States, trauma is the leading cause of death in patients younger than age 45 years and ranks as the fifth leading cause of death among all age groups. Hemorrhage remains the leading cause of preventable death in the trauma population,¹ and one of the most important recent changes in our care of the injured patient is the manner in which we manage hemorrhage. As noted earlier, there has been a paradigm shift away from large-volume crystalloid resuscitation and toward what has been termed “damage control resuscitation” (DCR).^2,3

The principles of the DCR strategy are aimed at preemptively treating the lethal triad of hypothermia, acidosis, and coagulopathy in conjunction with control of surgical bleeding using damage control surgery. The main principles of DCR include “permissive hypotension,” prevention of heat loss and/or active warming, minimizing the use of crystalloid infusions, and initiating resuscitation with blood products in a ratio that more closely resembles whole blood.²

Permissive Hypotension

Permissive hypotension, also referred to as hypotensive resuscitation, is not considered a goal or an endpoint, but rather a “bridge” to definitive surgical control of hemorrhage. The body’s initial response to injury involves vasoconstriction and early clot formation, a process facilitated by hypotension. The rationale for permissive hypotension is that attempting to drive the BP up to normal ranges may interfere with vasoconstriction, as well as physically disrupting this early clot, leading to increased bleeding and further hypotension.

This concept has been corroborated by many animal and human studies.³ In 1994, the landmark study by Bickell et al⁴ randomized patients with penetrating torso trauma and a systolic BP (SBP) of 90 mm Hg or lower to either immediate or delayed fluid resuscitation. Their study demonstrated that patients whose fluid resuscitation was delayed until they reached the operating room had improved outcomes. The study supported the long-time prehospital practice of the “scoop-and-run” strategy, especially in penetrating torso trauma.

In 2003, Sondeen et al⁵ used a swine model of aortic injury to find an inflection point for clot disruption and re-bleeding during volume resuscitation. They found the inflection point to be a mean arterial pressure (MAP) of 64 mm Hg and an SBP of 94 mm Hg, regardless of the size of the aortotomy. Using an animal model of hemorrhagic shock, Li et al⁶ demonstrated in 2011 that resuscitation to a MAP of 50 mm Hg was associated with a decreased amount of blood loss as well as with improved survival compared to patients who were resuscitated to a MAP of 80 mm Hg. However, they also showed that after a time period of more than 90 to 120 minutes, the lower MAP group had increased end organ damage and worse outcomes, emphasizing the importance of prompt surgical control of bleeding—regardless of preoperative resuscitation strategy.

Other studies, though, have not shown a clear benefit to permissive hypotension. A 2002 study by Dutton et al⁷ showed that titration of initial fluid to a lower SBP (70 mm Hg) did not affect mortality when compared to a target resuscitation MAP of more than 100 mm Hg. Further, in 2014, a plenary paper presented to the American Association for the Surgery of Trauma demonstrated that controlled resuscitation (CR) strategy was safe and feasible,⁸ but did not demonstrate a mortality benefit in the overall cohort, though patients with blunt trauma who received CR had improved survival at 24 hours.

The group at Ben Taub General Hospital in Houston, Texas recently performed a randomized controlled trial evaluating intraoperative hypotensive resuscitation strategies. Patients in hemorrhagic shock were randomized to either an intraoperative MAP goal of 50 mm Hg or 65 mm Hg.^9,10 Preliminary results suggested that targeting a lower MAP resulted in fewer blood product transfusions, less fluid administration, less coagulopathy, and lower mortality in the early postoperative period. Additionally, they demonstrated a nonsignificant trend toward improved 30-day mortality in the lower MAP group.⁹ Moreover, in this study there was no increased morbidity associated with the hypotensive strategy,¹⁰ suggesting that the approach was safe. Unfortunately, the trial was stopped early due to slow enrollment.

