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Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

JHMVol16No10_Simpson01371013e_t1.JPG

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

JHMVol16No10_Simpson01371013e_t1.JPG

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

JHMVol16No10_Simpson01371013e_t1.JPG

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

JHMVol16No10_Gay01141013e_t1.JPG

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

The authors thank Claire Campbell, MD, for her review of this manuscript.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

JHMVol16No10_Gay01141013e_t1.JPG

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

The authors thank Claire Campbell, MD, for her review of this manuscript.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

JHMVol16No10_Gay01141013e_t1.JPG

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

The authors thank Claire Campbell, MD, for her review of this manuscript.

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits an 80-year-old man for a chronic obstructive pulmonary disease exacerbation. The patient’s history is significant for chronic right knee pain. While hospitalized, the patient reports worsening of his knee pain. Radiographs of the right knee show severe osteoarthritic changes. Since acetaminophen does not relieve the patient’s pain, the hospitalist orders tramadol as needed.

Hospitalists, who commonly evaluate and treat acute and chronic pain in the inpatient setting, have a wide selection of interventions from which to choose, including tramadol. Tramadol hydrochloride is a synthetic, central-acting analgesic with multiple mechanisms of action. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a structure similar to venlafaxine and produces antineuropathic analgesic effects.¹ Tramadol and its primary active metabolite O-desmethyltramadol (also known as the M1 metabolite) mediate its effects by binding at the mu-opioid receptor.² Phase I metabolism in the liver by cytochrome P450 isoenzyme 2D6 (CYP2D6) facilitates conversion of tramadol to M1 (Figure). Importantly, genetic polymorphisms in CYP2D6 result in individual variations in gene expression, which impacts the metabolism of tramadol.²

JHMVol16No10_Glisch11991013e_f1.JPG

Although tramadol is available over the counter in some countries, in the United States it is a Schedule IV controlled substance. Tramadol consistently ranks among the top 50 prescribed medications in the United States.³

Given the growing concerns regarding the use of opioids, the pharmaceutical industry has marketed tramadol as a safer opioid option for pain management. Tramadol binds at the mu-opioid receptor with an affinity that is less than 4000-fold that of morphine; the binding potency of M1, the metabolite of tramadol, is less than 5-fold that of morphine.⁴ Due to its lower binding affinity at the mu-opioid receptor, tramadol is considered a weak opioid, one believed to have minimal withdrawal symptoms and a lower potential for overdose or misuse compared to other opioids.^1,5 Based on this characterization, many clinicians prescribe tramadol for elderly patients or patients otherwise at risk for medication misuse or adverse effects of opioids.⁶ In addition, hospitalized patients often have contraindications to nonopioid medications (eg, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]), limiting their options for pain management.

Despite being marketed as an effective and safe medication, tramadol has an unpredictable metabolism, complex pharmacology, and drug-drug interactions that can cause significant adverse effects. Similar to other opioids, tramadol is associated with a risk of misuse, physiologic dependency, and overdose. In addition, tramadol has a black box warning for addiction, misuse, respiratory depression, ultra-rapid metabolism, neonatal opioid withdrawal syndrome, CYP450 drug interactions, and interactions with other central nervous system depressants.

While tramadol has multiple mechanisms of action, the literature lacks high-quality evidence (eg, large randomized controlled trials) supporting its use, especially in hospitalized medical patients. A recent retrospective study of tramadol looked at the diagnoses of 250 hospitalized patients who received tramadol for pain management. While this study did not examine efficacy, it found mild-to-moderate acute noncancer pain to be the primary reason for prescribing tramadol.⁷ This study also showed the risk of severe drug-drug interactions increased the longer patients were on tramadol.⁷

As a result of the limited evidence in hospitalized patients, hospitalists must rely on outpatient studies.^8-10 The size and quality of these studies, especially given the magnitude of tramadol prescribing in the United States, make them less useful. A series of Cochrane reviews examining the beneficial effects of tramadol for neuropathic pain, osteoarthritis, and cancer pain show insufficient evidence for tramadol when compared to placebo or active controls such as acetaminophen, NSAIDs, or other opioids.^8-10

The side-effect profile of tramadol outweighs its mild analgesic effects. The 2019 American Geriatric Society Beers criteria for potentially inappropriate medication use in older adults strongly recommends clinicians use caution when prescribing tramadol to older adult patients, as tramadol may worsen or cause hyponatremia.¹¹ In one large, population-based study, the use of tramadol doubled patients’ risk of hospitalization for hyponatremia when compared to codeine, though the incidence remains rather low at 4.6 per 10,000 person-months.¹² Studies have also demonstrated an increased risk of hospitalization for hypoglycemia in nondiabetic patients receiving tramadol.¹³ A large propensity-score matched cohort study of patients with osteoarthritis found tramadol to have an associated higher all-cause mortality compared to NSAIDs; however, these differences may be due to confounding variables.¹ In addition to hyponatremia and all-cause mortality, patients taking tramadol also have an associated increased risk of falls and hip fractures when compared to codeine or NSAIDs.¹⁴

The increased serotonergic activity associated with tramadol can lead to serotonin syndrome (serotonin toxicity), a rare but serious condition. Although serotonin syndrome can develop in patients taking tramadol as a monotherapy, the risk for this toxidrome increases when tramadol is taken in combination with other serotonergic agents or agents that inhibit metabolism of tramadol at CYP2D6.⁵ Seizures may also occur with tramadol at therapeutic and supratherapeutic doses. Population-based studies estimate seizures occur in 0.15% to 0.86% of patients receiving tramadol, which is two to six times the risk of those not on tramadol.⁵ Patients concurrently taking tramadol with a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) are estimated to have seizures five to nine times more often than patients not taking a TCA or SSRI.⁵ Risk factors for tramadol-induced seizure include tramadol misuse or overdose, tramadol doses >1000 mg daily (maximum recommended dose is 400 mg/day), chronic tramadol use, concurrent use of a serotonergic agent or medications that inhibit CYP2D6, and history of epilepsy, renal disease, stroke, or traumatic brain injury.⁵ 

Differences in the genetic polymorphisms of CYP2D6 can produce a range of CYP2D6 activity from “poor metabolizers” (little-to-no analgesic effect) to “ultra-rapid metabolizers” (enhanced analgesia and increased risk of adverse effects), leading to unpredictable pharmacodynamic effects of tramadol.² In North Africa and the Arabian peninsula, more than 25% of the population rapidly metabolizes tramadol; these pharmacogenomic effects result in higher rates of tramadol addiction and overdose in these regions.⁵ An estimated 7% to 10% of Caucasians slowly metabolize tramadol, which may place them at risk of adverse effects from tramadol in addition to inadequate analgesia.¹⁵ In contrast, Ethiopian populations have the highest rate of ultra-rapid tramadol metabolism at 29%.¹⁵

Drugs that induce CYP2D6 (eg, dexamethasone, rifampin) or inhibit CYP2D6 (eg, bupropion, fluoxetine) also impact tramadol efficacy, pharmacokinetics, and pharmacodynamics.^16,17 Patients taking strong CYP2D6 inhibitors require significantly higher doses of tramadol to achieve analgesic effects.¹⁷ Tramadol undergoes extensive hepatic metabolism, producing several active metabolites, including M1 (Figure). Hepatic impairment increases the elimination half-life of tramadol and its metabolites.¹⁸ The majority of tramadol and its metabolites are eliminated through the kidneys. Accumulation of tramadol and its metabolites may occur in patients with renal impairment, placing them at increased risk of adverse effects.²

Finally, although some clinicians assume that tramadol has lower rates of misuse, diversion, or overdose compared to other opioids, rates of nonprescription use have increased with its proliferation.^19,20 The US Substance Abuse and Mental Health Services Administration estimates that 1,287,000 persons misused tramadol in 2019.²¹ Patients may exhibit symptoms of physiologic opioid dependence and withdrawal from chronic tramadol use.^2,22 In one study, patients prescribed tramadol monotherapy for acute pain from elective surgery had an increased risk for prolonged opioid use compared to patients prescribed other short-acting opioids.²²

Clinicians should determine the nature of the patient’s pain by obtaining a complete medical history, performing a thorough physical examination, and ordering diagnostic tests and imaging studies, as necessary. After consulting with the patient’s primary care physician, the clinician should employ a multimodal approach to pain that includes topical agents, psychotherapy, injections or interventions, and nonopioid medications. Patients with neuropathic pain may benefit from adjuvant analgesics such as gabapentinoids, TCAs, or SNRIs. In patients with evidence-based indications for opioid therapy (eg, pancreatitis, cancer pain, postsurgical pain), the hospitalist should assess the risk for opioid misuse and discuss risks and benefits with the patient before considering a time-limited trial of opioid therapy. If available and when indicated, clinicians should consult with specialists in pain management or palliative care. For cases wherein clinicians have already prescribed tramadol to the patient, they should discuss deprescribing strategies and alternative analgesic options with the patient and the patient’s primary care physician. Finally, before initiating tramadol therapy for hospitalized patients with pain, hospitalists should consider the risks, benefits, and alternative approaches to prescribing tramadol.

• For hospitalized patients reporting pain, complete a pain assessment by history, physical exam, chart review, and diagnostic studies to examine the etiology of the pain.
• Utilize multiple modalities for pain control when possible, including acetaminophen, NSAIDs, topical agents, ice or heat, neuropathic pain medications, and interventions such as injections, psychotherapy, or radiation, if indicated.
• Avoid prescribing tramadol due to unpredictable pharmacodynamics, adverse effects, and lack of quality evidence for efficacy in hospitalized medical patients.

Tramadol is a commonly used opioid medication associated with adverse effects and unpredictable analgesia. Regarding this case scenario, the use of tramadol in this patient places him at risk for drug-drug interactions, hyponatremia, hypoglycemia, serotonin syndrome, seizures, and pronounced side effects of opioid medications. Moderate quality evidence in the outpatient setting suggests that tramadol is unlikely to provide significant analgesia for his osteoarthritic pain.⁹ Instead of prescribing tramadol, the hospitalist should consider alternative treatments for this patient’s pain, such as intraarticular glucocorticoids, a short course of oral NSAIDs (unless contraindicated), topical treatments (eg, menthol, capsaicin, NSAIDs), physical therapy, and close follow-up with an orthopedist after hospital discharge. Further randomized controlled studies of tramadol vs active controls are needed.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits an 80-year-old man for a chronic obstructive pulmonary disease exacerbation. The patient’s history is significant for chronic right knee pain. While hospitalized, the patient reports worsening of his knee pain. Radiographs of the right knee show severe osteoarthritic changes. Since acetaminophen does not relieve the patient’s pain, the hospitalist orders tramadol as needed.

Hospitalists, who commonly evaluate and treat acute and chronic pain in the inpatient setting, have a wide selection of interventions from which to choose, including tramadol. Tramadol hydrochloride is a synthetic, central-acting analgesic with multiple mechanisms of action. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a structure similar to venlafaxine and produces antineuropathic analgesic effects.¹ Tramadol and its primary active metabolite O-desmethyltramadol (also known as the M1 metabolite) mediate its effects by binding at the mu-opioid receptor.² Phase I metabolism in the liver by cytochrome P450 isoenzyme 2D6 (CYP2D6) facilitates conversion of tramadol to M1 (Figure). Importantly, genetic polymorphisms in CYP2D6 result in individual variations in gene expression, which impacts the metabolism of tramadol.²

JHMVol16No10_Glisch11991013e_f1.JPG

Although tramadol is available over the counter in some countries, in the United States it is a Schedule IV controlled substance. Tramadol consistently ranks among the top 50 prescribed medications in the United States.³

Given the growing concerns regarding the use of opioids, the pharmaceutical industry has marketed tramadol as a safer opioid option for pain management. Tramadol binds at the mu-opioid receptor with an affinity that is less than 4000-fold that of morphine; the binding potency of M1, the metabolite of tramadol, is less than 5-fold that of morphine.⁴ Due to its lower binding affinity at the mu-opioid receptor, tramadol is considered a weak opioid, one believed to have minimal withdrawal symptoms and a lower potential for overdose or misuse compared to other opioids.^1,5 Based on this characterization, many clinicians prescribe tramadol for elderly patients or patients otherwise at risk for medication misuse or adverse effects of opioids.⁶ In addition, hospitalized patients often have contraindications to nonopioid medications (eg, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]), limiting their options for pain management.

Despite being marketed as an effective and safe medication, tramadol has an unpredictable metabolism, complex pharmacology, and drug-drug interactions that can cause significant adverse effects. Similar to other opioids, tramadol is associated with a risk of misuse, physiologic dependency, and overdose. In addition, tramadol has a black box warning for addiction, misuse, respiratory depression, ultra-rapid metabolism, neonatal opioid withdrawal syndrome, CYP450 drug interactions, and interactions with other central nervous system depressants.

While tramadol has multiple mechanisms of action, the literature lacks high-quality evidence (eg, large randomized controlled trials) supporting its use, especially in hospitalized medical patients. A recent retrospective study of tramadol looked at the diagnoses of 250 hospitalized patients who received tramadol for pain management. While this study did not examine efficacy, it found mild-to-moderate acute noncancer pain to be the primary reason for prescribing tramadol.⁷ This study also showed the risk of severe drug-drug interactions increased the longer patients were on tramadol.⁷

As a result of the limited evidence in hospitalized patients, hospitalists must rely on outpatient studies.^8-10 The size and quality of these studies, especially given the magnitude of tramadol prescribing in the United States, make them less useful. A series of Cochrane reviews examining the beneficial effects of tramadol for neuropathic pain, osteoarthritis, and cancer pain show insufficient evidence for tramadol when compared to placebo or active controls such as acetaminophen, NSAIDs, or other opioids.^8-10

The side-effect profile of tramadol outweighs its mild analgesic effects. The 2019 American Geriatric Society Beers criteria for potentially inappropriate medication use in older adults strongly recommends clinicians use caution when prescribing tramadol to older adult patients, as tramadol may worsen or cause hyponatremia.¹¹ In one large, population-based study, the use of tramadol doubled patients’ risk of hospitalization for hyponatremia when compared to codeine, though the incidence remains rather low at 4.6 per 10,000 person-months.¹² Studies have also demonstrated an increased risk of hospitalization for hypoglycemia in nondiabetic patients receiving tramadol.¹³ A large propensity-score matched cohort study of patients with osteoarthritis found tramadol to have an associated higher all-cause mortality compared to NSAIDs; however, these differences may be due to confounding variables.¹ In addition to hyponatremia and all-cause mortality, patients taking tramadol also have an associated increased risk of falls and hip fractures when compared to codeine or NSAIDs.¹⁴

The increased serotonergic activity associated with tramadol can lead to serotonin syndrome (serotonin toxicity), a rare but serious condition. Although serotonin syndrome can develop in patients taking tramadol as a monotherapy, the risk for this toxidrome increases when tramadol is taken in combination with other serotonergic agents or agents that inhibit metabolism of tramadol at CYP2D6.⁵ Seizures may also occur with tramadol at therapeutic and supratherapeutic doses. Population-based studies estimate seizures occur in 0.15% to 0.86% of patients receiving tramadol, which is two to six times the risk of those not on tramadol.⁵ Patients concurrently taking tramadol with a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) are estimated to have seizures five to nine times more often than patients not taking a TCA or SSRI.⁵ Risk factors for tramadol-induced seizure include tramadol misuse or overdose, tramadol doses >1000 mg daily (maximum recommended dose is 400 mg/day), chronic tramadol use, concurrent use of a serotonergic agent or medications that inhibit CYP2D6, and history of epilepsy, renal disease, stroke, or traumatic brain injury.⁵ 

Differences in the genetic polymorphisms of CYP2D6 can produce a range of CYP2D6 activity from “poor metabolizers” (little-to-no analgesic effect) to “ultra-rapid metabolizers” (enhanced analgesia and increased risk of adverse effects), leading to unpredictable pharmacodynamic effects of tramadol.² In North Africa and the Arabian peninsula, more than 25% of the population rapidly metabolizes tramadol; these pharmacogenomic effects result in higher rates of tramadol addiction and overdose in these regions.⁵ An estimated 7% to 10% of Caucasians slowly metabolize tramadol, which may place them at risk of adverse effects from tramadol in addition to inadequate analgesia.¹⁵ In contrast, Ethiopian populations have the highest rate of ultra-rapid tramadol metabolism at 29%.¹⁵

Drugs that induce CYP2D6 (eg, dexamethasone, rifampin) or inhibit CYP2D6 (eg, bupropion, fluoxetine) also impact tramadol efficacy, pharmacokinetics, and pharmacodynamics.^16,17 Patients taking strong CYP2D6 inhibitors require significantly higher doses of tramadol to achieve analgesic effects.¹⁷ Tramadol undergoes extensive hepatic metabolism, producing several active metabolites, including M1 (Figure). Hepatic impairment increases the elimination half-life of tramadol and its metabolites.¹⁸ The majority of tramadol and its metabolites are eliminated through the kidneys. Accumulation of tramadol and its metabolites may occur in patients with renal impairment, placing them at increased risk of adverse effects.²

Finally, although some clinicians assume that tramadol has lower rates of misuse, diversion, or overdose compared to other opioids, rates of nonprescription use have increased with its proliferation.^19,20 The US Substance Abuse and Mental Health Services Administration estimates that 1,287,000 persons misused tramadol in 2019.²¹ Patients may exhibit symptoms of physiologic opioid dependence and withdrawal from chronic tramadol use.^2,22 In one study, patients prescribed tramadol monotherapy for acute pain from elective surgery had an increased risk for prolonged opioid use compared to patients prescribed other short-acting opioids.²²

Clinicians should determine the nature of the patient’s pain by obtaining a complete medical history, performing a thorough physical examination, and ordering diagnostic tests and imaging studies, as necessary. After consulting with the patient’s primary care physician, the clinician should employ a multimodal approach to pain that includes topical agents, psychotherapy, injections or interventions, and nonopioid medications. Patients with neuropathic pain may benefit from adjuvant analgesics such as gabapentinoids, TCAs, or SNRIs. In patients with evidence-based indications for opioid therapy (eg, pancreatitis, cancer pain, postsurgical pain), the hospitalist should assess the risk for opioid misuse and discuss risks and benefits with the patient before considering a time-limited trial of opioid therapy. If available and when indicated, clinicians should consult with specialists in pain management or palliative care. For cases wherein clinicians have already prescribed tramadol to the patient, they should discuss deprescribing strategies and alternative analgesic options with the patient and the patient’s primary care physician. Finally, before initiating tramadol therapy for hospitalized patients with pain, hospitalists should consider the risks, benefits, and alternative approaches to prescribing tramadol.

• For hospitalized patients reporting pain, complete a pain assessment by history, physical exam, chart review, and diagnostic studies to examine the etiology of the pain.
• Utilize multiple modalities for pain control when possible, including acetaminophen, NSAIDs, topical agents, ice or heat, neuropathic pain medications, and interventions such as injections, psychotherapy, or radiation, if indicated.
• Avoid prescribing tramadol due to unpredictable pharmacodynamics, adverse effects, and lack of quality evidence for efficacy in hospitalized medical patients.

Tramadol is a commonly used opioid medication associated with adverse effects and unpredictable analgesia. Regarding this case scenario, the use of tramadol in this patient places him at risk for drug-drug interactions, hyponatremia, hypoglycemia, serotonin syndrome, seizures, and pronounced side effects of opioid medications. Moderate quality evidence in the outpatient setting suggests that tramadol is unlikely to provide significant analgesia for his osteoarthritic pain.⁹ Instead of prescribing tramadol, the hospitalist should consider alternative treatments for this patient’s pain, such as intraarticular glucocorticoids, a short course of oral NSAIDs (unless contraindicated), topical treatments (eg, menthol, capsaicin, NSAIDs), physical therapy, and close follow-up with an orthopedist after hospital discharge. Further randomized controlled studies of tramadol vs active controls are needed.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits an 80-year-old man for a chronic obstructive pulmonary disease exacerbation. The patient’s history is significant for chronic right knee pain. While hospitalized, the patient reports worsening of his knee pain. Radiographs of the right knee show severe osteoarthritic changes. Since acetaminophen does not relieve the patient’s pain, the hospitalist orders tramadol as needed.

Hospitalists, who commonly evaluate and treat acute and chronic pain in the inpatient setting, have a wide selection of interventions from which to choose, including tramadol. Tramadol hydrochloride is a synthetic, central-acting analgesic with multiple mechanisms of action. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a structure similar to venlafaxine and produces antineuropathic analgesic effects.¹ Tramadol and its primary active metabolite O-desmethyltramadol (also known as the M1 metabolite) mediate its effects by binding at the mu-opioid receptor.² Phase I metabolism in the liver by cytochrome P450 isoenzyme 2D6 (CYP2D6) facilitates conversion of tramadol to M1 (Figure). Importantly, genetic polymorphisms in CYP2D6 result in individual variations in gene expression, which impacts the metabolism of tramadol.²

JHMVol16No10_Glisch11991013e_f1.JPG

Although tramadol is available over the counter in some countries, in the United States it is a Schedule IV controlled substance. Tramadol consistently ranks among the top 50 prescribed medications in the United States.³

Given the growing concerns regarding the use of opioids, the pharmaceutical industry has marketed tramadol as a safer opioid option for pain management. Tramadol binds at the mu-opioid receptor with an affinity that is less than 4000-fold that of morphine; the binding potency of M1, the metabolite of tramadol, is less than 5-fold that of morphine.⁴ Due to its lower binding affinity at the mu-opioid receptor, tramadol is considered a weak opioid, one believed to have minimal withdrawal symptoms and a lower potential for overdose or misuse compared to other opioids.^1,5 Based on this characterization, many clinicians prescribe tramadol for elderly patients or patients otherwise at risk for medication misuse or adverse effects of opioids.⁶ In addition, hospitalized patients often have contraindications to nonopioid medications (eg, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]), limiting their options for pain management.

Despite being marketed as an effective and safe medication, tramadol has an unpredictable metabolism, complex pharmacology, and drug-drug interactions that can cause significant adverse effects. Similar to other opioids, tramadol is associated with a risk of misuse, physiologic dependency, and overdose. In addition, tramadol has a black box warning for addiction, misuse, respiratory depression, ultra-rapid metabolism, neonatal opioid withdrawal syndrome, CYP450 drug interactions, and interactions with other central nervous system depressants.

