Hospital Medicine

Thrombotic disorders, such as venous thromboembolism (VTE) and acute ischemic stroke, are highly prevalent,¹ morbid, and anxiety-provoking conditions for patients, their families, and providers.² Often, a clear cause for these thrombotic events cannot be found, leading to diagnoses of “cryptogenic stroke” or “idiopathic VTE.” In response, many patients and clinicians search for a cause with thrombophilia testing.

However, evaluation for thrombophilia is rarely clinically useful in hospitalized patients. Test results are often inaccurate in the setting of acute thrombosis or active anticoagulation. Even when thrombophilia results are reliable, they seldom alter immediate management of the underlying condition, especially for the inherited forms.³ An important exception is when there is high clinical suspicion for the antiphospholipid syndrome (APS), because APS test results may affect both short-term and long-term drug choices and international normalized ratio target range. Despite the broad recommendations against routine use of thrombophilia testing (including the Choosing Wisely campaign),⁴ patterns and cost of testing for inpatient thrombophilia evaluation have not been well reported.

In this issue of Journal of Hospital Medicine, Cox et al.⁵ and Mou et al.⁶ retrospectively review the appropriateness and impact of inpatient thrombophilia testing at 2 academic centers. In the report by Mou and colleagues, nearly half of all thrombophilia tests were felt to be inappropriate at an excess cost of over $40,000. Cox and colleagues identified that 77% of patients received 1 or more thrombophilia tests with minimal clinical utility. Perhaps most striking, Cox and colleagues report that management was affected in only 2 of 163 patients (1.2%) that received thrombophilia testing; both had cryptogenic stroke and both were started on anticoagulation after testing positive for multiple coagulation defects.

These studies confirm 2 key findings: first, that 43%-63% of tests are potentially inaccurate or of low utility, and second, that inpatient thrombophilia testing can be costly. Importantly, the costs of inappropriate testing were likely underestimated. For example, Mou et al. excluded 16.6% of tests that were performed for reasons that could not always be easily justified—such as “tests ordered with no documentation or justification” or “work-up sent solely on suspicion of possible thrombotic event without diagnostic confirmation.” Additionally, Mou et al. defined appropriateness more generously than current guidelines; for example, “recurrent provoked VTE” was listed as an appropriate indication for thrombophilia testing, although this is not supported by current guidelines for inherited thrombophilia evaluation. Similarly, Cox et al included cryptogenic stroke as an appropriate indication to perform thrombophilia testing; however, current American Heart Association and American Stroke Association guidelines state that usefulness of screening for hypercoagulable states in such patients is unknown.⁷ Furthermore, APS testing is not recommended in all cases of cryptogenic stroke in the absence of other clinical manifestations of APS.⁷

It remains puzzling why physicians continue to order inpatient thrombophilia testing despite their low clinical utility and inaccurate results. Cox and colleagues suggested that a lack of clinician and patient education may explain part of this reason. Likewise, easy access to “thrombophilia panels” make it easy for any clinician to order a number of tests that appear to be expert endorsed due to their inclusion in the panel. Cox et al. found that 79% of all thrombophilia tests were ordered as a part of a panel. Finally, patients and clinicians are continually searching for a reason why the thromboembolic event occurred. The thrombophilia test results (even if potentially inaccurate), may lead to a false sense of relief for both parties, no matter the results. If a thrombophilia is found, then patients and clinicians often have a sense for why the thrombotic event occurred. If the testing is negative, there may be a false sense of reassurance that “no genetic” cause for thrombosis exists.⁸

How can we improve care in this regard? Given the magnitude of financial and psychological cost of inappropriate inpatient thrombophilia testing,⁹ a robust deimplementation effort is needed.^10,11 Electronic-medical-record–based solutions may be the most effective tool to educate physicians at the point of care while simultaneously deterring inappropriate ordering. Examples include eliminating tests without evidence of clinical utility in the inpatient setting (ie, methylenetetrahydrofolate reductase); using hard stops to prevent unintentional duplicative tests¹²; and preventing providers from ordering tests that are not reliable in certain settings—such as protein S activity when patients are receiving warfarin. The latter intervention would have prevented 16% of tests (on 44% of the patients) performed in the Cox et al study. Other promising efforts include embedding guidelines into order sets and requiring the provider to choose a guideline-based reason before being allowed to order such a test. Finally, eliminating thrombophilia “panels” may reduce unnecessary duplicate testing and avoid giving a false sense of clinical validation to ordering providers who may not be familiar with the indications or nuances of each individual test.