Despite the overall promising results with permissive hypotension, it is important to remember that it is contraindicated in patients with known or suspected traumatic brain injury, as hypotension has been shown to be detrimental in this population.¹¹

Hemostatic Resuscitation and Coagulopathy

Avoiding Aggressive Crystalloid Resuscitation. While the ideal MAP to target during DCR remains unclear, the potential harm caused by aggressive crystalloid resuscitation has become more evident. Infusing excessive amounts of crystalloid has been shown to be associated with increased ventilator days, multisystem organ failure, abdominal compartment syndrome, and surgical-site infections¹²—all of which have also been associated with systemic consequences of increased inflammation, including increased release of tumor necrosis factor-alpha and other proinflammatory cytokines.¹³

Rodent studies have demonstrated large-volume crystalloid administration and breakdown or “thinning” of the endothelial glycocalyx, which leads to increased capillary leak, third-spacing, and ultimately intravascular volume depletion.^14,15 This mechanism has been linked to pulmonary complications, namely acute lung injury and acute respiratory distress syndrome. Enteric edema resulting from aggressive crystalloid resuscitation has also been associated with prolonged postoperative ileus, increased risk of anastomotic leak,¹³ and inability to achieve primary fascial closure.¹⁶ All of the aforementioned complications are reduced when employing a restrictive fluid resuscitation strategy.¹⁷

Aggressive crystalloid administration in hemorrhagic shock also leads to dilutional coagulopathy. Multiple animal and human studies have shown an association between increased crystalloid volumes in hemorrhaging patients and increasing coagulopathy, blood loss, and mortality. In 2004, Barak et al¹⁸ demonstrated that administration of a high volume of crystalloid fluid (>3 L) or colloid (500 mL) was associated with postoperative coagulopathy; whereas in 2017, Harada et al,¹⁹ at Cedars-Sinai Medical Center in New York, demonstrated over a 10-year period that decreased high-volume (>2 L) crystalloid resuscitation paralleled a decrease in mortality.

Massive Transfusion Protocols. Many trauma centers have shifted away from high-volume crystalloid resuscitation in favor of massive transfusion protocols (MTPs) utilizing standardized ratios that more closely mimic whole blood. The MTPs center on the principle of equal transfusion ratios of blood product as opposed to packed RBCs (PRBCs) alone. This means effecting a plasma-rich resuscitation and preemptive correction of coagulopathy with FFP and platelets in addition to PRBCs.

Data from a US Army combat support hospital have demonstrated improved survival with an FFP to PRBC ratio of more than 1:1.4,²⁰ and civilian studies have produced similar findings.^21-23 All of these studies also noted improved mortality with higher (>1:2) platelet to PRBC ratios.^22,23 Although, the ideal ratio remains unknown, many MTPs aim for 1:1:1 ratio (6 U FFP to 6 packed platelets to 6 U PRBC), which most closely mimics whole blood.

The Pragmatic Randomized Optimal Platelet and Plasma Ratios trial was a recent large multicenter randomized trial that compared transfusion ratios of 1:1:1 and 1:1:2. The trial was unable to demonstrate a difference in mortality at either 24 hours or 30 days, though more patients in the 1:1:1 ratio group achieved hemostasis and fewer patients in this group died from exsanguination in the first 24 hours.²⁴Prehospital PRBC Administration. A number of studies have looked at prehospital administration of PRBCs.^25-27 Holcomb et al²⁵ showed no overall survival advantage at 24 hours, but did demonstrate a negligible blood-product wastage. In 2015 Brown et al²⁶ found an increase probability of 24-hour survival, decreased shock, and lower 24-hour PRBC requirements with pretrauma-center PRBC transfusion. That same year Brown et al²⁷ demonstrated that prehospital PRBC transfusion in severely injured blunt trauma patients was associated with decreased 24-hour and 30-day mortality rates, and a lower risk of coagulopathy. Currently, the Prehospital Air Medical Plasma trial is enrolling patients to evaluate the prehospital administration of plasma.²⁸ The primary endpoint of the study is 30-day mortality; the tentative completion date for the study is January 2018.