While tramadol has multiple mechanisms of action, the literature lacks high-quality evidence (eg, large randomized controlled trials) supporting its use, especially in hospitalized medical patients. A recent retrospective study of tramadol looked at the diagnoses of 250 hospitalized patients who received tramadol for pain management. While this study did not examine efficacy, it found mild-to-moderate acute noncancer pain to be the primary reason for prescribing tramadol.⁷ This study also showed the risk of severe drug-drug interactions increased the longer patients were on tramadol.⁷

As a result of the limited evidence in hospitalized patients, hospitalists must rely on outpatient studies.^8-10 The size and quality of these studies, especially given the magnitude of tramadol prescribing in the United States, make them less useful. A series of Cochrane reviews examining the beneficial effects of tramadol for neuropathic pain, osteoarthritis, and cancer pain show insufficient evidence for tramadol when compared to placebo or active controls such as acetaminophen, NSAIDs, or other opioids.^8-10

The side-effect profile of tramadol outweighs its mild analgesic effects. The 2019 American Geriatric Society Beers criteria for potentially inappropriate medication use in older adults strongly recommends clinicians use caution when prescribing tramadol to older adult patients, as tramadol may worsen or cause hyponatremia.¹¹ In one large, population-based study, the use of tramadol doubled patients’ risk of hospitalization for hyponatremia when compared to codeine, though the incidence remains rather low at 4.6 per 10,000 person-months.¹² Studies have also demonstrated an increased risk of hospitalization for hypoglycemia in nondiabetic patients receiving tramadol.¹³ A large propensity-score matched cohort study of patients with osteoarthritis found tramadol to have an associated higher all-cause mortality compared to NSAIDs; however, these differences may be due to confounding variables.¹ In addition to hyponatremia and all-cause mortality, patients taking tramadol also have an associated increased risk of falls and hip fractures when compared to codeine or NSAIDs.¹⁴

The increased serotonergic activity associated with tramadol can lead to serotonin syndrome (serotonin toxicity), a rare but serious condition. Although serotonin syndrome can develop in patients taking tramadol as a monotherapy, the risk for this toxidrome increases when tramadol is taken in combination with other serotonergic agents or agents that inhibit metabolism of tramadol at CYP2D6.⁵ Seizures may also occur with tramadol at therapeutic and supratherapeutic doses. Population-based studies estimate seizures occur in 0.15% to 0.86% of patients receiving tramadol, which is two to six times the risk of those not on tramadol.⁵ Patients concurrently taking tramadol with a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) are estimated to have seizures five to nine times more often than patients not taking a TCA or SSRI.⁵ Risk factors for tramadol-induced seizure include tramadol misuse or overdose, tramadol doses >1000 mg daily (maximum recommended dose is 400 mg/day), chronic tramadol use, concurrent use of a serotonergic agent or medications that inhibit CYP2D6, and history of epilepsy, renal disease, stroke, or traumatic brain injury.⁵ 

Differences in the genetic polymorphisms of CYP2D6 can produce a range of CYP2D6 activity from “poor metabolizers” (little-to-no analgesic effect) to “ultra-rapid metabolizers” (enhanced analgesia and increased risk of adverse effects), leading to unpredictable pharmacodynamic effects of tramadol.² In North Africa and the Arabian peninsula, more than 25% of the population rapidly metabolizes tramadol; these pharmacogenomic effects result in higher rates of tramadol addiction and overdose in these regions.⁵ An estimated 7% to 10% of Caucasians slowly metabolize tramadol, which may place them at risk of adverse effects from tramadol in addition to inadequate analgesia.¹⁵ In contrast, Ethiopian populations have the highest rate of ultra-rapid tramadol metabolism at 29%.¹⁵

Drugs that induce CYP2D6 (eg, dexamethasone, rifampin) or inhibit CYP2D6 (eg, bupropion, fluoxetine) also impact tramadol efficacy, pharmacokinetics, and pharmacodynamics.^16,17 Patients taking strong CYP2D6 inhibitors require significantly higher doses of tramadol to achieve analgesic effects.¹⁷ Tramadol undergoes extensive hepatic metabolism, producing several active metabolites, including M1 (Figure). Hepatic impairment increases the elimination half-life of tramadol and its metabolites.¹⁸ The majority of tramadol and its metabolites are eliminated through the kidneys. Accumulation of tramadol and its metabolites may occur in patients with renal impairment, placing them at increased risk of adverse effects.²

Finally, although some clinicians assume that tramadol has lower rates of misuse, diversion, or overdose compared to other opioids, rates of nonprescription use have increased with its proliferation.^19,20 The US Substance Abuse and Mental Health Services Administration estimates that 1,287,000 persons misused tramadol in 2019.²¹ Patients may exhibit symptoms of physiologic opioid dependence and withdrawal from chronic tramadol use.^2,22 In one study, patients prescribed tramadol monotherapy for acute pain from elective surgery had an increased risk for prolonged opioid use compared to patients prescribed other short-acting opioids.²²

Clinicians should determine the nature of the patient’s pain by obtaining a complete medical history, performing a thorough physical examination, and ordering diagnostic tests and imaging studies, as necessary. After consulting with the patient’s primary care physician, the clinician should employ a multimodal approach to pain that includes topical agents, psychotherapy, injections or interventions, and nonopioid medications. Patients with neuropathic pain may benefit from adjuvant analgesics such as gabapentinoids, TCAs, or SNRIs. In patients with evidence-based indications for opioid therapy (eg, pancreatitis, cancer pain, postsurgical pain), the hospitalist should assess the risk for opioid misuse and discuss risks and benefits with the patient before considering a time-limited trial of opioid therapy. If available and when indicated, clinicians should consult with specialists in pain management or palliative care. For cases wherein clinicians have already prescribed tramadol to the patient, they should discuss deprescribing strategies and alternative analgesic options with the patient and the patient’s primary care physician. Finally, before initiating tramadol therapy for hospitalized patients with pain, hospitalists should consider the risks, benefits, and alternative approaches to prescribing tramadol.

• For hospitalized patients reporting pain, complete a pain assessment by history, physical exam, chart review, and diagnostic studies to examine the etiology of the pain.
• Utilize multiple modalities for pain control when possible, including acetaminophen, NSAIDs, topical agents, ice or heat, neuropathic pain medications, and interventions such as injections, psychotherapy, or radiation, if indicated.
• Avoid prescribing tramadol due to unpredictable pharmacodynamics, adverse effects, and lack of quality evidence for efficacy in hospitalized medical patients.

Tramadol is a commonly used opioid medication associated with adverse effects and unpredictable analgesia. Regarding this case scenario, the use of tramadol in this patient places him at risk for drug-drug interactions, hyponatremia, hypoglycemia, serotonin syndrome, seizures, and pronounced side effects of opioid medications. Moderate quality evidence in the outpatient setting suggests that tramadol is unlikely to provide significant analgesia for his osteoarthritic pain.⁹ Instead of prescribing tramadol, the hospitalist should consider alternative treatments for this patient’s pain, such as intraarticular glucocorticoids, a short course of oral NSAIDs (unless contraindicated), topical treatments (eg, menthol, capsaicin, NSAIDs), physical therapy, and close follow-up with an orthopedist after hospital discharge. Further randomized controlled studies of tramadol vs active controls are needed.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™" (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits a 56-year-old anuric man with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) for an acute coronary syndrome. He received his regularly scheduled HD the day before admission. Cardiology delays his coronary catheterization until nephrology can arrange for HD immediately after angiography. After angiography, the patient receives emergent HD even though he had acceptable metabolic parameters and did not show signs or symptoms of volume overload. The hospitalist wonders whether arranging emergent HD after the procedure with intravascular (IV) contrast was necessary for this patient.

Of the approximately 600 million radiological examinations performed annually, 75 million require iodinated contrast material (ICM).¹ ICM are small, highly diffusible, minimally protein-bound molecules. They are not metabolized by humans, with healthy kidneys excreting approximately 99.8% of the administered dose within 24 hours.² ICM has been associated with acute kidney injury (AKI), but its deleterious effects have not been thoroughly described, and the incidence and severity of contrast-associated nephropathy vary among studies.³ Not surprisingly, the strongest independent patient-related risk factor for developing contrast-induced AKI is preexisting chronic kidney disease.⁴ In patients with ESRD, the biliary system slowly clears the contrast, leading to long-standing retention. Newer low- or iso-osmolar contrast material is now used rather than older, conventional high-osmolality agents. These agents are less likely to lead to AKI.⁵

Recent studies have challenged the association between AKI and ICM administration.^6-8 In 2015, the American College of Radiology endorsed the terms contrast-associated acute kidney injury and contrast-induced acute kidney injury, instead of the contrast-induced nephropathy, to avoid the uncertainty about the causal relationship between AKI and ICM.⁹ ESRD patients have little or no functional renal tissue and are on renal replacement therapy, either HD or peritoneal dialysis. However, physicians apprehensive about the renal and cardiovascular toxicity caused by retained ICM might request postprocedural HD to promote quicker contrast clearance in patients with ESRD.

Clinicians divide patients with ESRD into two groups depending on their ability to produce urine. Those who produce urine have residual renal function (RRF), which independently predicts survival.¹⁰ Among a cohort of peritoneal and HD patients, Maiorca et al described a 40% reduction in the risk of death for each 1 mL/min increase in glomerular filtration rate (GFR).¹⁰ Therefore, patients on maintenance dialysis who have RRF are considered similar to patients with AKI and eGFR <30 mL/min/1.73 m².⁹ Clinicians might worry that contrast retention could reduce RRF by inducing AKI.^2,4,11

Volume overload is a second concern with ICM administration in ESRD patients. In mice, higher-osmolality ICM produced acute pulmonary edema, leading to death.¹² A rapid bolus of diatrizoate caused transient intravascular expansion as reflected by an average decrease in hemoglobin of 0.5 to 0.8 g/dL, depending on the osmolality of the agent.¹²

Conventional high-osmolar ICM also depresses myocardial contractile force, sinoatrial automaticity, and atrioventricular nodal conduction, resulting in bradycardia, transient heart blocks, and increased risk of ventricular fibrillation.¹² High-osmolar calcium-binding ICM transiently reduces systemic vascular resistance, resulting in transient hypotension and increased cardiac output. Researchers linked these adverse cardiac effects to the high-osmolality ionic ICM, not newer agents.¹² In one study of adverse outcomes linked to ICM, 36% of patients with normal kidney function exposed to contrast developed an adverse reaction; 2% of patients developed level 4 (severe) adverse reactions.¹³ The study noted a significantly increased risk of bradycardia (relative risk [RR], 17.9), hypotension (RR, 6.3), and angina (RR, 3.4) among those who received high-osmolality contrast agents.

HD removes 72% to 82% of ICM at 4 hours.¹⁴ Armed with data from mice or small-population studies that demonstrated the toxic effects of conventional high-osmolar ICM, many radiologists and clinicians recommend post-contrast HD for patients at high risk for contrast-induced AKI and chronic HD patients.² Moon et al suggested prophylactic HD for quicker removal of the iodinated contrast medium to prevent reduction in renal function among high-risk patients after angiographic interventions.¹⁵

Over the last 3 decades, we have transitioned from conventional radiocontrast to low-osmolality agents that are not directly toxic to the kidneys. Iodixanol, iohexol, and iopromide exposure during intravascular radiological procedures did not result in a decline of RRF among well-hydrated peritoneal dialysis patients with RRF.^16,17 The limited analysis of HD trials in the systematic review by Cruz et al concluded that periprocedural HD in patients with chronic kidney disease did not decrease the incidence of radiocontrast-associated nephropathy.¹⁸ A meta-analysis of nine studies (434 patients) concluded that ICM administration does not cause significant reduction of residual function in dialysis patients.¹⁹ Because anuric ESRD patients have no salvageable renal function and are on HD, managing AKI seems irrelevant.

Although volume overload is an important consideration, the theoretical increase in intravascular volume with administration of 100 mL of 1500 mOsm/L of conventional ICM to a 70 kg-patient is only 120 mL.¹⁴ More importantly, use of low-osmolar ICM substantially reduces any significant volume shifts.

Studies have not associated low-osmolality ICM with cardiovascular adverse effects.^20-23 A retrospective study by Takebayashi et al showed an absence of serious adverse reactions to low-osmolar contrast media when HD was performed on their regular HD schedule.²² Older, smaller prospective trials did not show a need for periprocedural HD after ICM exposure.^20,21,23 In a prospective study of 10 ESRD patients, Younathan et al assessed for postprocedural adverse effects of non-ionic contrast material and found that none required emergent HD.²³ Similarly, Hamani et al and Harasawa et al did not observe hemodynamic and cardiopulmonary effects of IV contrast in chronic HD patients (Table).^20,21 Injection of non-ionic contrast material in patients on chronic HD did not produce significant changes in blood pressure, electrocardiogram results, osmolality, extracellular fluid volume, or body weight.²³ Finally, the vasoconstrictor-mediated ischemic injury of ICM occurs within minutes of administration, making dialysis performed hours later of little benefit.

JHMVol16No9_Ninan00020915e_t1.JPG

HD is associated with adverse effects, including hypotension, which can jeopardize cardiovascular recovery after a myocardial infarction.²⁴ The retrospective study performed by Fujimoto et al demonstrated dialytic complications in 24% of patients dialyzed the day of angiography.²⁵ They noted that the amount of contrast agent administered independently predicted intradialytic hypotension.^25,26

Delays in performing cardiac revascularizations are associated with an increase in 30-day mortality. The 30-day mortality rates of patients diagnosed with ST-elevation myocardial infarction who underwent revascularization in <60 minutes, 61 to 75 minutes, 76 to 90 minutes, and >90 minutes from study enrollment were 1%, 3.7%, 4%, and 6.7%, respectively.²⁷ Delayed diagnosis of pulmonary embolism or acute limb ischemia was associated with increased rates of complications and mortality.^28,29 The benefits of essential radiocontrast procedures outweigh the potential cardiovascular and cerebrovascular complications for HD patients. Considering the evidence, the American College of Radiology’s 2020 Manual on Contrast Media and the European Society for Urogenital Radiology’s 2018 guidelines on contrast medium administration in patients on HD concluded that an extra session or a change in the usual timing of HD is unnecessary.^13,30

HD performed post-contrast exposure does not provide any protective benefit, regardless of the degree of RRF (anuric ESRD or otherwise), making the timing of HD irrelevant. Do not delay studies that provide essential information for clinical management of high-risk conditions. The decision to perform HD in a patient who needs contrast-enhanced studies should be made independent of whether they will receive contrast.

• Immediate post-procedural HD after ICM exposure in ESRD patients is not required.
• Do not delay vital diagnostic or therapeutic procedures requiring ICM in ESRD patients.
• The indication for HD is independent of contrast exposure in ESRD patients.

The hospitalist did not need to arrange emergent post-procedural HD because it does not improve clinical outcomes. Delaying potentially lifesaving diagnostic and therapeutic measures involving the use of radiocontrast to secure post-radiocontrast HD could lead to worse outcomes.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™" (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits a 56-year-old anuric man with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) for an acute coronary syndrome. He received his regularly scheduled HD the day before admission. Cardiology delays his coronary catheterization until nephrology can arrange for HD immediately after angiography. After angiography, the patient receives emergent HD even though he had acceptable metabolic parameters and did not show signs or symptoms of volume overload. The hospitalist wonders whether arranging emergent HD after the procedure with intravascular (IV) contrast was necessary for this patient.

Of the approximately 600 million radiological examinations performed annually, 75 million require iodinated contrast material (ICM).¹ ICM are small, highly diffusible, minimally protein-bound molecules. They are not metabolized by humans, with healthy kidneys excreting approximately 99.8% of the administered dose within 24 hours.² ICM has been associated with acute kidney injury (AKI), but its deleterious effects have not been thoroughly described, and the incidence and severity of contrast-associated nephropathy vary among studies.³ Not surprisingly, the strongest independent patient-related risk factor for developing contrast-induced AKI is preexisting chronic kidney disease.⁴ In patients with ESRD, the biliary system slowly clears the contrast, leading to long-standing retention. Newer low- or iso-osmolar contrast material is now used rather than older, conventional high-osmolality agents. These agents are less likely to lead to AKI.⁵

Recent studies have challenged the association between AKI and ICM administration.^6-8 In 2015, the American College of Radiology endorsed the terms contrast-associated acute kidney injury and contrast-induced acute kidney injury, instead of the contrast-induced nephropathy, to avoid the uncertainty about the causal relationship between AKI and ICM.⁹ ESRD patients have little or no functional renal tissue and are on renal replacement therapy, either HD or peritoneal dialysis. However, physicians apprehensive about the renal and cardiovascular toxicity caused by retained ICM might request postprocedural HD to promote quicker contrast clearance in patients with ESRD.

Clinicians divide patients with ESRD into two groups depending on their ability to produce urine. Those who produce urine have residual renal function (RRF), which independently predicts survival.¹⁰ Among a cohort of peritoneal and HD patients, Maiorca et al described a 40% reduction in the risk of death for each 1 mL/min increase in glomerular filtration rate (GFR).¹⁰ Therefore, patients on maintenance dialysis who have RRF are considered similar to patients with AKI and eGFR <30 mL/min/1.73 m².⁹ Clinicians might worry that contrast retention could reduce RRF by inducing AKI.^2,4,11

Volume overload is a second concern with ICM administration in ESRD patients. In mice, higher-osmolality ICM produced acute pulmonary edema, leading to death.¹² A rapid bolus of diatrizoate caused transient intravascular expansion as reflected by an average decrease in hemoglobin of 0.5 to 0.8 g/dL, depending on the osmolality of the agent.¹²

Conventional high-osmolar ICM also depresses myocardial contractile force, sinoatrial automaticity, and atrioventricular nodal conduction, resulting in bradycardia, transient heart blocks, and increased risk of ventricular fibrillation.¹² High-osmolar calcium-binding ICM transiently reduces systemic vascular resistance, resulting in transient hypotension and increased cardiac output. Researchers linked these adverse cardiac effects to the high-osmolality ionic ICM, not newer agents.¹² In one study of adverse outcomes linked to ICM, 36% of patients with normal kidney function exposed to contrast developed an adverse reaction; 2% of patients developed level 4 (severe) adverse reactions.¹³ The study noted a significantly increased risk of bradycardia (relative risk [RR], 17.9), hypotension (RR, 6.3), and angina (RR, 3.4) among those who received high-osmolality contrast agents.

HD removes 72% to 82% of ICM at 4 hours.¹⁴ Armed with data from mice or small-population studies that demonstrated the toxic effects of conventional high-osmolar ICM, many radiologists and clinicians recommend post-contrast HD for patients at high risk for contrast-induced AKI and chronic HD patients.² Moon et al suggested prophylactic HD for quicker removal of the iodinated contrast medium to prevent reduction in renal function among high-risk patients after angiographic interventions.¹⁵

Over the last 3 decades, we have transitioned from conventional radiocontrast to low-osmolality agents that are not directly toxic to the kidneys. Iodixanol, iohexol, and iopromide exposure during intravascular radiological procedures did not result in a decline of RRF among well-hydrated peritoneal dialysis patients with RRF.^16,17 The limited analysis of HD trials in the systematic review by Cruz et al concluded that periprocedural HD in patients with chronic kidney disease did not decrease the incidence of radiocontrast-associated nephropathy.¹⁸ A meta-analysis of nine studies (434 patients) concluded that ICM administration does not cause significant reduction of residual function in dialysis patients.¹⁹ Because anuric ESRD patients have no salvageable renal function and are on HD, managing AKI seems irrelevant.

Although volume overload is an important consideration, the theoretical increase in intravascular volume with administration of 100 mL of 1500 mOsm/L of conventional ICM to a 70 kg-patient is only 120 mL.¹⁴ More importantly, use of low-osmolar ICM substantially reduces any significant volume shifts.

Studies have not associated low-osmolality ICM with cardiovascular adverse effects.^20-23 A retrospective study by Takebayashi et al showed an absence of serious adverse reactions to low-osmolar contrast media when HD was performed on their regular HD schedule.²² Older, smaller prospective trials did not show a need for periprocedural HD after ICM exposure.^20,21,23 In a prospective study of 10 ESRD patients, Younathan et al assessed for postprocedural adverse effects of non-ionic contrast material and found that none required emergent HD.²³ Similarly, Hamani et al and Harasawa et al did not observe hemodynamic and cardiopulmonary effects of IV contrast in chronic HD patients (Table).^20,21 Injection of non-ionic contrast material in patients on chronic HD did not produce significant changes in blood pressure, electrocardiogram results, osmolality, extracellular fluid volume, or body weight.²³ Finally, the vasoconstrictor-mediated ischemic injury of ICM occurs within minutes of administration, making dialysis performed hours later of little benefit.

JHMVol16No9_Ninan00020915e_t1.JPG

HD is associated with adverse effects, including hypotension, which can jeopardize cardiovascular recovery after a myocardial infarction.²⁴ The retrospective study performed by Fujimoto et al demonstrated dialytic complications in 24% of patients dialyzed the day of angiography.²⁵ They noted that the amount of contrast agent administered independently predicted intradialytic hypotension.^25,26

Delays in performing cardiac revascularizations are associated with an increase in 30-day mortality. The 30-day mortality rates of patients diagnosed with ST-elevation myocardial infarction who underwent revascularization in <60 minutes, 61 to 75 minutes, 76 to 90 minutes, and >90 minutes from study enrollment were 1%, 3.7%, 4%, and 6.7%, respectively.²⁷ Delayed diagnosis of pulmonary embolism or acute limb ischemia was associated with increased rates of complications and mortality.^28,29 The benefits of essential radiocontrast procedures outweigh the potential cardiovascular and cerebrovascular complications for HD patients. Considering the evidence, the American College of Radiology’s 2020 Manual on Contrast Media and the European Society for Urogenital Radiology’s 2018 guidelines on contrast medium administration in patients on HD concluded that an extra session or a change in the usual timing of HD is unnecessary.^13,30

HD performed post-contrast exposure does not provide any protective benefit, regardless of the degree of RRF (anuric ESRD or otherwise), making the timing of HD irrelevant. Do not delay studies that provide essential information for clinical management of high-risk conditions. The decision to perform HD in a patient who needs contrast-enhanced studies should be made independent of whether they will receive contrast.

• Immediate post-procedural HD after ICM exposure in ESRD patients is not required.
• Do not delay vital diagnostic or therapeutic procedures requiring ICM in ESRD patients.
• The indication for HD is independent of contrast exposure in ESRD patients.

The hospitalist did not need to arrange emergent post-procedural HD because it does not improve clinical outcomes. Delaying potentially lifesaving diagnostic and therapeutic measures involving the use of radiocontrast to secure post-radiocontrast HD could lead to worse outcomes.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™" (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

The hospitalist admits a 56-year-old anuric man with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) for an acute coronary syndrome. He received his regularly scheduled HD the day before admission. Cardiology delays his coronary catheterization until nephrology can arrange for HD immediately after angiography. After angiography, the patient receives emergent HD even though he had acceptable metabolic parameters and did not show signs or symptoms of volume overload. The hospitalist wonders whether arranging emergent HD after the procedure with intravascular (IV) contrast was necessary for this patient.