Tranexamic Acid. Another important development in the treatment of hemorrhagic shock in recent years has been the use of TXA, an antifibrinolytic agent which inhibits the conversion of plasminogen to plasmin. It has been shown to decrease mortality in both civilian and military trauma populations.^29,30

The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 trial was a large multicenter randomized trial, which showed a survival benefit among those who received TXA. The generalizability of the study has been questioned in the setting of modern urban trauma centers, as most of those enrolled in the study were from hospitals with no formal MTPs and a limited availability of blood products. Additionally, no laboratory measures of fibrinolysis were available.³⁰

Most experts currently recommend TXA use as part of an MTP if there is evidence of hyperfibrinolysis on TEG or in severe hemorrhagic shock when the time from injury has been less than 3 hours, as studies have shown increased mortality when TXA was administered longer than 3 hours after injury.³⁰

Viscoelastic Assays

An alternative approach to standardized ratio MTPs involves goal-directed hemostatic resuscitation using viscoelastic assays to guide transfusion of blood-product components. Both TEG and rotational thromboelastometry (ROTEM) are point-of-care tools for assessment of coagulation parameters of whole blood. Although they are not new technology, their use in trauma resuscitation is a relatively new concept.

While ROTEM is more commonly used in Europe, TEG is more popular and commonly used in the United States, though not exclusively.^31,32

Thromboelastography

The TEG parameters most commonly used clinically are reaction time (R-time), kinetics time, angle, maximum amplitude (MA), and lysis at 30 minutes (LY30).

Reaction Time. The R-time is measured in minutes and represents the time to clot initiation, reflecting activity of coagulation factors. It is used in TEG-guided MTPs to trigger transfusion of FFP.^31,32 The R-time is measured at the time the clot strength reaches an amplitude of 2 mm.³¹ The angle reflects the rate of rise of the amplitude of the TEG tracing, or the rate of increase in clot strength. Clinically, the angle represents fibrinogen concentration and function, and is used to trigger transfusion of cryoprecipitate or fibrinogen concentrate in MTPs.^31,32

Maximum Amplitude. The MA is reached by the TEG tracing, or the maximum clot strength achieved. Although the MA has been shown to correlate with platelet count, it actually represents platelet count and function as well as fibrinogen activity, all of which contribute to clot strength. Clinically, MA is used to trigger platelet transfusion and/or administration of desmopressin in MTPs.^31,32

Lysis at 30 Minutes. The LY30 is defined as the percent reduction in clot strength 30 minutes after reaching MA.^31,32 Normal LY30 values are between 0% and 7.5%; however, these values have been challenged in recent studies, which have reported that an LY30 greater than 3% (termed hyperfibrinolysis) confers a significant increase in mortality and an increased likelihood of requiring massive transfusion.^31,33 These findings have led to incorporation of this lower threshold as a trigger for administration of TXA during MTPs. Furthermore, an LY30 of less than 0.8% (described as fibrinolysis shutdown) has also been found to confer an increase in mortality,³⁴ which has led many to advocate for goal-directed administration of TXA, rather than empiric administration, as these patients are more likely to be harmed than helped by such an intervention.³¹

Rapid Thromboelastography

Rapid TEG employs tissue factor to accelerate clot initiation and reaction time, providing an additional parameter which reflects coagulation factor activity: the activated clotting time (ACT).³²

Activated Clotting Time. Historically used in cardiac surgery to measure anticoagulation during a cardiopulmonary bypass, ACT represents the same phase of coagulation as R-time, but is measured in seconds instead of minutes.³¹ The ACT has been found to correlate with prothrombin time/international normalized ratio (PT/INR), and accurately predicts the need for MTP.

Cotton et al³⁵ found that an ACT of more than 128 seconds predicted patients requiring MTP, and an ACT lower than 105 seconds predicted those who required no transfusions in the first 24 hours after injury.³⁵

The ACT can be used to trigger transfusion of FFP, but at certain thresholds, may also be used to trigger the early transfusion of cryoprecipitate and platelets.³⁶ Moore et al³⁶ found that an ACT over 140 seconds was able to predict an abnormal angle and MA. This had led to using this threshold as a trigger for early administration of cryoprecipitate and platelets, given this parameter is available within 5 minutes—long before the angle and MA have resulted.

Efficacy

The use of a TEG-guided strategy for MTP in trauma has shown great promise. In 2013, Tapia et al³⁷ compared a historical cohort who received 1:1:1 MTP to a TEG-guided MTP and demonstrated improved mortality.In 2016, Gonzalez et al³⁸ compared TEG-guided transfusion vs conventional coagulation tests (PT/INR, PTT, fibrinogen, platelets). The authors found a significant decrease in mortality and platelet and FFP transfusion when TEG-guided resuscitation is used.

Endovascular Techniques

The use of endovascular techniques in trauma continues to evolve. According to the National Trauma Data Bank, the use of endovascular therapies has increased from 1% of trauma cases in 2002 to 11% in 2008.³⁹

Thoracic Endovascular Aortic Repair

Thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury has essentially replaced open surgical repair. (See Figures 1a and 1b for an example of a blunt traumatic aortic injury prior to and post-TEVAR placement.)

Transarterial Catheter Embolization

Endovascular treatments have also been used successfully in the management of injuries to aortic branch vessels and extremity vessels.⁴² Transarterial catheter embolization with coils, plugs, or gel foam is being employed with increasing frequency to achieve hemostasis in the pelvis and spleen.⁴² It may also be used as an adjunct to laparotomy and perihepatic packing in high-grade liver injuries, though it is associated with significant morbidity related to hepatic necrosis, bile leaks, and abscesses.^43,44

Resuscitative Endovascular Balloon Occlusion of the Aorta

Most recently, REBOA has been used for noncompressible torso hemorrhage following trauma. This method involves percutaneous arterial cannulation of the common femoral artery and advancement of a balloon into the aorta, where it is then inflated at the desired level.

Once inflated, the balloon obstructs arterial inflow to the area of hemorrhage, curtailing blood loss, and increases proximal BP, improving coronary and cerebral perfusion. Multiple case reports and case series have described successful use of REBOA for hemorrhage control, including prehospital use by physicians in the United Kingdom. The largest series to date looked at 114 patients, of whom 46 had REBOA placement and 68 had open aortic occlusion through resuscitative thoracotomy.⁴⁵ Those treated with REBOA were significantly more likely to achieve hemodynamic stability (defined as SBP >90 mm Hg for >5 minutes). Furthermore, the authors noted minimal complications from REBOA and no difference in time to successful aortic occlusion, regardless of technique. There was also no difference in mortality between the two groups. Despite the small number of studies in trauma patients, REBOA has been established as a viable alternative to open aortic occlusion. The prospective Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry established by the American Association for the Surgery of Trauma is continuing to enroll patients and will hopefully answer many of the current uncertainties regarding the use of REBOA.

Conclusion

Strategies and techniques for the care of the injured patient have changed significantly in the past few years. Damage control resuscitation includes three elements: damage control surgery, permissive hypotension, and blood-product resuscitation.

The goals of lowering MAP in hemorrhagic shock appear to be safe and make sense physiologically, but have yet to show clear mortality benefit. Avoidance of excessive crystalloid resuscitation and trends toward more physiological ratios of blood product resuscitation have shown better outcomes. While the ideal ratio of blood products in transfusion remains unknown, the use of a massive transfusion strategy is preferable to crystalloid fluids. The use of viscoelastic assays (TEG and ROTEM) have allowed for goal-directed blood product resuscitation and may improve outcomes when compared with prescribed resuscitation ratios.

Finally, endovascular techniques in trauma have been increasingly utilized over the past 15 years, making nonoperative management with angiographic embolization for solid organ injury common practice now in most trauma centers worldwide. Temporary aortic balloon occlusion with REBOA appears promising in many cases of noncompressible truncal hemorrhage until definitive hemostasis can be achieved, but studies are needed to determine its ultimate place in the care of the trauma patient.