Of the approximately 600 million radiological examinations performed annually, 75 million require iodinated contrast material (ICM).¹ ICM are small, highly diffusible, minimally protein-bound molecules. They are not metabolized by humans, with healthy kidneys excreting approximately 99.8% of the administered dose within 24 hours.² ICM has been associated with acute kidney injury (AKI), but its deleterious effects have not been thoroughly described, and the incidence and severity of contrast-associated nephropathy vary among studies.³ Not surprisingly, the strongest independent patient-related risk factor for developing contrast-induced AKI is preexisting chronic kidney disease.⁴ In patients with ESRD, the biliary system slowly clears the contrast, leading to long-standing retention. Newer low- or iso-osmolar contrast material is now used rather than older, conventional high-osmolality agents. These agents are less likely to lead to AKI.⁵

Recent studies have challenged the association between AKI and ICM administration.^6-8 In 2015, the American College of Radiology endorsed the terms contrast-associated acute kidney injury and contrast-induced acute kidney injury, instead of the contrast-induced nephropathy, to avoid the uncertainty about the causal relationship between AKI and ICM.⁹ ESRD patients have little or no functional renal tissue and are on renal replacement therapy, either HD or peritoneal dialysis. However, physicians apprehensive about the renal and cardiovascular toxicity caused by retained ICM might request postprocedural HD to promote quicker contrast clearance in patients with ESRD.

Clinicians divide patients with ESRD into two groups depending on their ability to produce urine. Those who produce urine have residual renal function (RRF), which independently predicts survival.¹⁰ Among a cohort of peritoneal and HD patients, Maiorca et al described a 40% reduction in the risk of death for each 1 mL/min increase in glomerular filtration rate (GFR).¹⁰ Therefore, patients on maintenance dialysis who have RRF are considered similar to patients with AKI and eGFR <30 mL/min/1.73 m².⁹ Clinicians might worry that contrast retention could reduce RRF by inducing AKI.^2,4,11

Volume overload is a second concern with ICM administration in ESRD patients. In mice, higher-osmolality ICM produced acute pulmonary edema, leading to death.¹² A rapid bolus of diatrizoate caused transient intravascular expansion as reflected by an average decrease in hemoglobin of 0.5 to 0.8 g/dL, depending on the osmolality of the agent.¹²

Conventional high-osmolar ICM also depresses myocardial contractile force, sinoatrial automaticity, and atrioventricular nodal conduction, resulting in bradycardia, transient heart blocks, and increased risk of ventricular fibrillation.¹² High-osmolar calcium-binding ICM transiently reduces systemic vascular resistance, resulting in transient hypotension and increased cardiac output. Researchers linked these adverse cardiac effects to the high-osmolality ionic ICM, not newer agents.¹² In one study of adverse outcomes linked to ICM, 36% of patients with normal kidney function exposed to contrast developed an adverse reaction; 2% of patients developed level 4 (severe) adverse reactions.¹³ The study noted a significantly increased risk of bradycardia (relative risk [RR], 17.9), hypotension (RR, 6.3), and angina (RR, 3.4) among those who received high-osmolality contrast agents.

HD removes 72% to 82% of ICM at 4 hours.¹⁴ Armed with data from mice or small-population studies that demonstrated the toxic effects of conventional high-osmolar ICM, many radiologists and clinicians recommend post-contrast HD for patients at high risk for contrast-induced AKI and chronic HD patients.² Moon et al suggested prophylactic HD for quicker removal of the iodinated contrast medium to prevent reduction in renal function among high-risk patients after angiographic interventions.¹⁵

Over the last 3 decades, we have transitioned from conventional radiocontrast to low-osmolality agents that are not directly toxic to the kidneys. Iodixanol, iohexol, and iopromide exposure during intravascular radiological procedures did not result in a decline of RRF among well-hydrated peritoneal dialysis patients with RRF.^16,17 The limited analysis of HD trials in the systematic review by Cruz et al concluded that periprocedural HD in patients with chronic kidney disease did not decrease the incidence of radiocontrast-associated nephropathy.¹⁸ A meta-analysis of nine studies (434 patients) concluded that ICM administration does not cause significant reduction of residual function in dialysis patients.¹⁹ Because anuric ESRD patients have no salvageable renal function and are on HD, managing AKI seems irrelevant.

Although volume overload is an important consideration, the theoretical increase in intravascular volume with administration of 100 mL of 1500 mOsm/L of conventional ICM to a 70 kg-patient is only 120 mL.¹⁴ More importantly, use of low-osmolar ICM substantially reduces any significant volume shifts.

Studies have not associated low-osmolality ICM with cardiovascular adverse effects.^20-23 A retrospective study by Takebayashi et al showed an absence of serious adverse reactions to low-osmolar contrast media when HD was performed on their regular HD schedule.²² Older, smaller prospective trials did not show a need for periprocedural HD after ICM exposure.^20,21,23 In a prospective study of 10 ESRD patients, Younathan et al assessed for postprocedural adverse effects of non-ionic contrast material and found that none required emergent HD.²³ Similarly, Hamani et al and Harasawa et al did not observe hemodynamic and cardiopulmonary effects of IV contrast in chronic HD patients (Table).^20,21 Injection of non-ionic contrast material in patients on chronic HD did not produce significant changes in blood pressure, electrocardiogram results, osmolality, extracellular fluid volume, or body weight.²³ Finally, the vasoconstrictor-mediated ischemic injury of ICM occurs within minutes of administration, making dialysis performed hours later of little benefit.

JHMVol16No9_Ninan00020915e_t1.JPG

HD is associated with adverse effects, including hypotension, which can jeopardize cardiovascular recovery after a myocardial infarction.²⁴ The retrospective study performed by Fujimoto et al demonstrated dialytic complications in 24% of patients dialyzed the day of angiography.²⁵ They noted that the amount of contrast agent administered independently predicted intradialytic hypotension.^25,26

Delays in performing cardiac revascularizations are associated with an increase in 30-day mortality. The 30-day mortality rates of patients diagnosed with ST-elevation myocardial infarction who underwent revascularization in <60 minutes, 61 to 75 minutes, 76 to 90 minutes, and >90 minutes from study enrollment were 1%, 3.7%, 4%, and 6.7%, respectively.²⁷ Delayed diagnosis of pulmonary embolism or acute limb ischemia was associated with increased rates of complications and mortality.^28,29 The benefits of essential radiocontrast procedures outweigh the potential cardiovascular and cerebrovascular complications for HD patients. Considering the evidence, the American College of Radiology’s 2020 Manual on Contrast Media and the European Society for Urogenital Radiology’s 2018 guidelines on contrast medium administration in patients on HD concluded that an extra session or a change in the usual timing of HD is unnecessary.^13,30

HD performed post-contrast exposure does not provide any protective benefit, regardless of the degree of RRF (anuric ESRD or otherwise), making the timing of HD irrelevant. Do not delay studies that provide essential information for clinical management of high-risk conditions. The decision to perform HD in a patient who needs contrast-enhanced studies should be made independent of whether they will receive contrast.

• Immediate post-procedural HD after ICM exposure in ESRD patients is not required.
• Do not delay vital diagnostic or therapeutic procedures requiring ICM in ESRD patients.
• The indication for HD is independent of contrast exposure in ESRD patients.

The hospitalist did not need to arrange emergent post-procedural HD because it does not improve clinical outcomes. Delaying potentially lifesaving diagnostic and therapeutic measures involving the use of radiocontrast to secure post-radiocontrast HD could lead to worse outcomes.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason™” topics by emailing TWDFNR@hospitalmedicine.org.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

On teaching rounds, a medical student presents the following case to the attending hospitalist: “Mrs. L is a 54-year-old Black female with chronic kidney disease who was admitted with community-acquired pneumonia. She continues to improve symptomatically on ceftriaxone. Currently, she is afebrile and her vitals are stable. Supplemental oxygen has been weaned to 2 L/min by nasal cannula. Exam reveals improved crackles in the left lower chest without dullness to percussion. Labs are notable for down-trending leukocytosis and a stable serum creatinine of 2.8 mg/dL.” The hospitalist considers how including racial descriptors in clinical presentations may influence the care of the patient.

For decades, medical educators have taught learners to include sociopolitical constructs such as race in the opening sentence of the history of present illness (HPI). This practice presumably stems from the assumption that race accurately reflects biogenetic information about patients and serves as a key attribute in problem representations.¹ Proponents of including race in the HPI suggest doing so aids the clinical assessment of patients’ risks for particular diseases and may inform the selection of race-appropriate therapies.²

The construct of race does sometimes correlate with the risk of disease or response to therapies. For example, sickle cell disease (SCD) occurs more commonly among patients who identify as Black rather than White. Specifically, ancestry from African nations such as Nigeria or the Democratic Republic of Congo increases the likelihood of having the disease-associated hemoglobin gene variant HbS.¹ Popular genomic ancestry tests often report ancestral groupings that map to racial categories and may reinforce the perception that race has a genetic basis.³

Race, a construct of sociopolitical origins, incorrectly conflates skin color with genetic variation. Associations between race and disease have the potential to cause diagnostic and therapeutic errors and inequitable allocation of resources. Increased illness burden in minority populations results primarily from social factors such as environment, access to care, housing instability, food insecurity, and experiences of discrimination, rather than genetic differences. The resulting chronic and recurrent physiologic stress—known as allostatic load—also contributes to the inequitable health outcomes observed in vulnerable populations, including patients who identify as Black.⁴

Historically, race evolved as a sociopolitical framework stemming from colonialism, discrimination, and exploitation.⁵ Numerous studies reveal a lack of genetic precision in racial categories. In fact, genetic data compared across major continental groups found greater variation of microsatellite loci and restriction fragment length polymorphisms within racial groups than between them.⁶ The evidence indicates that racial categories do not reflect homogenous population groups but rather “arbitrary division[s] of continuous variation” that cannot serve as a surrogate to genetic diversity.⁵ Not only are racial categories genetically inaccurate, but data on race within the electronic health record often differ from patients’ self-description of race, underscoring the problematic nature of even identifying race.⁷ In one study, up to 41% of patients self-reported identification with at least one other racial or ethnic group than the race or ethnicity documented in their electronic health record.⁷

Additionally, conflating race with genetic variation can lead to diagnostic errors. As an example, the incidence of cystic fibrosis (CF) varies widely across populations of European ancestry. The primary focus on CF’s occurrence in patients of European descent may divert attention from the identification of mutations causing CF in populations of African descent or the decreased survival observed in the United States among CF patients of Hispanic descent.^8,9 Similarly, India represents one of the countries largely affected by SCD, suggesting that a myopic focus on SCD among those identifying as Black can lead to underdiagnosis of SCD among those with Indian ancestry.

Perhaps more insidiously, linking disease to race or other social constructs can result in differential support for affected individuals. SCD offers a striking illustration of this point. Reflecting the legacy of transatlantic slave trading, the majority of people with SCD in the United States are Black and face interpersonal and structural racism within society and healthcare that amplify the effects of this devastating illness.¹⁰ Compulsory screening programs for sickle cell trait introduced by many states in the 1970s targeted Black Americans and resulted in stigmatization and the denial of insurance, educational opportunities, and jobs for many identified with sickle cell trait. Federal funding for SCD research remains low, particularly in comparison to the tenfold higher funding for CF, which afflicts fewer, but primarily White, Americans.¹⁰

The incorporation of race into risk models and guidelines—alongside biologically relevant variables such as age and comorbid conditions—has received increasing attention for its potential to compound racial disparities in health outcomes. The American Heart Association Heart Failure Risk Score, for instance, may lead to the exclusion of some Black patients from necessary care because “Black” race, for no clear physiologic reason, serves as a protective factor against heart failure mortality.¹¹ Likewise, race adjustments in pulmonary function tests, breast cancer risk models, and estimated glomerular filtration rate calculations, among others, have limited biological basis and the potential to divert care disproportionately from minority populations.¹¹

Researchers have even called into question the application of race to pharmacotherapies. A 2001 investigation on geographic patterns of genetic variation in drug response concluded that common racial and ethnic labels were “insufficient and inaccurate representations” of the individual genetic clusters.¹² Further, numerous experts have criticized two landmark studies of vasodilators and angiotensin-converting enzyme inhibitors in Black patients with heart failure for inconsistent results and nonsignificant associations between race and major outcomes, such as the development of heart failure or death.¹³

Race-based labels can also divert attention from true causes of health inequities. The National Academy of Sciences concluded that social determinants of health and structural racism are the root causes of health inequities, rather than genetics.¹⁴ Medical professionals may perpetuate these disparities: Most US physicians demonstrate an unconscious preference—or implicit bias—for White Americans over Black Americans.¹⁵ Beyond obscuring the role of social determinants of health and structural racism in health outcomes, race-based labels may exacerbate the ways in which physicians’ implicit biases contribute to racial and ethnic health disparities, primarily affecting Black Americans.² In a recent study, clinicians documented race in the HPI for 33% of Black patients compared with 16% of White patients, and White clinicians were twice as likely to document race as Black physicians.¹⁶ Moreover, training medical students to view race as an independent risk factor of disease without discussing structural inequities can pathologize race and reinforce implicit biases linking race and disease.¹⁵

Based on the current evidence, we believe routine use of race-based labels in clinical presentations confuses providers at a minimum and potentially produces far more damage by obscuring or perpetuating the role of racism in health inequities.

Instead of routinely presenting race in the HPI, we recommend including racial or ethnic information in the social history only when the patient reports it as a meaningful identity or when it informs health disparities stemming from structural or interpersonal racism. Clinicians should include physical characteristics pertaining to race, such as skin tone, in the physical exam only if required to describe exam findings accurately. When presenting race, clinicians should explicitly justify its use and take care to avoid obfuscatory, inaccurate, or stigmatizing mention of associations between race and disease. Clinicians should not use race in clinical algorithms. Medical educators should emphasize the role of social determinants of health and structural racism in health outcomes to inform the use of race in medicine, in hopes that doing so will help students minimize implicit biases and learn to mitigate racial inequities in healthcare.^2,16 In short, clinicians and medical educators alike should ensure that clinical care and the medical curriculum avoid presenting race as a proxy for pathology.

There is little evidence to guide proper inclusion of race in clinical interviews. In the absence of clear guidance about how to approach patients about race, we suggest not asking about it unless there is a reasonable probability that doing so will improve clinical care. If a clinician decides to ask about race, it is important to provide a rationale—such as explaining that the information can be used to assure high-quality care for all patients—since many patients are uncomfortable with questions about race.¹⁷ If clinicians report information about race in the social history, we advise using the patient’s description of race rather than traditional racial categories.

Clinicians who ask their patients about race should approach every patient in a uniform manner to avoid perpetuating biases. We hope future studies will inform equitable, inclusive, and person-centered approaches to discussing race with patients and promote a shared understanding of how racism contributes to illness.

• Avoid using racial descriptors in the HPI.
• Include racial and ethnic information in the social history only when it serves as a meaningful identity or it informs disparities stemming from racism.
• If racial or ethnic information is asked for, explain to patients why and how it will be used.
• Mention physical characteristics such as skin tone, rather than race, in the physical exam if required to describe findings accurately.
• Advocate for the replacement of race or race-adjusted algorithms in patient care.
• Expand the medical curriculum in the social determinants of health and structural racism, and develop systems to avoid the use of stigmatizing, race-based labels.

Race, a sociopolitical construct, does not accurately represent genetic variation. The routine use of race in the HPI can perpetuate racial biases and muddle both diagnoses and treatment. Only mention race in the social history if it is meaningful to the patient’s self-identity or explains health disparities arising from racism. All documentation and presentations should avoid the use of stigmatizing, race-based labels.

In the clinical scenario mentioned earlier, the attending hospitalist raises the issue of race-based labels in patient care in a nonjudgmental fashion. To provide illustrative specificity, she notes how the incorporation of race in formulas of glomerular filtration rate can lead to under-referral for renal transplant. The hospitalist then facilitates an open and inclusive discussion with the team regarding the use of race in clinical presentations and its potential impact on health disparities.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason^™” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

On teaching rounds, a medical student presents the following case to the attending hospitalist: “Mrs. L is a 54-year-old Black female with chronic kidney disease who was admitted with community-acquired pneumonia. She continues to improve symptomatically on ceftriaxone. Currently, she is afebrile and her vitals are stable. Supplemental oxygen has been weaned to 2 L/min by nasal cannula. Exam reveals improved crackles in the left lower chest without dullness to percussion. Labs are notable for down-trending leukocytosis and a stable serum creatinine of 2.8 mg/dL.” The hospitalist considers how including racial descriptors in clinical presentations may influence the care of the patient.

For decades, medical educators have taught learners to include sociopolitical constructs such as race in the opening sentence of the history of present illness (HPI). This practice presumably stems from the assumption that race accurately reflects biogenetic information about patients and serves as a key attribute in problem representations.¹ Proponents of including race in the HPI suggest doing so aids the clinical assessment of patients’ risks for particular diseases and may inform the selection of race-appropriate therapies.²

The construct of race does sometimes correlate with the risk of disease or response to therapies. For example, sickle cell disease (SCD) occurs more commonly among patients who identify as Black rather than White. Specifically, ancestry from African nations such as Nigeria or the Democratic Republic of Congo increases the likelihood of having the disease-associated hemoglobin gene variant HbS.¹ Popular genomic ancestry tests often report ancestral groupings that map to racial categories and may reinforce the perception that race has a genetic basis.³

Race, a construct of sociopolitical origins, incorrectly conflates skin color with genetic variation. Associations between race and disease have the potential to cause diagnostic and therapeutic errors and inequitable allocation of resources. Increased illness burden in minority populations results primarily from social factors such as environment, access to care, housing instability, food insecurity, and experiences of discrimination, rather than genetic differences. The resulting chronic and recurrent physiologic stress—known as allostatic load—also contributes to the inequitable health outcomes observed in vulnerable populations, including patients who identify as Black.⁴

Historically, race evolved as a sociopolitical framework stemming from colonialism, discrimination, and exploitation.⁵ Numerous studies reveal a lack of genetic precision in racial categories. In fact, genetic data compared across major continental groups found greater variation of microsatellite loci and restriction fragment length polymorphisms within racial groups than between them.⁶ The evidence indicates that racial categories do not reflect homogenous population groups but rather “arbitrary division[s] of continuous variation” that cannot serve as a surrogate to genetic diversity.⁵ Not only are racial categories genetically inaccurate, but data on race within the electronic health record often differ from patients’ self-description of race, underscoring the problematic nature of even identifying race.⁷ In one study, up to 41% of patients self-reported identification with at least one other racial or ethnic group than the race or ethnicity documented in their electronic health record.⁷

Additionally, conflating race with genetic variation can lead to diagnostic errors. As an example, the incidence of cystic fibrosis (CF) varies widely across populations of European ancestry. The primary focus on CF’s occurrence in patients of European descent may divert attention from the identification of mutations causing CF in populations of African descent or the decreased survival observed in the United States among CF patients of Hispanic descent.^8,9 Similarly, India represents one of the countries largely affected by SCD, suggesting that a myopic focus on SCD among those identifying as Black can lead to underdiagnosis of SCD among those with Indian ancestry.

Perhaps more insidiously, linking disease to race or other social constructs can result in differential support for affected individuals. SCD offers a striking illustration of this point. Reflecting the legacy of transatlantic slave trading, the majority of people with SCD in the United States are Black and face interpersonal and structural racism within society and healthcare that amplify the effects of this devastating illness.¹⁰ Compulsory screening programs for sickle cell trait introduced by many states in the 1970s targeted Black Americans and resulted in stigmatization and the denial of insurance, educational opportunities, and jobs for many identified with sickle cell trait. Federal funding for SCD research remains low, particularly in comparison to the tenfold higher funding for CF, which afflicts fewer, but primarily White, Americans.¹⁰

The incorporation of race into risk models and guidelines—alongside biologically relevant variables such as age and comorbid conditions—has received increasing attention for its potential to compound racial disparities in health outcomes. The American Heart Association Heart Failure Risk Score, for instance, may lead to the exclusion of some Black patients from necessary care because “Black” race, for no clear physiologic reason, serves as a protective factor against heart failure mortality.¹¹ Likewise, race adjustments in pulmonary function tests, breast cancer risk models, and estimated glomerular filtration rate calculations, among others, have limited biological basis and the potential to divert care disproportionately from minority populations.¹¹

Researchers have even called into question the application of race to pharmacotherapies. A 2001 investigation on geographic patterns of genetic variation in drug response concluded that common racial and ethnic labels were “insufficient and inaccurate representations” of the individual genetic clusters.¹² Further, numerous experts have criticized two landmark studies of vasodilators and angiotensin-converting enzyme inhibitors in Black patients with heart failure for inconsistent results and nonsignificant associations between race and major outcomes, such as the development of heart failure or death.¹³

Race-based labels can also divert attention from true causes of health inequities. The National Academy of Sciences concluded that social determinants of health and structural racism are the root causes of health inequities, rather than genetics.¹⁴ Medical professionals may perpetuate these disparities: Most US physicians demonstrate an unconscious preference—or implicit bias—for White Americans over Black Americans.¹⁵ Beyond obscuring the role of social determinants of health and structural racism in health outcomes, race-based labels may exacerbate the ways in which physicians’ implicit biases contribute to racial and ethnic health disparities, primarily affecting Black Americans.² In a recent study, clinicians documented race in the HPI for 33% of Black patients compared with 16% of White patients, and White clinicians were twice as likely to document race as Black physicians.¹⁶ Moreover, training medical students to view race as an independent risk factor of disease without discussing structural inequities can pathologize race and reinforce implicit biases linking race and disease.¹⁵

Based on the current evidence, we believe routine use of race-based labels in clinical presentations confuses providers at a minimum and potentially produces far more damage by obscuring or perpetuating the role of racism in health inequities.

Instead of routinely presenting race in the HPI, we recommend including racial or ethnic information in the social history only when the patient reports it as a meaningful identity or when it informs health disparities stemming from structural or interpersonal racism. Clinicians should include physical characteristics pertaining to race, such as skin tone, in the physical exam only if required to describe exam findings accurately. When presenting race, clinicians should explicitly justify its use and take care to avoid obfuscatory, inaccurate, or stigmatizing mention of associations between race and disease. Clinicians should not use race in clinical algorithms. Medical educators should emphasize the role of social determinants of health and structural racism in health outcomes to inform the use of race in medicine, in hopes that doing so will help students minimize implicit biases and learn to mitigate racial inequities in healthcare.^2,16 In short, clinicians and medical educators alike should ensure that clinical care and the medical curriculum avoid presenting race as a proxy for pathology.

There is little evidence to guide proper inclusion of race in clinical interviews. In the absence of clear guidance about how to approach patients about race, we suggest not asking about it unless there is a reasonable probability that doing so will improve clinical care. If a clinician decides to ask about race, it is important to provide a rationale—such as explaining that the information can be used to assure high-quality care for all patients—since many patients are uncomfortable with questions about race.¹⁷ If clinicians report information about race in the social history, we advise using the patient’s description of race rather than traditional racial categories.