In the days before this issue of Emergency Medicine (EM) went to press, the United States Senate tried unsuccessfully, first to repeal and replace the Affordable Care Act (ACA), then to repeal key provisions of ACA without a replacement bill. Despite having a majority in both the Senate and House of Representatives as well as a Republican President, after 7 years of vowing to repeal “Obama Care,” Republicans have still not been able to fulfill that vow.

When ACA was signed into law in March 2010 (See “Springing Forward,” April 2010 EM), we wrote “though the new law will undoubtedly be challenged, tested, modified, refined, used—and probably abused—it will not be repealed. As was the case with Medicare and Medicaid previously, this will change everything in subtle and not-so-subtle ways.” (For a discussion of how the healthcare industry has managed to co-opt and abuse ACA, see the recently published book An American Sickness by Elisabeth Rosenthal, who was an emergency physician [EP] in our department before becoming a senior science and healthcare reporter for the New York Times.)

But the failure of ACA to deliver on many of its promises, its uncertain financial future, and the lack of improvements to ACA since 2010, directly or indirectly affects every American. Predictably, for those in need of care who cannot find a physician to accept their insurance or schedule a timely appointment, the ED remains the safety net for obtaining care.

After the constitutionality of ACA was upheld by the Supreme Court in June 2012 (See “Our National Pastime,” July 2012 EM), we noted that “ACA contains no provisions for increasing the number of healthcare providers [and] if 24 million more Americans now have access to affordable health insurance, but there are no new providers, who will they go to for care?” Seven years after passage of ACA, the answer to this question has been provided by published studies confirming that even more insured Americans are now seeking care in EDs than before “affordable care” became available. At the same time, urgent care centers, freestanding EDs, and “convenient care” centers, have sprung up and proliferated throughout the country, while in many states, nurse practitioners, physician assistants, and now emergency medical technicians and paramedics have sought and received authorization to evaluate and treat patients independent of physician supervision and oversight. Telemedicine or “telehealth” is the latest attempt to stretch the available supply of physicians to manage patients remotely, in the hope of obviating the need for an ED visit. 

But none of these measures completely addresses a basic weakness of ACA: There are not enough physicians, including EPs, in this country to care for everyone entitled to healthcare; at the same time, there is a generation of highly qualified, highly motivated young men and women seeking entrance to medical school who will never get the opportunity to become fine physicians because there are not enough places for them. The solution to these problems seems obvious and the funds needed to finance it would be well spent, though the benefits of increasing the number of medical school places would not be realized for 4 to 8 years after they are made available.

In the meantime, we leave you with the solution President George W. Bush offered to a Cleveland audience on July 10, 2007 (See “Dream On,” March 2008 EM): “people have access to healthcare in America. After all, you just go to an emergency room.” 

In the days before this issue of Emergency Medicine (EM) went to press, the United States Senate tried unsuccessfully, first to repeal and replace the Affordable Care Act (ACA), then to repeal key provisions of ACA without a replacement bill. Despite having a majority in both the Senate and House of Representatives as well as a Republican President, after 7 years of vowing to repeal “Obama Care,” Republicans have still not been able to fulfill that vow.

When ACA was signed into law in March 2010 (See “Springing Forward,” April 2010 EM), we wrote “though the new law will undoubtedly be challenged, tested, modified, refined, used—and probably abused—it will not be repealed. As was the case with Medicare and Medicaid previously, this will change everything in subtle and not-so-subtle ways.” (For a discussion of how the healthcare industry has managed to co-opt and abuse ACA, see the recently published book An American Sickness by Elisabeth Rosenthal, who was an emergency physician [EP] in our department before becoming a senior science and healthcare reporter for the New York Times.)

But the failure of ACA to deliver on many of its promises, its uncertain financial future, and the lack of improvements to ACA since 2010, directly or indirectly affects every American. Predictably, for those in need of care who cannot find a physician to accept their insurance or schedule a timely appointment, the ED remains the safety net for obtaining care.