Clinicians who ask their patients about race should approach every patient in a uniform manner to avoid perpetuating biases. We hope future studies will inform equitable, inclusive, and person-centered approaches to discussing race with patients and promote a shared understanding of how racism contributes to illness.

• Avoid using racial descriptors in the HPI.
• Include racial and ethnic information in the social history only when it serves as a meaningful identity or it informs disparities stemming from racism.
• If racial or ethnic information is asked for, explain to patients why and how it will be used.
• Mention physical characteristics such as skin tone, rather than race, in the physical exam if required to describe findings accurately.
• Advocate for the replacement of race or race-adjusted algorithms in patient care.
• Expand the medical curriculum in the social determinants of health and structural racism, and develop systems to avoid the use of stigmatizing, race-based labels.

Race, a sociopolitical construct, does not accurately represent genetic variation. The routine use of race in the HPI can perpetuate racial biases and muddle both diagnoses and treatment. Only mention race in the social history if it is meaningful to the patient’s self-identity or explains health disparities arising from racism. All documentation and presentations should avoid the use of stigmatizing, race-based labels.

In the clinical scenario mentioned earlier, the attending hospitalist raises the issue of race-based labels in patient care in a nonjudgmental fashion. To provide illustrative specificity, she notes how the incorporation of race in formulas of glomerular filtration rate can lead to under-referral for renal transplant. The hospitalist then facilitates an open and inclusive discussion with the team regarding the use of race in clinical presentations and its potential impact on health disparities.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason^™” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

On teaching rounds, a medical student presents the following case to the attending hospitalist: “Mrs. L is a 54-year-old Black female with chronic kidney disease who was admitted with community-acquired pneumonia. She continues to improve symptomatically on ceftriaxone. Currently, she is afebrile and her vitals are stable. Supplemental oxygen has been weaned to 2 L/min by nasal cannula. Exam reveals improved crackles in the left lower chest without dullness to percussion. Labs are notable for down-trending leukocytosis and a stable serum creatinine of 2.8 mg/dL.” The hospitalist considers how including racial descriptors in clinical presentations may influence the care of the patient.

For decades, medical educators have taught learners to include sociopolitical constructs such as race in the opening sentence of the history of present illness (HPI). This practice presumably stems from the assumption that race accurately reflects biogenetic information about patients and serves as a key attribute in problem representations.¹ Proponents of including race in the HPI suggest doing so aids the clinical assessment of patients’ risks for particular diseases and may inform the selection of race-appropriate therapies.²

The construct of race does sometimes correlate with the risk of disease or response to therapies. For example, sickle cell disease (SCD) occurs more commonly among patients who identify as Black rather than White. Specifically, ancestry from African nations such as Nigeria or the Democratic Republic of Congo increases the likelihood of having the disease-associated hemoglobin gene variant HbS.¹ Popular genomic ancestry tests often report ancestral groupings that map to racial categories and may reinforce the perception that race has a genetic basis.³

Race, a construct of sociopolitical origins, incorrectly conflates skin color with genetic variation. Associations between race and disease have the potential to cause diagnostic and therapeutic errors and inequitable allocation of resources. Increased illness burden in minority populations results primarily from social factors such as environment, access to care, housing instability, food insecurity, and experiences of discrimination, rather than genetic differences. The resulting chronic and recurrent physiologic stress—known as allostatic load—also contributes to the inequitable health outcomes observed in vulnerable populations, including patients who identify as Black.⁴

Historically, race evolved as a sociopolitical framework stemming from colonialism, discrimination, and exploitation.⁵ Numerous studies reveal a lack of genetic precision in racial categories. In fact, genetic data compared across major continental groups found greater variation of microsatellite loci and restriction fragment length polymorphisms within racial groups than between them.⁶ The evidence indicates that racial categories do not reflect homogenous population groups but rather “arbitrary division[s] of continuous variation” that cannot serve as a surrogate to genetic diversity.⁵ Not only are racial categories genetically inaccurate, but data on race within the electronic health record often differ from patients’ self-description of race, underscoring the problematic nature of even identifying race.⁷ In one study, up to 41% of patients self-reported identification with at least one other racial or ethnic group than the race or ethnicity documented in their electronic health record.⁷

Additionally, conflating race with genetic variation can lead to diagnostic errors. As an example, the incidence of cystic fibrosis (CF) varies widely across populations of European ancestry. The primary focus on CF’s occurrence in patients of European descent may divert attention from the identification of mutations causing CF in populations of African descent or the decreased survival observed in the United States among CF patients of Hispanic descent.^8,9 Similarly, India represents one of the countries largely affected by SCD, suggesting that a myopic focus on SCD among those identifying as Black can lead to underdiagnosis of SCD among those with Indian ancestry.

Perhaps more insidiously, linking disease to race or other social constructs can result in differential support for affected individuals. SCD offers a striking illustration of this point. Reflecting the legacy of transatlantic slave trading, the majority of people with SCD in the United States are Black and face interpersonal and structural racism within society and healthcare that amplify the effects of this devastating illness.¹⁰ Compulsory screening programs for sickle cell trait introduced by many states in the 1970s targeted Black Americans and resulted in stigmatization and the denial of insurance, educational opportunities, and jobs for many identified with sickle cell trait. Federal funding for SCD research remains low, particularly in comparison to the tenfold higher funding for CF, which afflicts fewer, but primarily White, Americans.¹⁰

The incorporation of race into risk models and guidelines—alongside biologically relevant variables such as age and comorbid conditions—has received increasing attention for its potential to compound racial disparities in health outcomes. The American Heart Association Heart Failure Risk Score, for instance, may lead to the exclusion of some Black patients from necessary care because “Black” race, for no clear physiologic reason, serves as a protective factor against heart failure mortality.¹¹ Likewise, race adjustments in pulmonary function tests, breast cancer risk models, and estimated glomerular filtration rate calculations, among others, have limited biological basis and the potential to divert care disproportionately from minority populations.¹¹

Researchers have even called into question the application of race to pharmacotherapies. A 2001 investigation on geographic patterns of genetic variation in drug response concluded that common racial and ethnic labels were “insufficient and inaccurate representations” of the individual genetic clusters.¹² Further, numerous experts have criticized two landmark studies of vasodilators and angiotensin-converting enzyme inhibitors in Black patients with heart failure for inconsistent results and nonsignificant associations between race and major outcomes, such as the development of heart failure or death.¹³

Race-based labels can also divert attention from true causes of health inequities. The National Academy of Sciences concluded that social determinants of health and structural racism are the root causes of health inequities, rather than genetics.¹⁴ Medical professionals may perpetuate these disparities: Most US physicians demonstrate an unconscious preference—or implicit bias—for White Americans over Black Americans.¹⁵ Beyond obscuring the role of social determinants of health and structural racism in health outcomes, race-based labels may exacerbate the ways in which physicians’ implicit biases contribute to racial and ethnic health disparities, primarily affecting Black Americans.² In a recent study, clinicians documented race in the HPI for 33% of Black patients compared with 16% of White patients, and White clinicians were twice as likely to document race as Black physicians.¹⁶ Moreover, training medical students to view race as an independent risk factor of disease without discussing structural inequities can pathologize race and reinforce implicit biases linking race and disease.¹⁵

Based on the current evidence, we believe routine use of race-based labels in clinical presentations confuses providers at a minimum and potentially produces far more damage by obscuring or perpetuating the role of racism in health inequities.

Instead of routinely presenting race in the HPI, we recommend including racial or ethnic information in the social history only when the patient reports it as a meaningful identity or when it informs health disparities stemming from structural or interpersonal racism. Clinicians should include physical characteristics pertaining to race, such as skin tone, in the physical exam only if required to describe exam findings accurately. When presenting race, clinicians should explicitly justify its use and take care to avoid obfuscatory, inaccurate, or stigmatizing mention of associations between race and disease. Clinicians should not use race in clinical algorithms. Medical educators should emphasize the role of social determinants of health and structural racism in health outcomes to inform the use of race in medicine, in hopes that doing so will help students minimize implicit biases and learn to mitigate racial inequities in healthcare.^2,16 In short, clinicians and medical educators alike should ensure that clinical care and the medical curriculum avoid presenting race as a proxy for pathology.

There is little evidence to guide proper inclusion of race in clinical interviews. In the absence of clear guidance about how to approach patients about race, we suggest not asking about it unless there is a reasonable probability that doing so will improve clinical care. If a clinician decides to ask about race, it is important to provide a rationale—such as explaining that the information can be used to assure high-quality care for all patients—since many patients are uncomfortable with questions about race.¹⁷ If clinicians report information about race in the social history, we advise using the patient’s description of race rather than traditional racial categories.

Clinicians who ask their patients about race should approach every patient in a uniform manner to avoid perpetuating biases. We hope future studies will inform equitable, inclusive, and person-centered approaches to discussing race with patients and promote a shared understanding of how racism contributes to illness.

• Avoid using racial descriptors in the HPI.
• Include racial and ethnic information in the social history only when it serves as a meaningful identity or it informs disparities stemming from racism.
• If racial or ethnic information is asked for, explain to patients why and how it will be used.
• Mention physical characteristics such as skin tone, rather than race, in the physical exam if required to describe findings accurately.
• Advocate for the replacement of race or race-adjusted algorithms in patient care.
• Expand the medical curriculum in the social determinants of health and structural racism, and develop systems to avoid the use of stigmatizing, race-based labels.

Race, a sociopolitical construct, does not accurately represent genetic variation. The routine use of race in the HPI can perpetuate racial biases and muddle both diagnoses and treatment. Only mention race in the social history if it is meaningful to the patient’s self-identity or explains health disparities arising from racism. All documentation and presentations should avoid the use of stigmatizing, race-based labels.

In the clinical scenario mentioned earlier, the attending hospitalist raises the issue of race-based labels in patient care in a nonjudgmental fashion. To provide illustrative specificity, she notes how the incorporation of race in formulas of glomerular filtration rate can lead to under-referral for renal transplant. The hospitalist then facilitates an open and inclusive discussion with the team regarding the use of race in clinical presentations and its potential impact on health disparities.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason^™” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter.

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 32-year-old, previously healthy woman presented to the emergency department (ED) with 3 days of nasal pain, congestion, and cough. A day prior, she had consulted with her primary care provider by phone and had been prescribed amoxicillin-clavulanate for presumed bacterial sinusitis. She subsequently developed fever (39 oC) and pleuritic, left-upper-quadrant abdominal pain. In the ED, chest radiograph demonstrated right hilar opacification. Laboratory studies and computed tomography (CT) of the abdomen and pelvis did not identify a cause for her pain. Given the pleuritic nature of her left-upper-quadrant pain, CT pulmonary angiography was ordered. The CT revealed “mass-like” right hilar opacification and lymphadenopathy. No pulmonary emboli were identified. Levofloxacin was prescribed for presumed pneumonia, and the patient was discharged home. The following week, mediastinal biopsy was arranged for evaluation of the right hilar abnormality.

This is a young woman presenting with upper respiratory symptoms, abdominal pain, fever, and hilar lymphadenopathy. Upper respiratory symptoms are common and usually indicate an inflammatory response to allergens or infection, though autoimmune disorders may affect the upper airways. Fever and hilar lymphadenopathy likely also signify an inflammatory response. Taken together, these findings can be associated with mycobacterial or fungal infection, malignancy, and, particularly in a young woman, sarcoidosis, which could explain her abdominal pain if her presentation included splenomegaly. At this point she likely has a systemic illness involving at least the upper, and possibly the lower, respiratory tract.

Within days, her symptoms resolved. Mediastinal biopsy of the hilar node revealed scant pus. Pathology demonstrated suppurative granulomata. Gram stain; bacterial, mycobacterial, and fungal cultures; and 16S ribosomal analyses for bacteria and fungi from the biopsy were unrevealing. For unclear reasons, prior to the biopsy, she was given intramuscular Haemophilus influenzae type B and tetanus, diphtheria, and pertussis vaccines. Two weeks later, she presented again with fever and left-upper-quadrant pain as well as painful skin nodules at her biopsy and vaccination sites. She was admitted for further evaluation. Chest CT showed expansion of the mediastinal lesion and splenic enlargement. Biopsy of a skin lesion revealed suppurative granulomatous dermatitis and panniculitis. Repeat blood cultures were negative, though serum β-D-glucan was weakly positive at 173 pg/mL (reference range, <60 pg/mL). Tissue cultures and Gram, acid-fast, Fite, and Warthin-Starry stains from the skin biopsy were negative. She was discharged on fluconazole and then readmitted 2 days later with dyspnea, fever, and leukocytosis.

The young woman’s symptoms resolved, only to recur days later; her granulomatous hilar lesions grew larger, and new cutaneous and splenic findings appeared. The granulomatous lesions prompt consideration of infectious, malignant, and immune-mediated processes. The negative cultures make infection less likely, although the elevated β-D-glucan may suggest fungal infection. By description, the skin lesions are consistent with pathergy, a phenomenon characterized by trauma-provoked cutaneous lesions or ulcers, which is associated with numerous syndromes, including Behçet syndrome, inflammatory bowel disease, and neutrophilic dermatoses such as pyoderma gangrenosum (PG) and Sweet syndrome. In addition to details about her medical history, it is important to seek evidence of oral ulcers or vasculitis, as Behçet syndrome may be associated with cutaneous, visceral, and ophthalmologic vasculitis.

Her medical history included hypertension and active, 10-pack-year cigarette use. During childhood, she had occasional ingrown hairs and folliculitis. She did not take medications prior to this acute illness. Family history was notable for cardiovascular disease. She rarely consumed alcohol and did not use illicit drugs. She lived in a rural town in the mid–Willamette Valley of Oregon and worked as an administrative assistant. She spent time outdoors, including trail running and golfing. A case of tularemia was recently reported in an area near her home. Her only travel outside of Oregon was to Puerto Vallarta, Mexico, 16 years previously. She grew up on a farm and had no known tuberculosis exposure.

Tularemia is an interesting diagnostic consideration and could explain her fever, cutaneous lesions, and hilar adenopathy. It is plausible that she had clinically mild pneumonic tularemia at the outset and that her cutaneous lesions are variants of ulceroglandular tularemia. Positive antibodies for Francisella tularensis would be expected if this were the cause of her illness. The ingrown hairs raise the possibility of a primary immune deficiency syndrome predisposing her to abscesses. However, they seem to have been of trivial significance to her, making an immune deficiency syndrome unlikely.

On readmission, she was afebrile, normotensive, and tachycardic (114 beats/min), with a normal respiratory rate and oxygen saturation. She was not ill appearing. She had noninjected conjunctiva and no oral lesions. Apart from tachycardia, cardiovascular examination was unremarkable. Abdominal examination was notable for mild distension and a palpable, tender spleen. Musculoskeletal and neurologic examinations were normal. Her skin was notable for various sized (8 cm × 4 cm to 10 cm × 15 cm) painful ulcers with violaceous, friable borders—some with fluctuance and purulent drainage—on her right hand, bilateral arms, right axilla, sternum, and legs (Figure 1).

JHMVol16No9_Burnett14940915e_f1.JPG

Laboratory studies were notable for normocytic anemia (hemoglobin, 8.9 g/dL; range, 12.0-16.0 g/dL), leukocytosis (white blood cells, 24,900/µL; range, 4500-11,000/µL), thrombocytosis (platelet count, 690,000/µL; range, 150,000-400,000/µL), and elevated inflammatory markers (C-reactive protein, 33 mg/dL; range, <0.5 mg/dL; erythrocyte sedimentation rate, 78 mm/h; range, <20 mm/h). A complete metabolic panel was within normal limits. Repeat blood cultures and β -D-glucan and 16S ribosomal assays were negative. Polymerase chain reaction testing for Bartonella henselae was negative. Urine probes for Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Rapid plasma regain (RPR) was negative. Antibodies to toxoplasmosis, histoplasmosis, blastomycosis, and aspergillosis were unrevealing. A Coccidioides test by immunodiffusion was negative. Serum antigen tests for Cryptococcus and Epstein-Barr virus (EBV) were negative. EBV, HIV, and hepatitis antibody tests were negative. Rheumatologic studies, including antinuclear, anti-double-stranded DNA, anti-Smith, anti–Sjögren syndrome antigens A and B, anticentromere, anti-topoisomerase (anti-Scl-70), anti-histidyl-transfer-RNA-synthetase (anti-Jo-1), and anti-nucleosome (anti-chromatic) antibodies, were unrevealing. Levels of angiotensin-converting enzyme, rheumatoid factor, complement, cytoplasmic, and perinuclear antineutrophil cytoplasmic antibodies were also normal. A neutrophil oxidative burst test was negative. In addition, peripheral flow cytology and serum and urine protein electrophoresis were negative. Chest CT revealed bilateral lower lobe consolidations concerning for necrotizing pneumonia, splenic enlargement, numerous hypodense splenic lesions, and a 1.3-cm right hilar node, which had decreased in size compared with 1 month prior.

In summary, the patient presented with recurrent upper respiratory symptoms, fever, and abdominal pain; expanding granulomatous hilar lesions, splenomegaly, and cutaneous lesions consistent with pathergy; elevated inflammatory markers and leukocytosis; and a possible exposure to F tularensis. She has had extensive negative infectious workups, except for a weakly positive β-D-glucan, and completed several courses of apparently unhelpful antimicrobials. At this point, the most notable findings are her splenomegaly and inflammatory masses suggesting an inflammatory process, which may be autoimmune in nature. Both vasculitis and sarcoidosis remain possibilities, and malignancy is possible. Given her possible exposure to F tularensis, obtaining serum antibodies to F tularensis, in addition to biopsies of the skin lesions, is advisable.

Laboratory studies revealed a positive F tularensis antibody with a titer of 1:320 and an IgM of 7 U/mL and IgG of 30 U/mL. This was repeated, revealing a titer of 1:540 and an IgM and IgG of 5 U/mL and 20 U/mL, respectively. Given the potential exposure history, the clinical syndrome compatible with tularemia, and an otherwise extensive yet unrevealing evaluation, she was treated with a 10-day course of streptomycin. Her fever persisted, and the splenic lesions increased in size and number, prompting addition of moxifloxacin without apparent benefit. Skin biopsies taken from the patient’s arm were notable for nodular, suppurative, neutrophilic infiltrates and histiocytes in the medium and deep dermis without multinucleated histiocytes or evidence of vasculitis. Fungal, mycobacterial, and bacterial stains from the biopsy were negative. The findings were consistent with but not diagnostic of an acute neutrophilic dermatosis.

At this point, the patient has a confirmed exposure to F tularensis; she also has persistent fever, progressive splenomegaly, and new skin biopsies consistent with neutrophilic dermatosis. Despite the F tularensis antibody positivity, her negative cultures and lack of improvement with multiple courses of antimicrobials argue against an infectious etiology. Accordingly, malignancy should be considered but seems less likely given that no laboratory, imaging, or tissue samples support it. This leaves immune-mediated etiologies, especially autoimmune conditions associated with neutrophilic dermatoses, as the most likely explanation of her inflammatory syndrome. Neutrophilic dermatoses include some vasculitides, Sweet syndrome, PG, Behçet syndrome, and other inflammatory entities. She has no evidence of vasculitis on biopsy. Given the evidence of inflammation and the history of pathergy, Behçet syndrome and PG should be seriously considered.

She underwent incision and drainage of the left leg and mediastinal lesions. A follow-up chest CT revealed stable cutaneous and deep tissue lesions and continued splenic enlargement. She was started on prednisone and dapsone for presumed cutaneous and visceral PG. The lesions improved dramatically and, following a month-long hospitalization, she was discharged on dapsone and a slow prednisone taper. Three weeks after discharge, while on dapsone and prednisone, she developed a new skin lesion. Cyclosporine was added, with improvement. Eight weeks after discharge, she developed fever, acute left-upper-quadrant pain, and marked splenomegaly with abscesses seen on CT imaging (Figure 2).

JHMVol16No9_Burnett14940915e_f2.JPG

This continues to be a very puzzling case, and it is worth revisiting her clinical course once again. This is a previously healthy 32-year-old woman with multiple hospital presentations for upper-respiratory symptoms, persistent fever, abdominal pain, and painful cutaneous lesions consistent with pathergy; she was found to have granulomatous hilar lesions, progressive splenomegaly, and skin biopsies consistent with neutrophilic dermatosis. Exhaustive infectious and rheumatologic workup was negative, and no evident malignancy was found. Finally, despite multiple courses of antimicrobials, including standard treatments for tularemia (for which she had positive antibodies), her clinical course failed to improve until the addition of systemic anti-inflammatory agents, which resulted in rapid improvement. She then presented 8 weeks later with recurrent fever and splenomegaly. Given the recurrence and the severity of the splenic pathology, a diagnostic splenectomy is advisable for what appears to be visceral PG. In addition, attempting to identify a trigger of her syndrome is important. PG can be associated with inflammatory bowel disease, hematologic disorders (eg, leukemia, myeloma, myelodysplastic syndrome, and myelofibrosis), and autoimmune diseases, especially inflammatory arthritis.¹ Therefore, a diagnostic colonoscopy and bone marrow biopsy should be considered. With no history or examination supporting inflammatory arthritis and a broad, unrevealing workup, her rheumatologic evaluation is sufficient.

The patient underwent splenectomy. Gross description of the spleen was notable for multiple abscesses, consisting on microscopy of large areas of necrosis with islands of dense neutrophil collections (Figure 3). Microscopic examination failed to demonstrate microorganisms on multiple stains, and there was no microscopic or flow cytometric evidence of lymphoma. The final pathologic diagnosis was multiple sterile splenic abscesses with siderosis, which, in the context of her overall syndrome, was consistent with an entity termed aseptic abscess syndrome (AAS). After discharge, she underwent a slow steroid taper and was ultimately maintained on daily low-dose prednisone. Cyclosporine and dapsone were discontinued in favor of infliximab infusions. She underwent additional diagnostic workup, including an unremarkable colonoscopy and a bone marrow biopsy, which showed monoclonal gammopathy of undetermined significance (MGUS) with an insignificant IgA monoclonal gammopathy. All cutaneous lesions healed. Three years after the splenectomy, while still on infliximab and prednisone, she developed a new aseptic lung abscess, which resolved after increasing her prednisone dose. Six years after splenectomy, she developed an aseptic liver abscess, which resolved after again increasing the frequency of her infliximab infusions.

JHMVol16No9_Burnett14940915e_f3.JPG

Diagnostic uncertainty is an intrinsic feature of medical practice—in part because patients often present with undifferentiated and evolving symptoms.² When faced with uncertainty, clinicians are well served by prioritizing a thoughtful differential diagnosis, adopting a stepwise management strategy, and engaging in iterative reassessments of the patient. In this case, a 32-year-old, previously healthy woman presented with an array of symptoms, including abdominal pain, fever, leukocytosis, necrotic skin lesions, necrotizing mediastinal lymphadenitis, pathergy, and splenomegaly. Elements of the history, examination, and diagnostic studies supported a differential diagnosis of tularemia, PG, and AAS. Through stepwise management and ongoing reassessment, she was ultimately diagnosed with AAS.