After the constitutionality of ACA was upheld by the Supreme Court in June 2012 (See “Our National Pastime,” July 2012 EM), we noted that “ACA contains no provisions for increasing the number of healthcare providers [and] if 24 million more Americans now have access to affordable health insurance, but there are no new providers, who will they go to for care?” Seven years after passage of ACA, the answer to this question has been provided by published studies confirming that even more insured Americans are now seeking care in EDs than before “affordable care” became available. At the same time, urgent care centers, freestanding EDs, and “convenient care” centers, have sprung up and proliferated throughout the country, while in many states, nurse practitioners, physician assistants, and now emergency medical technicians and paramedics have sought and received authorization to evaluate and treat patients independent of physician supervision and oversight. Telemedicine or “telehealth” is the latest attempt to stretch the available supply of physicians to manage patients remotely, in the hope of obviating the need for an ED visit. 

But none of these measures completely addresses a basic weakness of ACA: There are not enough physicians, including EPs, in this country to care for everyone entitled to healthcare; at the same time, there is a generation of highly qualified, highly motivated young men and women seeking entrance to medical school who will never get the opportunity to become fine physicians because there are not enough places for them. The solution to these problems seems obvious and the funds needed to finance it would be well spent, though the benefits of increasing the number of medical school places would not be realized for 4 to 8 years after they are made available.

In the meantime, we leave you with the solution President George W. Bush offered to a Cleveland audience on July 10, 2007 (See “Dream On,” March 2008 EM): “people have access to healthcare in America. After all, you just go to an emergency room.” 

In the days before this issue of Emergency Medicine (EM) went to press, the United States Senate tried unsuccessfully, first to repeal and replace the Affordable Care Act (ACA), then to repeal key provisions of ACA without a replacement bill. Despite having a majority in both the Senate and House of Representatives as well as a Republican President, after 7 years of vowing to repeal “Obama Care,” Republicans have still not been able to fulfill that vow.

When ACA was signed into law in March 2010 (See “Springing Forward,” April 2010 EM), we wrote “though the new law will undoubtedly be challenged, tested, modified, refined, used—and probably abused—it will not be repealed. As was the case with Medicare and Medicaid previously, this will change everything in subtle and not-so-subtle ways.” (For a discussion of how the healthcare industry has managed to co-opt and abuse ACA, see the recently published book An American Sickness by Elisabeth Rosenthal, who was an emergency physician [EP] in our department before becoming a senior science and healthcare reporter for the New York Times.)

But the failure of ACA to deliver on many of its promises, its uncertain financial future, and the lack of improvements to ACA since 2010, directly or indirectly affects every American. Predictably, for those in need of care who cannot find a physician to accept their insurance or schedule a timely appointment, the ED remains the safety net for obtaining care.

After the constitutionality of ACA was upheld by the Supreme Court in June 2012 (See “Our National Pastime,” July 2012 EM), we noted that “ACA contains no provisions for increasing the number of healthcare providers [and] if 24 million more Americans now have access to affordable health insurance, but there are no new providers, who will they go to for care?” Seven years after passage of ACA, the answer to this question has been provided by published studies confirming that even more insured Americans are now seeking care in EDs than before “affordable care” became available. At the same time, urgent care centers, freestanding EDs, and “convenient care” centers, have sprung up and proliferated throughout the country, while in many states, nurse practitioners, physician assistants, and now emergency medical technicians and paramedics have sought and received authorization to evaluate and treat patients independent of physician supervision and oversight. Telemedicine or “telehealth” is the latest attempt to stretch the available supply of physicians to manage patients remotely, in the hope of obviating the need for an ED visit. 

But none of these measures completely addresses a basic weakness of ACA: There are not enough physicians, including EPs, in this country to care for everyone entitled to healthcare; at the same time, there is a generation of highly qualified, highly motivated young men and women seeking entrance to medical school who will never get the opportunity to become fine physicians because there are not enough places for them. The solution to these problems seems obvious and the funds needed to finance it would be well spent, though the benefits of increasing the number of medical school places would not be realized for 4 to 8 years after they are made available.

In the meantime, we leave you with the solution President George W. Bush offered to a Cleveland audience on July 10, 2007 (See “Dream On,” March 2008 EM): “people have access to healthcare in America. After all, you just go to an emergency room.”