Tularemia was initially an important diagnostic consideration in this patient, given her potential exposure and positive F tularensis serum antibodies. Francisella tularensis is a Gram-negative coccobacillus found in more than 250 species of fish, ticks, birds, and mammals. In humans, an incubation period of 3 to 5 days is typical. Although clinical manifestations vary, they often include fever, headache, and malaise.³ Other findings may include lymphadenopathy with or without ulcerative cutaneous lesions (glandular or ulceroglandular tularemia) and cough, dyspnea, pleuritic chest pain, and hilar adenopathy (pneumonic tularemia). As noted by the discussant, a pneumonic tularemia syndrome could have explained this patient’s fever, respiratory symptoms, and hilar adenopathy; ulceroglandular tularemia might have explained her cutaneous lesions. Since splenomegaly may be seen in tularemia, this finding was also consistent with the diagnosis. Serum antibody testing is supportive of the diagnosis, while culture confirms it. Standard treatment consists of a 10- to 14-day course of streptomycin, and combination therapy with a fluoroquinolone is recommended in severe cases.⁴ In this patient, however, F tularensis was not demonstrated on culture. Furthermore, she did not experience the expected clinical improvement with treatment. Finally, because both IgG and IgM tularemia antibodies may co-occur up to 10 years following infection, her positive F tularensis serum antibodies did not provide evidence of acute infection.⁵

Recognizing inconsistencies in the diagnosis of tularemia, the focus shifted to PG owing to the patient’s neutrophilic cutaneous lesions, negative infectious workup, and pathergy. Pyoderma gangrenosum is a neutrophilic dermatosis—one of a heterogeneous group of skin conditions characterized by perivascular and diffuse neutrophilic infiltrates without an identifiable infectious agent.⁶ It is a chronic, recurrent cutaneous disease with several variants.⁷ The classic presentation includes painful lower-extremity ulcers with violaceous undermined borders and may be associated with pathergy. Guiding principles for the management of PG include controlling inflammation, optimizing wound healing, and minimizing exacerbating factors.¹ As such, treatment mainstays include local and systemic anti-inflammatory agents and wound care. As the discussant highlighted, in this case the inflammatory skin lesions were suggestive of PG. However, other features of the case, notably, splenomegaly, splenic abscesses, and necrotizing mediastinal lymphadenitis, were more consistent with another diagnosis: AAS. Aseptic abscess syndrome is an autoinflammatory disorder defined by deep, noninfectious abscesses that preferentially affect the spleen.⁸ Additional clinical manifestations include weight loss, fever, abdominal pain, and leukocytosis. Lesions may also affect bone, kidney, liver, lung, lymph node, and skin. In one case series, neutrophilic dermatoses were seen in 20% of AAS cases.⁸ In all cases of AAS, extensive infectious workup is unrevealing, and antibiotics are ineffective. The pathophysiology of AAS is unknown.

Similar to PG, the majority of AAS cases are associated with inflammatory bowel disease, especially Crohn disease.⁹ However, AAS also has associations with conditions such as MGUS, rheumatoid arthritis, spondyloarthritis, and relapsing polychondritis. Histologically, early lesions demonstrate a necrotic core of neutrophils, with or without surrounding palisading histiocytes, and giant cells. In older lesions, neutrophils may be absent; fibrous tissue may be present.⁸ Treatment regimens include splenectomy, corticosteroids, colchicine, thalidomide, tumor necrosis factor (TNF) antagonists, and cyclophosphamide. The discussant astutely recommended a splenectomy for this patient, which was both diagnostic and therapeutic. As in this case, relapse is common. Optimal maintenance therapy is yet to be determined.⁹

Given the overlapping clinical manifestations, shared disease associations, and similar responsiveness to immunosuppression, it is unclear whether AAS represents a new disease entity or a variant of known autoinflammatory disorders. Aseptic abscess syndrome is likely part of a spectrum of autoinflammatory disorders with inflammatory bowel diseases, neutrophilic dermatoses, and other similar diseases.⁸ While infectious visceral abscesses remain more common, this case highlights the clinical manifestation of an emerging and likely underrecognized entity.

• Aseptic abscess syndrome should be considered in patients who present with visceral (particularly splenic) abscesses and negative infectious workup.
• Aseptic abscess syndrome is commonly associated with other autoinflammatory disorders; the majority of reported cases are associated with inflammatory bowel disease, especially Crohn disease.
• Up to 20% of AAS cases are associated with neutrophilic dermatoses such as PG.
• The initial treatment for this syndrome is high-dose intravenous glucocorticoids; maintenance treatment regimens include corticosteroids, colchicine, thalidomide, TNF antagonists, and cyclophosphamide.

The authors would thank Dr Bob Pelz and Dr John Townes for their contributions to the case.

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 32-year-old, previously healthy woman presented to the emergency department (ED) with 3 days of nasal pain, congestion, and cough. A day prior, she had consulted with her primary care provider by phone and had been prescribed amoxicillin-clavulanate for presumed bacterial sinusitis. She subsequently developed fever (39 oC) and pleuritic, left-upper-quadrant abdominal pain. In the ED, chest radiograph demonstrated right hilar opacification. Laboratory studies and computed tomography (CT) of the abdomen and pelvis did not identify a cause for her pain. Given the pleuritic nature of her left-upper-quadrant pain, CT pulmonary angiography was ordered. The CT revealed “mass-like” right hilar opacification and lymphadenopathy. No pulmonary emboli were identified. Levofloxacin was prescribed for presumed pneumonia, and the patient was discharged home. The following week, mediastinal biopsy was arranged for evaluation of the right hilar abnormality.

This is a young woman presenting with upper respiratory symptoms, abdominal pain, fever, and hilar lymphadenopathy. Upper respiratory symptoms are common and usually indicate an inflammatory response to allergens or infection, though autoimmune disorders may affect the upper airways. Fever and hilar lymphadenopathy likely also signify an inflammatory response. Taken together, these findings can be associated with mycobacterial or fungal infection, malignancy, and, particularly in a young woman, sarcoidosis, which could explain her abdominal pain if her presentation included splenomegaly. At this point she likely has a systemic illness involving at least the upper, and possibly the lower, respiratory tract.

Within days, her symptoms resolved. Mediastinal biopsy of the hilar node revealed scant pus. Pathology demonstrated suppurative granulomata. Gram stain; bacterial, mycobacterial, and fungal cultures; and 16S ribosomal analyses for bacteria and fungi from the biopsy were unrevealing. For unclear reasons, prior to the biopsy, she was given intramuscular Haemophilus influenzae type B and tetanus, diphtheria, and pertussis vaccines. Two weeks later, she presented again with fever and left-upper-quadrant pain as well as painful skin nodules at her biopsy and vaccination sites. She was admitted for further evaluation. Chest CT showed expansion of the mediastinal lesion and splenic enlargement. Biopsy of a skin lesion revealed suppurative granulomatous dermatitis and panniculitis. Repeat blood cultures were negative, though serum β-D-glucan was weakly positive at 173 pg/mL (reference range, <60 pg/mL). Tissue cultures and Gram, acid-fast, Fite, and Warthin-Starry stains from the skin biopsy were negative. She was discharged on fluconazole and then readmitted 2 days later with dyspnea, fever, and leukocytosis.

The young woman’s symptoms resolved, only to recur days later; her granulomatous hilar lesions grew larger, and new cutaneous and splenic findings appeared. The granulomatous lesions prompt consideration of infectious, malignant, and immune-mediated processes. The negative cultures make infection less likely, although the elevated β-D-glucan may suggest fungal infection. By description, the skin lesions are consistent with pathergy, a phenomenon characterized by trauma-provoked cutaneous lesions or ulcers, which is associated with numerous syndromes, including Behçet syndrome, inflammatory bowel disease, and neutrophilic dermatoses such as pyoderma gangrenosum (PG) and Sweet syndrome. In addition to details about her medical history, it is important to seek evidence of oral ulcers or vasculitis, as Behçet syndrome may be associated with cutaneous, visceral, and ophthalmologic vasculitis.

Her medical history included hypertension and active, 10-pack-year cigarette use. During childhood, she had occasional ingrown hairs and folliculitis. She did not take medications prior to this acute illness. Family history was notable for cardiovascular disease. She rarely consumed alcohol and did not use illicit drugs. She lived in a rural town in the mid–Willamette Valley of Oregon and worked as an administrative assistant. She spent time outdoors, including trail running and golfing. A case of tularemia was recently reported in an area near her home. Her only travel outside of Oregon was to Puerto Vallarta, Mexico, 16 years previously. She grew up on a farm and had no known tuberculosis exposure.

Tularemia is an interesting diagnostic consideration and could explain her fever, cutaneous lesions, and hilar adenopathy. It is plausible that she had clinically mild pneumonic tularemia at the outset and that her cutaneous lesions are variants of ulceroglandular tularemia. Positive antibodies for Francisella tularensis would be expected if this were the cause of her illness. The ingrown hairs raise the possibility of a primary immune deficiency syndrome predisposing her to abscesses. However, they seem to have been of trivial significance to her, making an immune deficiency syndrome unlikely.

On readmission, she was afebrile, normotensive, and tachycardic (114 beats/min), with a normal respiratory rate and oxygen saturation. She was not ill appearing. She had noninjected conjunctiva and no oral lesions. Apart from tachycardia, cardiovascular examination was unremarkable. Abdominal examination was notable for mild distension and a palpable, tender spleen. Musculoskeletal and neurologic examinations were normal. Her skin was notable for various sized (8 cm × 4 cm to 10 cm × 15 cm) painful ulcers with violaceous, friable borders—some with fluctuance and purulent drainage—on her right hand, bilateral arms, right axilla, sternum, and legs (Figure 1).

JHMVol16No9_Burnett14940915e_f1.JPG

Laboratory studies were notable for normocytic anemia (hemoglobin, 8.9 g/dL; range, 12.0-16.0 g/dL), leukocytosis (white blood cells, 24,900/µL; range, 4500-11,000/µL), thrombocytosis (platelet count, 690,000/µL; range, 150,000-400,000/µL), and elevated inflammatory markers (C-reactive protein, 33 mg/dL; range, <0.5 mg/dL; erythrocyte sedimentation rate, 78 mm/h; range, <20 mm/h). A complete metabolic panel was within normal limits. Repeat blood cultures and β -D-glucan and 16S ribosomal assays were negative. Polymerase chain reaction testing for Bartonella henselae was negative. Urine probes for Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Rapid plasma regain (RPR) was negative. Antibodies to toxoplasmosis, histoplasmosis, blastomycosis, and aspergillosis were unrevealing. A Coccidioides test by immunodiffusion was negative. Serum antigen tests for Cryptococcus and Epstein-Barr virus (EBV) were negative. EBV, HIV, and hepatitis antibody tests were negative. Rheumatologic studies, including antinuclear, anti-double-stranded DNA, anti-Smith, anti–Sjögren syndrome antigens A and B, anticentromere, anti-topoisomerase (anti-Scl-70), anti-histidyl-transfer-RNA-synthetase (anti-Jo-1), and anti-nucleosome (anti-chromatic) antibodies, were unrevealing. Levels of angiotensin-converting enzyme, rheumatoid factor, complement, cytoplasmic, and perinuclear antineutrophil cytoplasmic antibodies were also normal. A neutrophil oxidative burst test was negative. In addition, peripheral flow cytology and serum and urine protein electrophoresis were negative. Chest CT revealed bilateral lower lobe consolidations concerning for necrotizing pneumonia, splenic enlargement, numerous hypodense splenic lesions, and a 1.3-cm right hilar node, which had decreased in size compared with 1 month prior.

In summary, the patient presented with recurrent upper respiratory symptoms, fever, and abdominal pain; expanding granulomatous hilar lesions, splenomegaly, and cutaneous lesions consistent with pathergy; elevated inflammatory markers and leukocytosis; and a possible exposure to F tularensis. She has had extensive negative infectious workups, except for a weakly positive β-D-glucan, and completed several courses of apparently unhelpful antimicrobials. At this point, the most notable findings are her splenomegaly and inflammatory masses suggesting an inflammatory process, which may be autoimmune in nature. Both vasculitis and sarcoidosis remain possibilities, and malignancy is possible. Given her possible exposure to F tularensis, obtaining serum antibodies to F tularensis, in addition to biopsies of the skin lesions, is advisable.

Laboratory studies revealed a positive F tularensis antibody with a titer of 1:320 and an IgM of 7 U/mL and IgG of 30 U/mL. This was repeated, revealing a titer of 1:540 and an IgM and IgG of 5 U/mL and 20 U/mL, respectively. Given the potential exposure history, the clinical syndrome compatible with tularemia, and an otherwise extensive yet unrevealing evaluation, she was treated with a 10-day course of streptomycin. Her fever persisted, and the splenic lesions increased in size and number, prompting addition of moxifloxacin without apparent benefit. Skin biopsies taken from the patient’s arm were notable for nodular, suppurative, neutrophilic infiltrates and histiocytes in the medium and deep dermis without multinucleated histiocytes or evidence of vasculitis. Fungal, mycobacterial, and bacterial stains from the biopsy were negative. The findings were consistent with but not diagnostic of an acute neutrophilic dermatosis.

At this point, the patient has a confirmed exposure to F tularensis; she also has persistent fever, progressive splenomegaly, and new skin biopsies consistent with neutrophilic dermatosis. Despite the F tularensis antibody positivity, her negative cultures and lack of improvement with multiple courses of antimicrobials argue against an infectious etiology. Accordingly, malignancy should be considered but seems less likely given that no laboratory, imaging, or tissue samples support it. This leaves immune-mediated etiologies, especially autoimmune conditions associated with neutrophilic dermatoses, as the most likely explanation of her inflammatory syndrome. Neutrophilic dermatoses include some vasculitides, Sweet syndrome, PG, Behçet syndrome, and other inflammatory entities. She has no evidence of vasculitis on biopsy. Given the evidence of inflammation and the history of pathergy, Behçet syndrome and PG should be seriously considered.

She underwent incision and drainage of the left leg and mediastinal lesions. A follow-up chest CT revealed stable cutaneous and deep tissue lesions and continued splenic enlargement. She was started on prednisone and dapsone for presumed cutaneous and visceral PG. The lesions improved dramatically and, following a month-long hospitalization, she was discharged on dapsone and a slow prednisone taper. Three weeks after discharge, while on dapsone and prednisone, she developed a new skin lesion. Cyclosporine was added, with improvement. Eight weeks after discharge, she developed fever, acute left-upper-quadrant pain, and marked splenomegaly with abscesses seen on CT imaging (Figure 2).

JHMVol16No9_Burnett14940915e_f2.JPG

This continues to be a very puzzling case, and it is worth revisiting her clinical course once again. This is a previously healthy 32-year-old woman with multiple hospital presentations for upper-respiratory symptoms, persistent fever, abdominal pain, and painful cutaneous lesions consistent with pathergy; she was found to have granulomatous hilar lesions, progressive splenomegaly, and skin biopsies consistent with neutrophilic dermatosis. Exhaustive infectious and rheumatologic workup was negative, and no evident malignancy was found. Finally, despite multiple courses of antimicrobials, including standard treatments for tularemia (for which she had positive antibodies), her clinical course failed to improve until the addition of systemic anti-inflammatory agents, which resulted in rapid improvement. She then presented 8 weeks later with recurrent fever and splenomegaly. Given the recurrence and the severity of the splenic pathology, a diagnostic splenectomy is advisable for what appears to be visceral PG. In addition, attempting to identify a trigger of her syndrome is important. PG can be associated with inflammatory bowel disease, hematologic disorders (eg, leukemia, myeloma, myelodysplastic syndrome, and myelofibrosis), and autoimmune diseases, especially inflammatory arthritis.¹ Therefore, a diagnostic colonoscopy and bone marrow biopsy should be considered. With no history or examination supporting inflammatory arthritis and a broad, unrevealing workup, her rheumatologic evaluation is sufficient.

The patient underwent splenectomy. Gross description of the spleen was notable for multiple abscesses, consisting on microscopy of large areas of necrosis with islands of dense neutrophil collections (Figure 3). Microscopic examination failed to demonstrate microorganisms on multiple stains, and there was no microscopic or flow cytometric evidence of lymphoma. The final pathologic diagnosis was multiple sterile splenic abscesses with siderosis, which, in the context of her overall syndrome, was consistent with an entity termed aseptic abscess syndrome (AAS). After discharge, she underwent a slow steroid taper and was ultimately maintained on daily low-dose prednisone. Cyclosporine and dapsone were discontinued in favor of infliximab infusions. She underwent additional diagnostic workup, including an unremarkable colonoscopy and a bone marrow biopsy, which showed monoclonal gammopathy of undetermined significance (MGUS) with an insignificant IgA monoclonal gammopathy. All cutaneous lesions healed. Three years after the splenectomy, while still on infliximab and prednisone, she developed a new aseptic lung abscess, which resolved after increasing her prednisone dose. Six years after splenectomy, she developed an aseptic liver abscess, which resolved after again increasing the frequency of her infliximab infusions.

JHMVol16No9_Burnett14940915e_f3.JPG

Diagnostic uncertainty is an intrinsic feature of medical practice—in part because patients often present with undifferentiated and evolving symptoms.² When faced with uncertainty, clinicians are well served by prioritizing a thoughtful differential diagnosis, adopting a stepwise management strategy, and engaging in iterative reassessments of the patient. In this case, a 32-year-old, previously healthy woman presented with an array of symptoms, including abdominal pain, fever, leukocytosis, necrotic skin lesions, necrotizing mediastinal lymphadenitis, pathergy, and splenomegaly. Elements of the history, examination, and diagnostic studies supported a differential diagnosis of tularemia, PG, and AAS. Through stepwise management and ongoing reassessment, she was ultimately diagnosed with AAS.

Tularemia was initially an important diagnostic consideration in this patient, given her potential exposure and positive F tularensis serum antibodies. Francisella tularensis is a Gram-negative coccobacillus found in more than 250 species of fish, ticks, birds, and mammals. In humans, an incubation period of 3 to 5 days is typical. Although clinical manifestations vary, they often include fever, headache, and malaise.³ Other findings may include lymphadenopathy with or without ulcerative cutaneous lesions (glandular or ulceroglandular tularemia) and cough, dyspnea, pleuritic chest pain, and hilar adenopathy (pneumonic tularemia). As noted by the discussant, a pneumonic tularemia syndrome could have explained this patient’s fever, respiratory symptoms, and hilar adenopathy; ulceroglandular tularemia might have explained her cutaneous lesions. Since splenomegaly may be seen in tularemia, this finding was also consistent with the diagnosis. Serum antibody testing is supportive of the diagnosis, while culture confirms it. Standard treatment consists of a 10- to 14-day course of streptomycin, and combination therapy with a fluoroquinolone is recommended in severe cases.⁴ In this patient, however, F tularensis was not demonstrated on culture. Furthermore, she did not experience the expected clinical improvement with treatment. Finally, because both IgG and IgM tularemia antibodies may co-occur up to 10 years following infection, her positive F tularensis serum antibodies did not provide evidence of acute infection.⁵

Recognizing inconsistencies in the diagnosis of tularemia, the focus shifted to PG owing to the patient’s neutrophilic cutaneous lesions, negative infectious workup, and pathergy. Pyoderma gangrenosum is a neutrophilic dermatosis—one of a heterogeneous group of skin conditions characterized by perivascular and diffuse neutrophilic infiltrates without an identifiable infectious agent.⁶ It is a chronic, recurrent cutaneous disease with several variants.⁷ The classic presentation includes painful lower-extremity ulcers with violaceous undermined borders and may be associated with pathergy. Guiding principles for the management of PG include controlling inflammation, optimizing wound healing, and minimizing exacerbating factors.¹ As such, treatment mainstays include local and systemic anti-inflammatory agents and wound care. As the discussant highlighted, in this case the inflammatory skin lesions were suggestive of PG. However, other features of the case, notably, splenomegaly, splenic abscesses, and necrotizing mediastinal lymphadenitis, were more consistent with another diagnosis: AAS. Aseptic abscess syndrome is an autoinflammatory disorder defined by deep, noninfectious abscesses that preferentially affect the spleen.⁸ Additional clinical manifestations include weight loss, fever, abdominal pain, and leukocytosis. Lesions may also affect bone, kidney, liver, lung, lymph node, and skin. In one case series, neutrophilic dermatoses were seen in 20% of AAS cases.⁸ In all cases of AAS, extensive infectious workup is unrevealing, and antibiotics are ineffective. The pathophysiology of AAS is unknown.

Similar to PG, the majority of AAS cases are associated with inflammatory bowel disease, especially Crohn disease.⁹ However, AAS also has associations with conditions such as MGUS, rheumatoid arthritis, spondyloarthritis, and relapsing polychondritis. Histologically, early lesions demonstrate a necrotic core of neutrophils, with or without surrounding palisading histiocytes, and giant cells. In older lesions, neutrophils may be absent; fibrous tissue may be present.⁸ Treatment regimens include splenectomy, corticosteroids, colchicine, thalidomide, tumor necrosis factor (TNF) antagonists, and cyclophosphamide. The discussant astutely recommended a splenectomy for this patient, which was both diagnostic and therapeutic. As in this case, relapse is common. Optimal maintenance therapy is yet to be determined.⁹

Given the overlapping clinical manifestations, shared disease associations, and similar responsiveness to immunosuppression, it is unclear whether AAS represents a new disease entity or a variant of known autoinflammatory disorders. Aseptic abscess syndrome is likely part of a spectrum of autoinflammatory disorders with inflammatory bowel diseases, neutrophilic dermatoses, and other similar diseases.⁸ While infectious visceral abscesses remain more common, this case highlights the clinical manifestation of an emerging and likely underrecognized entity.

• Aseptic abscess syndrome should be considered in patients who present with visceral (particularly splenic) abscesses and negative infectious workup.
• Aseptic abscess syndrome is commonly associated with other autoinflammatory disorders; the majority of reported cases are associated with inflammatory bowel disease, especially Crohn disease.
• Up to 20% of AAS cases are associated with neutrophilic dermatoses such as PG.
• The initial treatment for this syndrome is high-dose intravenous glucocorticoids; maintenance treatment regimens include corticosteroids, colchicine, thalidomide, TNF antagonists, and cyclophosphamide.

The authors would thank Dr Bob Pelz and Dr John Townes for their contributions to the case.

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 32-year-old, previously healthy woman presented to the emergency department (ED) with 3 days of nasal pain, congestion, and cough. A day prior, she had consulted with her primary care provider by phone and had been prescribed amoxicillin-clavulanate for presumed bacterial sinusitis. She subsequently developed fever (39 oC) and pleuritic, left-upper-quadrant abdominal pain. In the ED, chest radiograph demonstrated right hilar opacification. Laboratory studies and computed tomography (CT) of the abdomen and pelvis did not identify a cause for her pain. Given the pleuritic nature of her left-upper-quadrant pain, CT pulmonary angiography was ordered. The CT revealed “mass-like” right hilar opacification and lymphadenopathy. No pulmonary emboli were identified. Levofloxacin was prescribed for presumed pneumonia, and the patient was discharged home. The following week, mediastinal biopsy was arranged for evaluation of the right hilar abnormality.

This is a young woman presenting with upper respiratory symptoms, abdominal pain, fever, and hilar lymphadenopathy. Upper respiratory symptoms are common and usually indicate an inflammatory response to allergens or infection, though autoimmune disorders may affect the upper airways. Fever and hilar lymphadenopathy likely also signify an inflammatory response. Taken together, these findings can be associated with mycobacterial or fungal infection, malignancy, and, particularly in a young woman, sarcoidosis, which could explain her abdominal pain if her presentation included splenomegaly. At this point she likely has a systemic illness involving at least the upper, and possibly the lower, respiratory tract.

Within days, her symptoms resolved. Mediastinal biopsy of the hilar node revealed scant pus. Pathology demonstrated suppurative granulomata. Gram stain; bacterial, mycobacterial, and fungal cultures; and 16S ribosomal analyses for bacteria and fungi from the biopsy were unrevealing. For unclear reasons, prior to the biopsy, she was given intramuscular Haemophilus influenzae type B and tetanus, diphtheria, and pertussis vaccines. Two weeks later, she presented again with fever and left-upper-quadrant pain as well as painful skin nodules at her biopsy and vaccination sites. She was admitted for further evaluation. Chest CT showed expansion of the mediastinal lesion and splenic enlargement. Biopsy of a skin lesion revealed suppurative granulomatous dermatitis and panniculitis. Repeat blood cultures were negative, though serum β-D-glucan was weakly positive at 173 pg/mL (reference range, <60 pg/mL). Tissue cultures and Gram, acid-fast, Fite, and Warthin-Starry stains from the skin biopsy were negative. She was discharged on fluconazole and then readmitted 2 days later with dyspnea, fever, and leukocytosis.

The young woman’s symptoms resolved, only to recur days later; her granulomatous hilar lesions grew larger, and new cutaneous and splenic findings appeared. The granulomatous lesions prompt consideration of infectious, malignant, and immune-mediated processes. The negative cultures make infection less likely, although the elevated β-D-glucan may suggest fungal infection. By description, the skin lesions are consistent with pathergy, a phenomenon characterized by trauma-provoked cutaneous lesions or ulcers, which is associated with numerous syndromes, including Behçet syndrome, inflammatory bowel disease, and neutrophilic dermatoses such as pyoderma gangrenosum (PG) and Sweet syndrome. In addition to details about her medical history, it is important to seek evidence of oral ulcers or vasculitis, as Behçet syndrome may be associated with cutaneous, visceral, and ophthalmologic vasculitis.

Her medical history included hypertension and active, 10-pack-year cigarette use. During childhood, she had occasional ingrown hairs and folliculitis. She did not take medications prior to this acute illness. Family history was notable for cardiovascular disease. She rarely consumed alcohol and did not use illicit drugs. She lived in a rural town in the mid–Willamette Valley of Oregon and worked as an administrative assistant. She spent time outdoors, including trail running and golfing. A case of tularemia was recently reported in an area near her home. Her only travel outside of Oregon was to Puerto Vallarta, Mexico, 16 years previously. She grew up on a farm and had no known tuberculosis exposure.

Tularemia is an interesting diagnostic consideration and could explain her fever, cutaneous lesions, and hilar adenopathy. It is plausible that she had clinically mild pneumonic tularemia at the outset and that her cutaneous lesions are variants of ulceroglandular tularemia. Positive antibodies for Francisella tularensis would be expected if this were the cause of her illness. The ingrown hairs raise the possibility of a primary immune deficiency syndrome predisposing her to abscesses. However, they seem to have been of trivial significance to her, making an immune deficiency syndrome unlikely.

On readmission, she was afebrile, normotensive, and tachycardic (114 beats/min), with a normal respiratory rate and oxygen saturation. She was not ill appearing. She had noninjected conjunctiva and no oral lesions. Apart from tachycardia, cardiovascular examination was unremarkable. Abdominal examination was notable for mild distension and a palpable, tender spleen. Musculoskeletal and neurologic examinations were normal. Her skin was notable for various sized (8 cm × 4 cm to 10 cm × 15 cm) painful ulcers with violaceous, friable borders—some with fluctuance and purulent drainage—on her right hand, bilateral arms, right axilla, sternum, and legs (Figure 1).

JHMVol16No9_Burnett14940915e_f1.JPG

Laboratory studies were notable for normocytic anemia (hemoglobin, 8.9 g/dL; range, 12.0-16.0 g/dL), leukocytosis (white blood cells, 24,900/µL; range, 4500-11,000/µL), thrombocytosis (platelet count, 690,000/µL; range, 150,000-400,000/µL), and elevated inflammatory markers (C-reactive protein, 33 mg/dL; range, <0.5 mg/dL; erythrocyte sedimentation rate, 78 mm/h; range, <20 mm/h). A complete metabolic panel was within normal limits. Repeat blood cultures and β -D-glucan and 16S ribosomal assays were negative. Polymerase chain reaction testing for Bartonella henselae was negative. Urine probes for Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Rapid plasma regain (RPR) was negative. Antibodies to toxoplasmosis, histoplasmosis, blastomycosis, and aspergillosis were unrevealing. A Coccidioides test by immunodiffusion was negative. Serum antigen tests for Cryptococcus and Epstein-Barr virus (EBV) were negative. EBV, HIV, and hepatitis antibody tests were negative. Rheumatologic studies, including antinuclear, anti-double-stranded DNA, anti-Smith, anti–Sjögren syndrome antigens A and B, anticentromere, anti-topoisomerase (anti-Scl-70), anti-histidyl-transfer-RNA-synthetase (anti-Jo-1), and anti-nucleosome (anti-chromatic) antibodies, were unrevealing. Levels of angiotensin-converting enzyme, rheumatoid factor, complement, cytoplasmic, and perinuclear antineutrophil cytoplasmic antibodies were also normal. A neutrophil oxidative burst test was negative. In addition, peripheral flow cytology and serum and urine protein electrophoresis were negative. Chest CT revealed bilateral lower lobe consolidations concerning for necrotizing pneumonia, splenic enlargement, numerous hypodense splenic lesions, and a 1.3-cm right hilar node, which had decreased in size compared with 1 month prior.

In summary, the patient presented with recurrent upper respiratory symptoms, fever, and abdominal pain; expanding granulomatous hilar lesions, splenomegaly, and cutaneous lesions consistent with pathergy; elevated inflammatory markers and leukocytosis; and a possible exposure to F tularensis. She has had extensive negative infectious workups, except for a weakly positive β-D-glucan, and completed several courses of apparently unhelpful antimicrobials. At this point, the most notable findings are her splenomegaly and inflammatory masses suggesting an inflammatory process, which may be autoimmune in nature. Both vasculitis and sarcoidosis remain possibilities, and malignancy is possible. Given her possible exposure to F tularensis, obtaining serum antibodies to F tularensis, in addition to biopsies of the skin lesions, is advisable.

Laboratory studies revealed a positive F tularensis antibody with a titer of 1:320 and an IgM of 7 U/mL and IgG of 30 U/mL. This was repeated, revealing a titer of 1:540 and an IgM and IgG of 5 U/mL and 20 U/mL, respectively. Given the potential exposure history, the clinical syndrome compatible with tularemia, and an otherwise extensive yet unrevealing evaluation, she was treated with a 10-day course of streptomycin. Her fever persisted, and the splenic lesions increased in size and number, prompting addition of moxifloxacin without apparent benefit. Skin biopsies taken from the patient’s arm were notable for nodular, suppurative, neutrophilic infiltrates and histiocytes in the medium and deep dermis without multinucleated histiocytes or evidence of vasculitis. Fungal, mycobacterial, and bacterial stains from the biopsy were negative. The findings were consistent with but not diagnostic of an acute neutrophilic dermatosis.

At this point, the patient has a confirmed exposure to F tularensis; she also has persistent fever, progressive splenomegaly, and new skin biopsies consistent with neutrophilic dermatosis. Despite the F tularensis antibody positivity, her negative cultures and lack of improvement with multiple courses of antimicrobials argue against an infectious etiology. Accordingly, malignancy should be considered but seems less likely given that no laboratory, imaging, or tissue samples support it. This leaves immune-mediated etiologies, especially autoimmune conditions associated with neutrophilic dermatoses, as the most likely explanation of her inflammatory syndrome. Neutrophilic dermatoses include some vasculitides, Sweet syndrome, PG, Behçet syndrome, and other inflammatory entities. She has no evidence of vasculitis on biopsy. Given the evidence of inflammation and the history of pathergy, Behçet syndrome and PG should be seriously considered.

She underwent incision and drainage of the left leg and mediastinal lesions. A follow-up chest CT revealed stable cutaneous and deep tissue lesions and continued splenic enlargement. She was started on prednisone and dapsone for presumed cutaneous and visceral PG. The lesions improved dramatically and, following a month-long hospitalization, she was discharged on dapsone and a slow prednisone taper. Three weeks after discharge, while on dapsone and prednisone, she developed a new skin lesion. Cyclosporine was added, with improvement. Eight weeks after discharge, she developed fever, acute left-upper-quadrant pain, and marked splenomegaly with abscesses seen on CT imaging (Figure 2).

JHMVol16No9_Burnett14940915e_f2.JPG

This continues to be a very puzzling case, and it is worth revisiting her clinical course once again. This is a previously healthy 32-year-old woman with multiple hospital presentations for upper-respiratory symptoms, persistent fever, abdominal pain, and painful cutaneous lesions consistent with pathergy; she was found to have granulomatous hilar lesions, progressive splenomegaly, and skin biopsies consistent with neutrophilic dermatosis. Exhaustive infectious and rheumatologic workup was negative, and no evident malignancy was found. Finally, despite multiple courses of antimicrobials, including standard treatments for tularemia (for which she had positive antibodies), her clinical course failed to improve until the addition of systemic anti-inflammatory agents, which resulted in rapid improvement. She then presented 8 weeks later with recurrent fever and splenomegaly. Given the recurrence and the severity of the splenic pathology, a diagnostic splenectomy is advisable for what appears to be visceral PG. In addition, attempting to identify a trigger of her syndrome is important. PG can be associated with inflammatory bowel disease, hematologic disorders (eg, leukemia, myeloma, myelodysplastic syndrome, and myelofibrosis), and autoimmune diseases, especially inflammatory arthritis.¹ Therefore, a diagnostic colonoscopy and bone marrow biopsy should be considered. With no history or examination supporting inflammatory arthritis and a broad, unrevealing workup, her rheumatologic evaluation is sufficient.

The patient underwent splenectomy. Gross description of the spleen was notable for multiple abscesses, consisting on microscopy of large areas of necrosis with islands of dense neutrophil collections (Figure 3). Microscopic examination failed to demonstrate microorganisms on multiple stains, and there was no microscopic or flow cytometric evidence of lymphoma. The final pathologic diagnosis was multiple sterile splenic abscesses with siderosis, which, in the context of her overall syndrome, was consistent with an entity termed aseptic abscess syndrome (AAS). After discharge, she underwent a slow steroid taper and was ultimately maintained on daily low-dose prednisone. Cyclosporine and dapsone were discontinued in favor of infliximab infusions. She underwent additional diagnostic workup, including an unremarkable colonoscopy and a bone marrow biopsy, which showed monoclonal gammopathy of undetermined significance (MGUS) with an insignificant IgA monoclonal gammopathy. All cutaneous lesions healed. Three years after the splenectomy, while still on infliximab and prednisone, she developed a new aseptic lung abscess, which resolved after increasing her prednisone dose. Six years after splenectomy, she developed an aseptic liver abscess, which resolved after again increasing the frequency of her infliximab infusions.

JHMVol16No9_Burnett14940915e_f3.JPG

Diagnostic uncertainty is an intrinsic feature of medical practice—in part because patients often present with undifferentiated and evolving symptoms.² When faced with uncertainty, clinicians are well served by prioritizing a thoughtful differential diagnosis, adopting a stepwise management strategy, and engaging in iterative reassessments of the patient. In this case, a 32-year-old, previously healthy woman presented with an array of symptoms, including abdominal pain, fever, leukocytosis, necrotic skin lesions, necrotizing mediastinal lymphadenitis, pathergy, and splenomegaly. Elements of the history, examination, and diagnostic studies supported a differential diagnosis of tularemia, PG, and AAS. Through stepwise management and ongoing reassessment, she was ultimately diagnosed with AAS.

Tularemia was initially an important diagnostic consideration in this patient, given her potential exposure and positive F tularensis serum antibodies. Francisella tularensis is a Gram-negative coccobacillus found in more than 250 species of fish, ticks, birds, and mammals. In humans, an incubation period of 3 to 5 days is typical. Although clinical manifestations vary, they often include fever, headache, and malaise.³ Other findings may include lymphadenopathy with or without ulcerative cutaneous lesions (glandular or ulceroglandular tularemia) and cough, dyspnea, pleuritic chest pain, and hilar adenopathy (pneumonic tularemia). As noted by the discussant, a pneumonic tularemia syndrome could have explained this patient’s fever, respiratory symptoms, and hilar adenopathy; ulceroglandular tularemia might have explained her cutaneous lesions. Since splenomegaly may be seen in tularemia, this finding was also consistent with the diagnosis. Serum antibody testing is supportive of the diagnosis, while culture confirms it. Standard treatment consists of a 10- to 14-day course of streptomycin, and combination therapy with a fluoroquinolone is recommended in severe cases.⁴ In this patient, however, F tularensis was not demonstrated on culture. Furthermore, she did not experience the expected clinical improvement with treatment. Finally, because both IgG and IgM tularemia antibodies may co-occur up to 10 years following infection, her positive F tularensis serum antibodies did not provide evidence of acute infection.⁵

Recognizing inconsistencies in the diagnosis of tularemia, the focus shifted to PG owing to the patient’s neutrophilic cutaneous lesions, negative infectious workup, and pathergy. Pyoderma gangrenosum is a neutrophilic dermatosis—one of a heterogeneous group of skin conditions characterized by perivascular and diffuse neutrophilic infiltrates without an identifiable infectious agent.⁶ It is a chronic, recurrent cutaneous disease with several variants.⁷ The classic presentation includes painful lower-extremity ulcers with violaceous undermined borders and may be associated with pathergy. Guiding principles for the management of PG include controlling inflammation, optimizing wound healing, and minimizing exacerbating factors.¹ As such, treatment mainstays include local and systemic anti-inflammatory agents and wound care. As the discussant highlighted, in this case the inflammatory skin lesions were suggestive of PG. However, other features of the case, notably, splenomegaly, splenic abscesses, and necrotizing mediastinal lymphadenitis, were more consistent with another diagnosis: AAS. Aseptic abscess syndrome is an autoinflammatory disorder defined by deep, noninfectious abscesses that preferentially affect the spleen.⁸ Additional clinical manifestations include weight loss, fever, abdominal pain, and leukocytosis. Lesions may also affect bone, kidney, liver, lung, lymph node, and skin. In one case series, neutrophilic dermatoses were seen in 20% of AAS cases.⁸ In all cases of AAS, extensive infectious workup is unrevealing, and antibiotics are ineffective. The pathophysiology of AAS is unknown.

Similar to PG, the majority of AAS cases are associated with inflammatory bowel disease, especially Crohn disease.⁹ However, AAS also has associations with conditions such as MGUS, rheumatoid arthritis, spondyloarthritis, and relapsing polychondritis. Histologically, early lesions demonstrate a necrotic core of neutrophils, with or without surrounding palisading histiocytes, and giant cells. In older lesions, neutrophils may be absent; fibrous tissue may be present.⁸ Treatment regimens include splenectomy, corticosteroids, colchicine, thalidomide, tumor necrosis factor (TNF) antagonists, and cyclophosphamide. The discussant astutely recommended a splenectomy for this patient, which was both diagnostic and therapeutic. As in this case, relapse is common. Optimal maintenance therapy is yet to be determined.⁹

Given the overlapping clinical manifestations, shared disease associations, and similar responsiveness to immunosuppression, it is unclear whether AAS represents a new disease entity or a variant of known autoinflammatory disorders. Aseptic abscess syndrome is likely part of a spectrum of autoinflammatory disorders with inflammatory bowel diseases, neutrophilic dermatoses, and other similar diseases.⁸ While infectious visceral abscesses remain more common, this case highlights the clinical manifestation of an emerging and likely underrecognized entity.

• Aseptic abscess syndrome should be considered in patients who present with visceral (particularly splenic) abscesses and negative infectious workup.
• Aseptic abscess syndrome is commonly associated with other autoinflammatory disorders; the majority of reported cases are associated with inflammatory bowel disease, especially Crohn disease.
• Up to 20% of AAS cases are associated with neutrophilic dermatoses such as PG.
• The initial treatment for this syndrome is high-dose intravenous glucocorticoids; maintenance treatment regimens include corticosteroids, colchicine, thalidomide, TNF antagonists, and cyclophosphamide.

The authors would thank Dr Bob Pelz and Dr John Townes for their contributions to the case.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old woman presents to the emergency department with a 2-week history of abdominal pain associated with nausea and an episode of nonbilious, nonbloody emesis. Her last bowel movement was 2 days prior to her presentation. The patient has tachycardia to 105 beats per minute but otherwise normal vital signs. Findings on her physical examination include dry mucous membranes and increased bowel sounds. A review of systems reveals an unintentional weight loss of 15 kg over the past 4 months and increased fatigue. Computed tomography scan of the abdomen and pelvis with contrast reveals multiple areas of attenuation in the liver and small bowel obstruction. The hospitalist admits the patient to the medicine service for supportive treatment and workup for underlying malignancy. Her admitting team orders serum tumor biomarkers on admission to expedite the diagnosis.

When patients present with unexplained weight loss or with metastasis from an unknown primary location, the initial workup often includes imaging and a tumor biomarker panel (eg, cancer antigen 125 [CA125], carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA]). The CA125, CA19-9, and CEA biomarkers are traditionally associated with ovarian, pancreatic, and colorectal cancer, respectively.¹ While clinicians initially used these serum biomarkers to monitor for cancer recurrence or treatment response, they have since become widely used in multiple clinical stages of oncological evaluation.

Hospitalists routinely order biomarkers as part of the malignancy workup. More than a dozen oncology biomarkers are used in the clinical setting to risk stratify, plan treatment, and monitor for recurrence. For example, studies associate elevated preoperative levels of CEA and CA19-9 with metastatic invasion of colorectal² and gastric³ cancers and with poor prognosis of intrahepatic cholangiocarcinoma. Similarly, CA125 has demonstrated utility in monitoring response to ovarian cancer treatment.⁴ Specific biomarkers, such as alpha-fetoprotein, improve diagnosis of liver and nonseminomatous testicular tumors.⁵ Clinicians often apply the same paradigm to other biomarkers due to their widespread availability, noninvasiveness, reproducibility, and ease of use, particularly in acute settings wherein any new information is perceived to be potentially helpful.

Utilizing these serum biomarkers to diagnose cancer has the potential for diagnostic error and can result in unnecessary patient anxiety and follow-up testing. Since tissue sampling is necessary and remains the gold standard in most cancer diagnoses, obtaining these tumor biomarkers in the early diagnostic stage does not change management and may even lead to harm. Furthermore, due to their poor sensitivity and specificity, these biomarkers cannot rule in or rule out cancer. Elevated CA125, CA19-9, and CEA biomarkers occur in a variety of malignancies, including gastric, gallbladder, hepatocellular, bladder, and breast cancers.^1,3,6 In addition, these biomarkers have a very limited role in the workup of cancer of unknown primary origin.⁷

Even in the setting of a known pelvic mass, the use of CA125 alone has poor sensitivity at a cut-off level of 35 U/mL as a biomarker for the diagnosis of early ovarian cancer.⁸

Serum CA19-9 is not a useful diagnostic biomarker as elevated CA19-9 can occur in benign conditions, including cirrhosis, chronic pancreatitis, and cholangitis. In a systematic review of patients with histologic confirmation of pancreatic malignancy, the median positive predictive value of CA19-9 was 72% (interquartile range, 41%-95%).⁹ Additionally, patients with Lewis-null blood type, which is present in 5% to 10% of the Caucasian population, do not produce CA19-9.¹⁰ Therefore, CA19-9 will be 0% specific for tumors in this population.

The use of CEA in the diagnosis of colorectal cancer is also questionable. In stage I colorectal cancer, CEA was only 38.1% sensitive at a cut-off level of 2.41 ng/mL; it was 78.3% sensitive in stage IV disease.¹¹ The specificity of CEA is limited since elevated CEA occurs in benign conditions, such as inflammatory bowel disease, smoking, hypothyroidism, pancreatitis, biliary obstruction, peptic ulcers, and cirrhosis—though CEA levels in these conditions are rarely >10 ng/mL.¹¹ Regardless of the results of biomarker testing, definitive diagnosis requires tissue biopsy; therefore, biomarker findings are of little utility in the initial workup.

In addition to variable diagnostic utility, overreliance on these biomarkers has the potential for serious patient harm. In a study examining patients with established rectal cancer, combination CEA and CA19-9 testing alone was insufficient to predict the pathologic stage of disease correctly.² A cancer misdiagnosis not only traumatizes patients but also erodes their trust in clinicians and creates anxiety during future clinical encounters. Overutilization of these tumor biomarkers is also costly and contributes to waste in the US healthcare system.

There is a role for tumor biomarker testing in specific cancers after the primary source of malignancy has been determined. When evaluating a known pelvic mass, CA125 testing is performed in conjunction with transvaginal ultrasound and assessment of menopausal status in the risk of ovarian malignancy algorithm for prognostication of disease prior to surgery.¹² This algorithm takes into account levels of CA125 in addition to levels of human epididymis protein 4 and patient age, yielding an area under the curve as high as 0.93 for ovarian cancer risk classification.⁸ Beyond the prognostication process, oncologists follow CA125 to monitor response to first-line ovarian cancer treatment. However, CA125 has a less defined role in surveillance for ovarian cancer recurrence.

CA19-9 has demonstrated utility for pancreatic cancer and cholangiocarcinoma survival estimates. A national cohort analysis of patients with established intrahepatic cholangiocarcinoma found that CA19-9 independently predicted increased mortality. Patients with elevated CA19-9 also had significantly more nodal metastases and positive-margin resections.⁶ A study of 353 patients with pancreatic ductal adenocarcinoma undergoing radical resection further demonstrated the utility of CA19-9. In this study, patients with postoperative CA19-9 normalization had improved survival by almost 12 months when compared to those with consistently elevated CA19-9.¹³

Last, the literature describes CEA biomarker testing in the surveillance of patients after curative treatment of colon and rectal cancer. The American Society of Colon and Rectal Surgeons recommends regularly tracking this biomarker following curative resection, in conjunction with colonoscopy and chest and liver imaging studies.¹⁴ A prospective randomized controlled study that followed this monitoring protocol in cured asymptomatic patients on a bimonthly basis found that early diagnosis of recurrent colorectal cancer improved survival.¹⁵ The use of CEA testing as a monitoring tool should therefore be a point of discussion between providers and patients, as its utility varies based on patient comorbidities, their ability to tolerate surgery or chemotherapy, risk factors for recurrence, performance status, compliance, age, and preference.¹⁴

The use of CA125, CA19-9, and CEA testing alone as initial diagnostic tools for malignancy are problematic due to their poor sensitivities and/or positive predictive value. Multiple studies have demonstrated their utility as markers of metastasis or malignancy progression rather than as clinically useful markers for the detection of any one type of cancer.^1,3,6 In an undiagnosed symptomatic patient with unexplained weight loss or symptoms of a tumor mass, elevated CA125, CA19-9, and CEA add no new information as metastatic pancreatic, colorectal, ovarian, gastric, gallbladder, hepatocellular, bladder, ovarian, and breast cancers all remain in the differential diagnosis. Clinicians should approach the initial diagnosis of cancer in such patients with appropriate imaging studies, a thorough physical examination, and prompt biopsy of abnormal findings, as long as these are consistent with the patient’s goals of care. After establishing a tissue diagnosis, some tumor biomarkers have valid prognostic, staging, and monitoring roles.^6,13,14

• Do not routinely order CA125, CA19-9, and CEA tests for the initial diagnostic workup of visceral malignancy of unknown origin regardless of whether imaging studies have been obtained.
• Use appropriate imaging, perform a thorough physical examination, and obtain tissue biopsy in the initial diagnostic workup of a visceral malignancy of unknown origin.

Clinicians should use serum biomarkers, like any other diagnostic test, to maximize benefit while preventing patient harm. In general, CA125, CA19-9, and CEA do not have a role in cancer diagnosis. The patient described in our clinical scenario would not benefit from a serum tumor biomarker panel at the time of admission. Regardless of findings from these tests, a tissue sample is required to make a definitive diagnosis of underlying malignancy in this patient.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old woman presents to the emergency department with a 2-week history of abdominal pain associated with nausea and an episode of nonbilious, nonbloody emesis. Her last bowel movement was 2 days prior to her presentation. The patient has tachycardia to 105 beats per minute but otherwise normal vital signs. Findings on her physical examination include dry mucous membranes and increased bowel sounds. A review of systems reveals an unintentional weight loss of 15 kg over the past 4 months and increased fatigue. Computed tomography scan of the abdomen and pelvis with contrast reveals multiple areas of attenuation in the liver and small bowel obstruction. The hospitalist admits the patient to the medicine service for supportive treatment and workup for underlying malignancy. Her admitting team orders serum tumor biomarkers on admission to expedite the diagnosis.

When patients present with unexplained weight loss or with metastasis from an unknown primary location, the initial workup often includes imaging and a tumor biomarker panel (eg, cancer antigen 125 [CA125], carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA]). The CA125, CA19-9, and CEA biomarkers are traditionally associated with ovarian, pancreatic, and colorectal cancer, respectively.¹ While clinicians initially used these serum biomarkers to monitor for cancer recurrence or treatment response, they have since become widely used in multiple clinical stages of oncological evaluation.

Hospitalists routinely order biomarkers as part of the malignancy workup. More than a dozen oncology biomarkers are used in the clinical setting to risk stratify, plan treatment, and monitor for recurrence. For example, studies associate elevated preoperative levels of CEA and CA19-9 with metastatic invasion of colorectal² and gastric³ cancers and with poor prognosis of intrahepatic cholangiocarcinoma. Similarly, CA125 has demonstrated utility in monitoring response to ovarian cancer treatment.⁴ Specific biomarkers, such as alpha-fetoprotein, improve diagnosis of liver and nonseminomatous testicular tumors.⁵ Clinicians often apply the same paradigm to other biomarkers due to their widespread availability, noninvasiveness, reproducibility, and ease of use, particularly in acute settings wherein any new information is perceived to be potentially helpful.

Utilizing these serum biomarkers to diagnose cancer has the potential for diagnostic error and can result in unnecessary patient anxiety and follow-up testing. Since tissue sampling is necessary and remains the gold standard in most cancer diagnoses, obtaining these tumor biomarkers in the early diagnostic stage does not change management and may even lead to harm. Furthermore, due to their poor sensitivity and specificity, these biomarkers cannot rule in or rule out cancer. Elevated CA125, CA19-9, and CEA biomarkers occur in a variety of malignancies, including gastric, gallbladder, hepatocellular, bladder, and breast cancers.^1,3,6 In addition, these biomarkers have a very limited role in the workup of cancer of unknown primary origin.⁷

Even in the setting of a known pelvic mass, the use of CA125 alone has poor sensitivity at a cut-off level of 35 U/mL as a biomarker for the diagnosis of early ovarian cancer.⁸

Serum CA19-9 is not a useful diagnostic biomarker as elevated CA19-9 can occur in benign conditions, including cirrhosis, chronic pancreatitis, and cholangitis. In a systematic review of patients with histologic confirmation of pancreatic malignancy, the median positive predictive value of CA19-9 was 72% (interquartile range, 41%-95%).⁹ Additionally, patients with Lewis-null blood type, which is present in 5% to 10% of the Caucasian population, do not produce CA19-9.¹⁰ Therefore, CA19-9 will be 0% specific for tumors in this population.

The use of CEA in the diagnosis of colorectal cancer is also questionable. In stage I colorectal cancer, CEA was only 38.1% sensitive at a cut-off level of 2.41 ng/mL; it was 78.3% sensitive in stage IV disease.¹¹ The specificity of CEA is limited since elevated CEA occurs in benign conditions, such as inflammatory bowel disease, smoking, hypothyroidism, pancreatitis, biliary obstruction, peptic ulcers, and cirrhosis—though CEA levels in these conditions are rarely >10 ng/mL.¹¹ Regardless of the results of biomarker testing, definitive diagnosis requires tissue biopsy; therefore, biomarker findings are of little utility in the initial workup.

In addition to variable diagnostic utility, overreliance on these biomarkers has the potential for serious patient harm. In a study examining patients with established rectal cancer, combination CEA and CA19-9 testing alone was insufficient to predict the pathologic stage of disease correctly.² A cancer misdiagnosis not only traumatizes patients but also erodes their trust in clinicians and creates anxiety during future clinical encounters. Overutilization of these tumor biomarkers is also costly and contributes to waste in the US healthcare system.

There is a role for tumor biomarker testing in specific cancers after the primary source of malignancy has been determined. When evaluating a known pelvic mass, CA125 testing is performed in conjunction with transvaginal ultrasound and assessment of menopausal status in the risk of ovarian malignancy algorithm for prognostication of disease prior to surgery.¹² This algorithm takes into account levels of CA125 in addition to levels of human epididymis protein 4 and patient age, yielding an area under the curve as high as 0.93 for ovarian cancer risk classification.⁸ Beyond the prognostication process, oncologists follow CA125 to monitor response to first-line ovarian cancer treatment. However, CA125 has a less defined role in surveillance for ovarian cancer recurrence.

CA19-9 has demonstrated utility for pancreatic cancer and cholangiocarcinoma survival estimates. A national cohort analysis of patients with established intrahepatic cholangiocarcinoma found that CA19-9 independently predicted increased mortality. Patients with elevated CA19-9 also had significantly more nodal metastases and positive-margin resections.⁶ A study of 353 patients with pancreatic ductal adenocarcinoma undergoing radical resection further demonstrated the utility of CA19-9. In this study, patients with postoperative CA19-9 normalization had improved survival by almost 12 months when compared to those with consistently elevated CA19-9.¹³

Last, the literature describes CEA biomarker testing in the surveillance of patients after curative treatment of colon and rectal cancer. The American Society of Colon and Rectal Surgeons recommends regularly tracking this biomarker following curative resection, in conjunction with colonoscopy and chest and liver imaging studies.¹⁴ A prospective randomized controlled study that followed this monitoring protocol in cured asymptomatic patients on a bimonthly basis found that early diagnosis of recurrent colorectal cancer improved survival.¹⁵ The use of CEA testing as a monitoring tool should therefore be a point of discussion between providers and patients, as its utility varies based on patient comorbidities, their ability to tolerate surgery or chemotherapy, risk factors for recurrence, performance status, compliance, age, and preference.¹⁴

The use of CA125, CA19-9, and CEA testing alone as initial diagnostic tools for malignancy are problematic due to their poor sensitivities and/or positive predictive value. Multiple studies have demonstrated their utility as markers of metastasis or malignancy progression rather than as clinically useful markers for the detection of any one type of cancer.^1,3,6 In an undiagnosed symptomatic patient with unexplained weight loss or symptoms of a tumor mass, elevated CA125, CA19-9, and CEA add no new information as metastatic pancreatic, colorectal, ovarian, gastric, gallbladder, hepatocellular, bladder, ovarian, and breast cancers all remain in the differential diagnosis. Clinicians should approach the initial diagnosis of cancer in such patients with appropriate imaging studies, a thorough physical examination, and prompt biopsy of abnormal findings, as long as these are consistent with the patient’s goals of care. After establishing a tissue diagnosis, some tumor biomarkers have valid prognostic, staging, and monitoring roles.^6,13,14

• Do not routinely order CA125, CA19-9, and CEA tests for the initial diagnostic workup of visceral malignancy of unknown origin regardless of whether imaging studies have been obtained.
• Use appropriate imaging, perform a thorough physical examination, and obtain tissue biopsy in the initial diagnostic workup of a visceral malignancy of unknown origin.

Clinicians should use serum biomarkers, like any other diagnostic test, to maximize benefit while preventing patient harm. In general, CA125, CA19-9, and CEA do not have a role in cancer diagnosis. The patient described in our clinical scenario would not benefit from a serum tumor biomarker panel at the time of admission. Regardless of findings from these tests, a tissue sample is required to make a definitive diagnosis of underlying malignancy in this patient.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old woman presents to the emergency department with a 2-week history of abdominal pain associated with nausea and an episode of nonbilious, nonbloody emesis. Her last bowel movement was 2 days prior to her presentation. The patient has tachycardia to 105 beats per minute but otherwise normal vital signs. Findings on her physical examination include dry mucous membranes and increased bowel sounds. A review of systems reveals an unintentional weight loss of 15 kg over the past 4 months and increased fatigue. Computed tomography scan of the abdomen and pelvis with contrast reveals multiple areas of attenuation in the liver and small bowel obstruction. The hospitalist admits the patient to the medicine service for supportive treatment and workup for underlying malignancy. Her admitting team orders serum tumor biomarkers on admission to expedite the diagnosis.

When patients present with unexplained weight loss or with metastasis from an unknown primary location, the initial workup often includes imaging and a tumor biomarker panel (eg, cancer antigen 125 [CA125], carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA]). The CA125, CA19-9, and CEA biomarkers are traditionally associated with ovarian, pancreatic, and colorectal cancer, respectively.¹ While clinicians initially used these serum biomarkers to monitor for cancer recurrence or treatment response, they have since become widely used in multiple clinical stages of oncological evaluation.

Hospitalists routinely order biomarkers as part of the malignancy workup. More than a dozen oncology biomarkers are used in the clinical setting to risk stratify, plan treatment, and monitor for recurrence. For example, studies associate elevated preoperative levels of CEA and CA19-9 with metastatic invasion of colorectal² and gastric³ cancers and with poor prognosis of intrahepatic cholangiocarcinoma. Similarly, CA125 has demonstrated utility in monitoring response to ovarian cancer treatment.⁴ Specific biomarkers, such as alpha-fetoprotein, improve diagnosis of liver and nonseminomatous testicular tumors.⁵ Clinicians often apply the same paradigm to other biomarkers due to their widespread availability, noninvasiveness, reproducibility, and ease of use, particularly in acute settings wherein any new information is perceived to be potentially helpful.

Utilizing these serum biomarkers to diagnose cancer has the potential for diagnostic error and can result in unnecessary patient anxiety and follow-up testing. Since tissue sampling is necessary and remains the gold standard in most cancer diagnoses, obtaining these tumor biomarkers in the early diagnostic stage does not change management and may even lead to harm. Furthermore, due to their poor sensitivity and specificity, these biomarkers cannot rule in or rule out cancer. Elevated CA125, CA19-9, and CEA biomarkers occur in a variety of malignancies, including gastric, gallbladder, hepatocellular, bladder, and breast cancers.^1,3,6 In addition, these biomarkers have a very limited role in the workup of cancer of unknown primary origin.⁷

Even in the setting of a known pelvic mass, the use of CA125 alone has poor sensitivity at a cut-off level of 35 U/mL as a biomarker for the diagnosis of early ovarian cancer.⁸

Serum CA19-9 is not a useful diagnostic biomarker as elevated CA19-9 can occur in benign conditions, including cirrhosis, chronic pancreatitis, and cholangitis. In a systematic review of patients with histologic confirmation of pancreatic malignancy, the median positive predictive value of CA19-9 was 72% (interquartile range, 41%-95%).⁹ Additionally, patients with Lewis-null blood type, which is present in 5% to 10% of the Caucasian population, do not produce CA19-9.¹⁰ Therefore, CA19-9 will be 0% specific for tumors in this population.

The use of CEA in the diagnosis of colorectal cancer is also questionable. In stage I colorectal cancer, CEA was only 38.1% sensitive at a cut-off level of 2.41 ng/mL; it was 78.3% sensitive in stage IV disease.¹¹ The specificity of CEA is limited since elevated CEA occurs in benign conditions, such as inflammatory bowel disease, smoking, hypothyroidism, pancreatitis, biliary obstruction, peptic ulcers, and cirrhosis—though CEA levels in these conditions are rarely >10 ng/mL.¹¹ Regardless of the results of biomarker testing, definitive diagnosis requires tissue biopsy; therefore, biomarker findings are of little utility in the initial workup.

In addition to variable diagnostic utility, overreliance on these biomarkers has the potential for serious patient harm. In a study examining patients with established rectal cancer, combination CEA and CA19-9 testing alone was insufficient to predict the pathologic stage of disease correctly.² A cancer misdiagnosis not only traumatizes patients but also erodes their trust in clinicians and creates anxiety during future clinical encounters. Overutilization of these tumor biomarkers is also costly and contributes to waste in the US healthcare system.

There is a role for tumor biomarker testing in specific cancers after the primary source of malignancy has been determined. When evaluating a known pelvic mass, CA125 testing is performed in conjunction with transvaginal ultrasound and assessment of menopausal status in the risk of ovarian malignancy algorithm for prognostication of disease prior to surgery.¹² This algorithm takes into account levels of CA125 in addition to levels of human epididymis protein 4 and patient age, yielding an area under the curve as high as 0.93 for ovarian cancer risk classification.⁸ Beyond the prognostication process, oncologists follow CA125 to monitor response to first-line ovarian cancer treatment. However, CA125 has a less defined role in surveillance for ovarian cancer recurrence.

CA19-9 has demonstrated utility for pancreatic cancer and cholangiocarcinoma survival estimates. A national cohort analysis of patients with established intrahepatic cholangiocarcinoma found that CA19-9 independently predicted increased mortality. Patients with elevated CA19-9 also had significantly more nodal metastases and positive-margin resections.⁶ A study of 353 patients with pancreatic ductal adenocarcinoma undergoing radical resection further demonstrated the utility of CA19-9. In this study, patients with postoperative CA19-9 normalization had improved survival by almost 12 months when compared to those with consistently elevated CA19-9.¹³

Last, the literature describes CEA biomarker testing in the surveillance of patients after curative treatment of colon and rectal cancer. The American Society of Colon and Rectal Surgeons recommends regularly tracking this biomarker following curative resection, in conjunction with colonoscopy and chest and liver imaging studies.¹⁴ A prospective randomized controlled study that followed this monitoring protocol in cured asymptomatic patients on a bimonthly basis found that early diagnosis of recurrent colorectal cancer improved survival.¹⁵ The use of CEA testing as a monitoring tool should therefore be a point of discussion between providers and patients, as its utility varies based on patient comorbidities, their ability to tolerate surgery or chemotherapy, risk factors for recurrence, performance status, compliance, age, and preference.¹⁴

The use of CA125, CA19-9, and CEA testing alone as initial diagnostic tools for malignancy are problematic due to their poor sensitivities and/or positive predictive value. Multiple studies have demonstrated their utility as markers of metastasis or malignancy progression rather than as clinically useful markers for the detection of any one type of cancer.^1,3,6 In an undiagnosed symptomatic patient with unexplained weight loss or symptoms of a tumor mass, elevated CA125, CA19-9, and CEA add no new information as metastatic pancreatic, colorectal, ovarian, gastric, gallbladder, hepatocellular, bladder, ovarian, and breast cancers all remain in the differential diagnosis. Clinicians should approach the initial diagnosis of cancer in such patients with appropriate imaging studies, a thorough physical examination, and prompt biopsy of abnormal findings, as long as these are consistent with the patient’s goals of care. After establishing a tissue diagnosis, some tumor biomarkers have valid prognostic, staging, and monitoring roles.^6,13,14

• Do not routinely order CA125, CA19-9, and CEA tests for the initial diagnostic workup of visceral malignancy of unknown origin regardless of whether imaging studies have been obtained.
• Use appropriate imaging, perform a thorough physical examination, and obtain tissue biopsy in the initial diagnostic workup of a visceral malignancy of unknown origin.

Clinicians should use serum biomarkers, like any other diagnostic test, to maximize benefit while preventing patient harm. In general, CA125, CA19-9, and CEA do not have a role in cancer diagnosis. The patient described in our clinical scenario would not benefit from a serum tumor biomarker panel at the time of admission. Regardless of findings from these tests, a tissue sample is required to make a definitive diagnosis of underlying malignancy in this patient.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A hospitalist admits a 29-year-old man with hypertension, obesity, and type 2 diabetes (type 2 DM) for a posterior neck abscess that failed outpatient oral antibiotic therapy. The patient’s medications include metformin monotherapy. Vital signs taken upon admission include a blood pressure of 136/82 mm Hg, heart rate of 98 beats per minute, respiratory rate 18 of breaths per minute, oxygen saturation of 100% on room air, and temperature of 38.5 oC. Laboratory evaluation revealed a glucose level of 212 mg/dL, with a hemoglobin A1c of 8.0%, lactic acid of 1.4 mmol/L, and normal renal and hepatic function. Based on these findings, the hospitalist holds metformin and starts the patient on sliding-scale insulin therapy.

Metformin, an oral medication used to treat type 2 DM, is a biguanide that increases peripheral glucose utilization and decreases hepatic gluconeogenesis. However, metformin-associated shunting of metabolism toward anaerobic respiration increases the risk of lactic acidosis.¹ Because the kidneys excrete metformin, the risk of developing metformin-associated lactic acidosis (MALA) increases with renal impairment. Disease states common among hospitalized patients, such as hypoperfusion, advanced cirrhosis, alcohol abuse, cardiac failure, muscle ischemia, and severe infection, increase the risk of acute kidney injury (AKI) and elevate blood lactate levels. Therefore, hospitalists regularly hold metformin in the inpatient setting.

Following the introduction of metformin in the United States, the US Food and Drug Administration (FDA) received 47 confirmed reports of nonfatal lactic acidosis associated with the use of metformin, all of which involved cardiac disease (specifically congestive heart failure [CHF]), renal insufficiency, hypoxia, or sepsis.² Consequently, the FDA listed CHF as a contraindication to metformin use; however, it has since changed the use of metformin in CHF from a contraindication to a warning/precaution for lactic acidosis. The FDA also added a warning against the use of metformin in patients with sepsis or in patients older than 80 years who have abnormal creatinine clearance.

Acute kidney injury, a common inpatient condition, occurs in 20% of hospitalized patients and more than 50% of intensive care patients.³ Moreover, a retrospective observational study showed approximately 50% of all patients hospitalized for COVID-19 had AKI.⁴ Iodinated contrast, a diagnostic media commonly used in the hospital, may also increase the risk of renal dysfunction. The FDA recommends providers discontinue metformin at or before initiating imaging studies with iodinated contrast⁵ in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m². The FDA also advises that providers not restart metformin until 48 hours after an intra-arterial (IA) or intravenous (IV) contrast study in patients with an eGFR <60 mL/min/1.73 m² (equivalent to chronic kidney disease [CKD] stage 3 or worse).⁵ The American Diabetes Association (ADA) recommends the same eGFR cutoff level in its clinical practice recommendations, as well as withholding metformin 48 hours before patients receive IV contrast.⁶ Given the risk of AKI in hospitalized patients and concerns of increased MALA, clinicians reflexively hold metformin.

Holding metformin is also consistent with professional guidelines. The 2009 American Association of Clinical Endocrinology and ADA Consensus Statement on Inpatient Glycemic Control recommends cautious use of metformin in the inpatient setting “because of the potential development of a contraindication during the hospitalization.”⁷ Similarly, the 2012 Endocrine Society guidelines recommend withholding metformin in almost all hospitalized patients.⁸

Routinely holding metformin in hospitalized patients is unnecessary and potentially harmful. First, MALA is exceedingly rare, and experts question the causal link. Furthermore, iodinated contrast does not place patients with normal renal function at increased risk of MALA. Finally, holding metformin leads to worsened glycemic control and increased use of insulin, both of which may result in adverse patient outcomes.

The concerns about MALA stem from clinical experiences with phenformin, an older and more potent biguanide. Phenformin shares a similar mechanism of action with metformin but causes more lactic acid production. In 1978, following 306 documented cases of phenformin-associated lactic acidosis, the FDA removed this medication from the market.⁹ Since the initial 47 cases of MALA were reported to the FDA, repeated studies and systematic reviews have disputed the link between metformin and lactic acidosis, particularly in the absence of significant risk factors or in patients with an eGFR ≥30 mL/min/1.73 m². In fact, a large observational study showed a reduction in acidosis and mortality in outpatients with stage 3a CKD (eGFR, 45-59 mL/min/1.73 m²) who were taking metformin compared to patients taking insulin or other oral hypoglycemics agents.¹⁰ In patients with stage 3b CKD (eGFR, 30-44 mL/min/1.73 m²), this study found no difference in the same outcomes.¹⁰

Studies show that metformin does not cause elevated lactate levels in patients with stage 4 CKD (eGFR >15mL/min/1.73²) or lower stages of CKD as long as doses are adjusted appropriately to reflect renal function.¹¹ These and other investigations reveal that in the absence of other risk factors, metformin does not cause lactic acidosis (Table).^10-15 Based on these findings, the Endocrine Society changed the strength of its recommendation to withhold metformin in hospitalized patients to “weak,” with “very low-quality evidence.” The FDA similarly revised its warnings⁸ to allow metformin use in all patients with an eGFR ≥30 mL/min/1.73 m². A large community-based cohort study, which demonstrated no association between hospitalization with acidosis and metformin use in patients with stage 3b CKD or lower stages of CKD, supports this change in treatment threshold.¹⁵

JHMVol16No8_Cohen10740818e_t1.JPG

Published evidence also does not support the practice of routinely holding metformin before contrast administration, despite concerns regarding contrast-induced nephropathy. Retrospective chart reviews and a direct comparison in human models have not shown any significant difference in the risk of AKI between the IV and IA contrast.¹⁶ Moreover, evidence suggests no interaction between metformin and contrast media in patients with normal renal function.¹⁷ In response, the American College of Radiology, Canadian Association of Radiology, Royal College of Radiologists, and Royal Australian and New Zealand College of Radiologists all recommend continuing metformin in patients with normal renal function (eGFR ≥30 mL/min/1.73m²) receiving IV contrast. They advise holding metformin for 48 hours in patients with renal insufficiency (eGFR <30 mL/min/1.73m²) or those undergoing IA catheter studies that might result in renal artery emboli.¹⁸

Finally, continuing metformin maintains steady blood glucose control. The practice of replacing metformin with sliding-scale insulin monotherapy for hospitalized patients significantly increases the risk of hyperglycemia and is associated with an increased length of stay.¹⁹ Additionally, unlike insulin, metformin does not increase the risk of hypoglycemia. Finally, a recent matched cohort study comparing the use of oral hypoglycemic agents (metformin, thiazolidines, and sulfonylureas) vs insulin monotherapy in patients undergoing emergency abdominal surgery showed that the patients admitted with sepsis and treated with oral agents had a lower 30-day mortality rate and a shorter length of stay.²⁰ Based on the evidence showing that inpatient oral hypoglycemic agents improve quality metrics and mitigate safety events, the ADA advocates resuming oral antihyperglycemic medications (most commonly metformin) 1 to 2 days before discharge.⁷

Clinicians should continue metformin in all hospitalized patients who are not at significant risk of developing lactic acidosis. Risk factors for MALA include severe sepsis (in the setting of end-organ damage as defined by systemic inflammatory response syndrome criteria), hypoxia requiring oxygen supplementation, hypoperfusion (as from CHF), AKI, CKD (eGFR <30 mL/min/1.73 m²), and advanced cirrhosis. Given the high rates of hypoxia and AKI in admitted patients with COVID-19, clinicians should hold metformin on admission. Continue metformin for patients receiving IV contrast media with an eGFR >30 mL/min/1.73 m². For patients undergoing IA catheter studies associated with a risk for renal artery emboli, or in patients with renal insufficiency (eGFR <30 mL/min/1.73 m²), temporarily hold metformin for 48 hours. When held, restart metformin as soon as risk factors resolve.

• Hold metformin in patients with or undergoing the following:
  • High risk for or currently suffering from decompensated heart failure, severe sepsis, or other disease states resulting in hypoxia or tissue hypoperfusion;
  • An eGFR <30 mL/min/1.73 m² or AKI; resume metformin when the AKI resolves;
  • COVID-19 infection, until the risk of hypoxia has resolved;
  • IV contrast study in the presence of acute renal failure or an eGFR <30 mL/min/1.73 m²; resume metformin 48 hours after contrast administration;
  • Intra-arterial catheter study that might result in renal artery emboli; resume metformin when renal function normalizes.
• Continue metformin in all hospitalized patients in the absence of the aforementioned disease states or contrast-related indications.

Returning to the patient in our clinical scenario, we recommend continuing metformin given the lack of risk factors or disease states associated with increased lactic acidosis. The practice of withholding metformin in hospitalized patients for fear of MALA is based on minimal evidence. Clinicians should, however, hold metformin in patients who have true contraindications, including existing acidosis, hypoperfusion, renal insufficiency, CHF, severe sepsis, hypoxia, advanced cirrhosis, and COVID-19. With regard to iodinated contrast studies, temporarily withhold metformin for 48 hours in patients with an eGFR <30 mL/min/1.73 m², acute kidney injury, or in patients undergoing an IA catheter study at risk for renal artery emboli. Patients should be restarted on metformin 48 hours after these studies and as renal function normalizes. When withholding metformin during a hospitalization, restart it once risk factors have resolved.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter  (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A hospitalist admits a 29-year-old man with hypertension, obesity, and type 2 diabetes (type 2 DM) for a posterior neck abscess that failed outpatient oral antibiotic therapy. The patient’s medications include metformin monotherapy. Vital signs taken upon admission include a blood pressure of 136/82 mm Hg, heart rate of 98 beats per minute, respiratory rate 18 of breaths per minute, oxygen saturation of 100% on room air, and temperature of 38.5 oC. Laboratory evaluation revealed a glucose level of 212 mg/dL, with a hemoglobin A1c of 8.0%, lactic acid of 1.4 mmol/L, and normal renal and hepatic function. Based on these findings, the hospitalist holds metformin and starts the patient on sliding-scale insulin therapy.

Metformin, an oral medication used to treat type 2 DM, is a biguanide that increases peripheral glucose utilization and decreases hepatic gluconeogenesis. However, metformin-associated shunting of metabolism toward anaerobic respiration increases the risk of lactic acidosis.¹ Because the kidneys excrete metformin, the risk of developing metformin-associated lactic acidosis (MALA) increases with renal impairment. Disease states common among hospitalized patients, such as hypoperfusion, advanced cirrhosis, alcohol abuse, cardiac failure, muscle ischemia, and severe infection, increase the risk of acute kidney injury (AKI) and elevate blood lactate levels. Therefore, hospitalists regularly hold metformin in the inpatient setting.

Following the introduction of metformin in the United States, the US Food and Drug Administration (FDA) received 47 confirmed reports of nonfatal lactic acidosis associated with the use of metformin, all of which involved cardiac disease (specifically congestive heart failure [CHF]), renal insufficiency, hypoxia, or sepsis.² Consequently, the FDA listed CHF as a contraindication to metformin use; however, it has since changed the use of metformin in CHF from a contraindication to a warning/precaution for lactic acidosis. The FDA also added a warning against the use of metformin in patients with sepsis or in patients older than 80 years who have abnormal creatinine clearance.

Acute kidney injury, a common inpatient condition, occurs in 20% of hospitalized patients and more than 50% of intensive care patients.³ Moreover, a retrospective observational study showed approximately 50% of all patients hospitalized for COVID-19 had AKI.⁴ Iodinated contrast, a diagnostic media commonly used in the hospital, may also increase the risk of renal dysfunction. The FDA recommends providers discontinue metformin at or before initiating imaging studies with iodinated contrast⁵ in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m². The FDA also advises that providers not restart metformin until 48 hours after an intra-arterial (IA) or intravenous (IV) contrast study in patients with an eGFR <60 mL/min/1.73 m² (equivalent to chronic kidney disease [CKD] stage 3 or worse).⁵ The American Diabetes Association (ADA) recommends the same eGFR cutoff level in its clinical practice recommendations, as well as withholding metformin 48 hours before patients receive IV contrast.⁶ Given the risk of AKI in hospitalized patients and concerns of increased MALA, clinicians reflexively hold metformin.

Holding metformin is also consistent with professional guidelines. The 2009 American Association of Clinical Endocrinology and ADA Consensus Statement on Inpatient Glycemic Control recommends cautious use of metformin in the inpatient setting “because of the potential development of a contraindication during the hospitalization.”⁷ Similarly, the 2012 Endocrine Society guidelines recommend withholding metformin in almost all hospitalized patients.⁸

Routinely holding metformin in hospitalized patients is unnecessary and potentially harmful. First, MALA is exceedingly rare, and experts question the causal link. Furthermore, iodinated contrast does not place patients with normal renal function at increased risk of MALA. Finally, holding metformin leads to worsened glycemic control and increased use of insulin, both of which may result in adverse patient outcomes.

The concerns about MALA stem from clinical experiences with phenformin, an older and more potent biguanide. Phenformin shares a similar mechanism of action with metformin but causes more lactic acid production. In 1978, following 306 documented cases of phenformin-associated lactic acidosis, the FDA removed this medication from the market.⁹ Since the initial 47 cases of MALA were reported to the FDA, repeated studies and systematic reviews have disputed the link between metformin and lactic acidosis, particularly in the absence of significant risk factors or in patients with an eGFR ≥30 mL/min/1.73 m². In fact, a large observational study showed a reduction in acidosis and mortality in outpatients with stage 3a CKD (eGFR, 45-59 mL/min/1.73 m²) who were taking metformin compared to patients taking insulin or other oral hypoglycemics agents.¹⁰ In patients with stage 3b CKD (eGFR, 30-44 mL/min/1.73 m²), this study found no difference in the same outcomes.¹⁰

Studies show that metformin does not cause elevated lactate levels in patients with stage 4 CKD (eGFR >15mL/min/1.73²) or lower stages of CKD as long as doses are adjusted appropriately to reflect renal function.¹¹ These and other investigations reveal that in the absence of other risk factors, metformin does not cause lactic acidosis (Table).^10-15 Based on these findings, the Endocrine Society changed the strength of its recommendation to withhold metformin in hospitalized patients to “weak,” with “very low-quality evidence.” The FDA similarly revised its warnings⁸ to allow metformin use in all patients with an eGFR ≥30 mL/min/1.73 m². A large community-based cohort study, which demonstrated no association between hospitalization with acidosis and metformin use in patients with stage 3b CKD or lower stages of CKD, supports this change in treatment threshold.¹⁵

JHMVol16No8_Cohen10740818e_t1.JPG

Published evidence also does not support the practice of routinely holding metformin before contrast administration, despite concerns regarding contrast-induced nephropathy. Retrospective chart reviews and a direct comparison in human models have not shown any significant difference in the risk of AKI between the IV and IA contrast.¹⁶ Moreover, evidence suggests no interaction between metformin and contrast media in patients with normal renal function.¹⁷ In response, the American College of Radiology, Canadian Association of Radiology, Royal College of Radiologists, and Royal Australian and New Zealand College of Radiologists all recommend continuing metformin in patients with normal renal function (eGFR ≥30 mL/min/1.73m²) receiving IV contrast. They advise holding metformin for 48 hours in patients with renal insufficiency (eGFR <30 mL/min/1.73m²) or those undergoing IA catheter studies that might result in renal artery emboli.¹⁸

Finally, continuing metformin maintains steady blood glucose control. The practice of replacing metformin with sliding-scale insulin monotherapy for hospitalized patients significantly increases the risk of hyperglycemia and is associated with an increased length of stay.¹⁹ Additionally, unlike insulin, metformin does not increase the risk of hypoglycemia. Finally, a recent matched cohort study comparing the use of oral hypoglycemic agents (metformin, thiazolidines, and sulfonylureas) vs insulin monotherapy in patients undergoing emergency abdominal surgery showed that the patients admitted with sepsis and treated with oral agents had a lower 30-day mortality rate and a shorter length of stay.²⁰ Based on the evidence showing that inpatient oral hypoglycemic agents improve quality metrics and mitigate safety events, the ADA advocates resuming oral antihyperglycemic medications (most commonly metformin) 1 to 2 days before discharge.⁷

Clinicians should continue metformin in all hospitalized patients who are not at significant risk of developing lactic acidosis. Risk factors for MALA include severe sepsis (in the setting of end-organ damage as defined by systemic inflammatory response syndrome criteria), hypoxia requiring oxygen supplementation, hypoperfusion (as from CHF), AKI, CKD (eGFR <30 mL/min/1.73 m²), and advanced cirrhosis. Given the high rates of hypoxia and AKI in admitted patients with COVID-19, clinicians should hold metformin on admission. Continue metformin for patients receiving IV contrast media with an eGFR >30 mL/min/1.73 m². For patients undergoing IA catheter studies associated with a risk for renal artery emboli, or in patients with renal insufficiency (eGFR <30 mL/min/1.73 m²), temporarily hold metformin for 48 hours. When held, restart metformin as soon as risk factors resolve.

• Hold metformin in patients with or undergoing the following:
  • High risk for or currently suffering from decompensated heart failure, severe sepsis, or other disease states resulting in hypoxia or tissue hypoperfusion;
  • An eGFR <30 mL/min/1.73 m² or AKI; resume metformin when the AKI resolves;
  • COVID-19 infection, until the risk of hypoxia has resolved;
  • IV contrast study in the presence of acute renal failure or an eGFR <30 mL/min/1.73 m²; resume metformin 48 hours after contrast administration;
  • Intra-arterial catheter study that might result in renal artery emboli; resume metformin when renal function normalizes.
• Continue metformin in all hospitalized patients in the absence of the aforementioned disease states or contrast-related indications.

Returning to the patient in our clinical scenario, we recommend continuing metformin given the lack of risk factors or disease states associated with increased lactic acidosis. The practice of withholding metformin in hospitalized patients for fear of MALA is based on minimal evidence. Clinicians should, however, hold metformin in patients who have true contraindications, including existing acidosis, hypoperfusion, renal insufficiency, CHF, severe sepsis, hypoxia, advanced cirrhosis, and COVID-19. With regard to iodinated contrast studies, temporarily withhold metformin for 48 hours in patients with an eGFR <30 mL/min/1.73 m², acute kidney injury, or in patients undergoing an IA catheter study at risk for renal artery emboli. Patients should be restarted on metformin 48 hours after these studies and as renal function normalizes. When withholding metformin during a hospitalization, restart it once risk factors have resolved.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter  (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A hospitalist admits a 29-year-old man with hypertension, obesity, and type 2 diabetes (type 2 DM) for a posterior neck abscess that failed outpatient oral antibiotic therapy. The patient’s medications include metformin monotherapy. Vital signs taken upon admission include a blood pressure of 136/82 mm Hg, heart rate of 98 beats per minute, respiratory rate 18 of breaths per minute, oxygen saturation of 100% on room air, and temperature of 38.5 oC. Laboratory evaluation revealed a glucose level of 212 mg/dL, with a hemoglobin A1c of 8.0%, lactic acid of 1.4 mmol/L, and normal renal and hepatic function. Based on these findings, the hospitalist holds metformin and starts the patient on sliding-scale insulin therapy.

Metformin, an oral medication used to treat type 2 DM, is a biguanide that increases peripheral glucose utilization and decreases hepatic gluconeogenesis. However, metformin-associated shunting of metabolism toward anaerobic respiration increases the risk of lactic acidosis.¹ Because the kidneys excrete metformin, the risk of developing metformin-associated lactic acidosis (MALA) increases with renal impairment. Disease states common among hospitalized patients, such as hypoperfusion, advanced cirrhosis, alcohol abuse, cardiac failure, muscle ischemia, and severe infection, increase the risk of acute kidney injury (AKI) and elevate blood lactate levels. Therefore, hospitalists regularly hold metformin in the inpatient setting.

Following the introduction of metformin in the United States, the US Food and Drug Administration (FDA) received 47 confirmed reports of nonfatal lactic acidosis associated with the use of metformin, all of which involved cardiac disease (specifically congestive heart failure [CHF]), renal insufficiency, hypoxia, or sepsis.² Consequently, the FDA listed CHF as a contraindication to metformin use; however, it has since changed the use of metformin in CHF from a contraindication to a warning/precaution for lactic acidosis. The FDA also added a warning against the use of metformin in patients with sepsis or in patients older than 80 years who have abnormal creatinine clearance.

Acute kidney injury, a common inpatient condition, occurs in 20% of hospitalized patients and more than 50% of intensive care patients.³ Moreover, a retrospective observational study showed approximately 50% of all patients hospitalized for COVID-19 had AKI.⁴ Iodinated contrast, a diagnostic media commonly used in the hospital, may also increase the risk of renal dysfunction. The FDA recommends providers discontinue metformin at or before initiating imaging studies with iodinated contrast⁵ in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m². The FDA also advises that providers not restart metformin until 48 hours after an intra-arterial (IA) or intravenous (IV) contrast study in patients with an eGFR <60 mL/min/1.73 m² (equivalent to chronic kidney disease [CKD] stage 3 or worse).⁵ The American Diabetes Association (ADA) recommends the same eGFR cutoff level in its clinical practice recommendations, as well as withholding metformin 48 hours before patients receive IV contrast.⁶ Given the risk of AKI in hospitalized patients and concerns of increased MALA, clinicians reflexively hold metformin.

Holding metformin is also consistent with professional guidelines. The 2009 American Association of Clinical Endocrinology and ADA Consensus Statement on Inpatient Glycemic Control recommends cautious use of metformin in the inpatient setting “because of the potential development of a contraindication during the hospitalization.”⁷ Similarly, the 2012 Endocrine Society guidelines recommend withholding metformin in almost all hospitalized patients.⁸

Routinely holding metformin in hospitalized patients is unnecessary and potentially harmful. First, MALA is exceedingly rare, and experts question the causal link. Furthermore, iodinated contrast does not place patients with normal renal function at increased risk of MALA. Finally, holding metformin leads to worsened glycemic control and increased use of insulin, both of which may result in adverse patient outcomes.

The concerns about MALA stem from clinical experiences with phenformin, an older and more potent biguanide. Phenformin shares a similar mechanism of action with metformin but causes more lactic acid production. In 1978, following 306 documented cases of phenformin-associated lactic acidosis, the FDA removed this medication from the market.⁹ Since the initial 47 cases of MALA were reported to the FDA, repeated studies and systematic reviews have disputed the link between metformin and lactic acidosis, particularly in the absence of significant risk factors or in patients with an eGFR ≥30 mL/min/1.73 m². In fact, a large observational study showed a reduction in acidosis and mortality in outpatients with stage 3a CKD (eGFR, 45-59 mL/min/1.73 m²) who were taking metformin compared to patients taking insulin or other oral hypoglycemics agents.¹⁰ In patients with stage 3b CKD (eGFR, 30-44 mL/min/1.73 m²), this study found no difference in the same outcomes.¹⁰

Studies show that metformin does not cause elevated lactate levels in patients with stage 4 CKD (eGFR >15mL/min/1.73²) or lower stages of CKD as long as doses are adjusted appropriately to reflect renal function.¹¹ These and other investigations reveal that in the absence of other risk factors, metformin does not cause lactic acidosis (Table).^10-15 Based on these findings, the Endocrine Society changed the strength of its recommendation to withhold metformin in hospitalized patients to “weak,” with “very low-quality evidence.” The FDA similarly revised its warnings⁸ to allow metformin use in all patients with an eGFR ≥30 mL/min/1.73 m². A large community-based cohort study, which demonstrated no association between hospitalization with acidosis and metformin use in patients with stage 3b CKD or lower stages of CKD, supports this change in treatment threshold.¹⁵

JHMVol16No8_Cohen10740818e_t1.JPG

Published evidence also does not support the practice of routinely holding metformin before contrast administration, despite concerns regarding contrast-induced nephropathy. Retrospective chart reviews and a direct comparison in human models have not shown any significant difference in the risk of AKI between the IV and IA contrast.¹⁶ Moreover, evidence suggests no interaction between metformin and contrast media in patients with normal renal function.¹⁷ In response, the American College of Radiology, Canadian Association of Radiology, Royal College of Radiologists, and Royal Australian and New Zealand College of Radiologists all recommend continuing metformin in patients with normal renal function (eGFR ≥30 mL/min/1.73m²) receiving IV contrast. They advise holding metformin for 48 hours in patients with renal insufficiency (eGFR <30 mL/min/1.73m²) or those undergoing IA catheter studies that might result in renal artery emboli.¹⁸

Finally, continuing metformin maintains steady blood glucose control. The practice of replacing metformin with sliding-scale insulin monotherapy for hospitalized patients significantly increases the risk of hyperglycemia and is associated with an increased length of stay.¹⁹ Additionally, unlike insulin, metformin does not increase the risk of hypoglycemia. Finally, a recent matched cohort study comparing the use of oral hypoglycemic agents (metformin, thiazolidines, and sulfonylureas) vs insulin monotherapy in patients undergoing emergency abdominal surgery showed that the patients admitted with sepsis and treated with oral agents had a lower 30-day mortality rate and a shorter length of stay.²⁰ Based on the evidence showing that inpatient oral hypoglycemic agents improve quality metrics and mitigate safety events, the ADA advocates resuming oral antihyperglycemic medications (most commonly metformin) 1 to 2 days before discharge.⁷

Clinicians should continue metformin in all hospitalized patients who are not at significant risk of developing lactic acidosis. Risk factors for MALA include severe sepsis (in the setting of end-organ damage as defined by systemic inflammatory response syndrome criteria), hypoxia requiring oxygen supplementation, hypoperfusion (as from CHF), AKI, CKD (eGFR <30 mL/min/1.73 m²), and advanced cirrhosis. Given the high rates of hypoxia and AKI in admitted patients with COVID-19, clinicians should hold metformin on admission. Continue metformin for patients receiving IV contrast media with an eGFR >30 mL/min/1.73 m². For patients undergoing IA catheter studies associated with a risk for renal artery emboli, or in patients with renal insufficiency (eGFR <30 mL/min/1.73 m²), temporarily hold metformin for 48 hours. When held, restart metformin as soon as risk factors resolve.

• Hold metformin in patients with or undergoing the following:
  • High risk for or currently suffering from decompensated heart failure, severe sepsis, or other disease states resulting in hypoxia or tissue hypoperfusion;
  • An eGFR <30 mL/min/1.73 m² or AKI; resume metformin when the AKI resolves;
  • COVID-19 infection, until the risk of hypoxia has resolved;
  • IV contrast study in the presence of acute renal failure or an eGFR <30 mL/min/1.73 m²; resume metformin 48 hours after contrast administration;
  • Intra-arterial catheter study that might result in renal artery emboli; resume metformin when renal function normalizes.
• Continue metformin in all hospitalized patients in the absence of the aforementioned disease states or contrast-related indications.

Returning to the patient in our clinical scenario, we recommend continuing metformin given the lack of risk factors or disease states associated with increased lactic acidosis. The practice of withholding metformin in hospitalized patients for fear of MALA is based on minimal evidence. Clinicians should, however, hold metformin in patients who have true contraindications, including existing acidosis, hypoperfusion, renal insufficiency, CHF, severe sepsis, hypoxia, advanced cirrhosis, and COVID-19. With regard to iodinated contrast studies, temporarily withhold metformin for 48 hours in patients with an eGFR <30 mL/min/1.73 m², acute kidney injury, or in patients undergoing an IA catheter study at risk for renal artery emboli. Patients should be restarted on metformin 48 hours after these studies and as renal function normalizes. When withholding metformin during a hospitalization, restart it once risk factors have resolved.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter  (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing TWDFNR@hospitalmedicine.org

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.