In light of mounting evidence, including the 2 important studies discussed above, it is no longer appropriate or wise to allow unfettered access to thrombophilia testing in hospitalized patients. The evidence suggests that these tests are often ordered without regard to expense, utility, or accuracy in hospital-based settings. Deimplementation efforts that provide hard stops, education, and limited access to such testing in the electronic medical ordering system when ordering thrombophilia workups now appear necessary.

Disclosure

Lauren Heidemann and Christopher Petrilli have no conflicts of interest to report. Geoffrey Barnes reports the following conflicts of interest: Research funding from NIH/NHLBI (K01 HL135392), Blue Cross-Blue Shield of Michigan, and BMS/Pfizer. Consulting from BMS/Pfizer and Portola.

Thrombotic disorders, such as venous thromboembolism (VTE) and acute ischemic stroke, are highly prevalent,¹ morbid, and anxiety-provoking conditions for patients, their families, and providers.² Often, a clear cause for these thrombotic events cannot be found, leading to diagnoses of “cryptogenic stroke” or “idiopathic VTE.” In response, many patients and clinicians search for a cause with thrombophilia testing.

However, evaluation for thrombophilia is rarely clinically useful in hospitalized patients. Test results are often inaccurate in the setting of acute thrombosis or active anticoagulation. Even when thrombophilia results are reliable, they seldom alter immediate management of the underlying condition, especially for the inherited forms.³ An important exception is when there is high clinical suspicion for the antiphospholipid syndrome (APS), because APS test results may affect both short-term and long-term drug choices and international normalized ratio target range. Despite the broad recommendations against routine use of thrombophilia testing (including the Choosing Wisely campaign),⁴ patterns and cost of testing for inpatient thrombophilia evaluation have not been well reported.

In this issue of Journal of Hospital Medicine, Cox et al.⁵ and Mou et al.⁶ retrospectively review the appropriateness and impact of inpatient thrombophilia testing at 2 academic centers. In the report by Mou and colleagues, nearly half of all thrombophilia tests were felt to be inappropriate at an excess cost of over $40,000. Cox and colleagues identified that 77% of patients received 1 or more thrombophilia tests with minimal clinical utility. Perhaps most striking, Cox and colleagues report that management was affected in only 2 of 163 patients (1.2%) that received thrombophilia testing; both had cryptogenic stroke and both were started on anticoagulation after testing positive for multiple coagulation defects.

These studies confirm 2 key findings: first, that 43%-63% of tests are potentially inaccurate or of low utility, and second, that inpatient thrombophilia testing can be costly. Importantly, the costs of inappropriate testing were likely underestimated. For example, Mou et al. excluded 16.6% of tests that were performed for reasons that could not always be easily justified—such as “tests ordered with no documentation or justification” or “work-up sent solely on suspicion of possible thrombotic event without diagnostic confirmation.” Additionally, Mou et al. defined appropriateness more generously than current guidelines; for example, “recurrent provoked VTE” was listed as an appropriate indication for thrombophilia testing, although this is not supported by current guidelines for inherited thrombophilia evaluation. Similarly, Cox et al included cryptogenic stroke as an appropriate indication to perform thrombophilia testing; however, current American Heart Association and American Stroke Association guidelines state that usefulness of screening for hypercoagulable states in such patients is unknown.⁷ Furthermore, APS testing is not recommended in all cases of cryptogenic stroke in the absence of other clinical manifestations of APS.⁷

It remains puzzling why physicians continue to order inpatient thrombophilia testing despite their low clinical utility and inaccurate results. Cox and colleagues suggested that a lack of clinician and patient education may explain part of this reason. Likewise, easy access to “thrombophilia panels” make it easy for any clinician to order a number of tests that appear to be expert endorsed due to their inclusion in the panel. Cox et al. found that 79% of all thrombophilia tests were ordered as a part of a panel. Finally, patients and clinicians are continually searching for a reason why the thromboembolic event occurred. The thrombophilia test results (even if potentially inaccurate), may lead to a false sense of relief for both parties, no matter the results. If a thrombophilia is found, then patients and clinicians often have a sense for why the thrombotic event occurred. If the testing is negative, there may be a false sense of reassurance that “no genetic” cause for thrombosis exists.⁸

How can we improve care in this regard? Given the magnitude of financial and psychological cost of inappropriate inpatient thrombophilia testing,⁹ a robust deimplementation effort is needed.^10,11 Electronic-medical-record–based solutions may be the most effective tool to educate physicians at the point of care while simultaneously deterring inappropriate ordering. Examples include eliminating tests without evidence of clinical utility in the inpatient setting (ie, methylenetetrahydrofolate reductase); using hard stops to prevent unintentional duplicative tests¹²; and preventing providers from ordering tests that are not reliable in certain settings—such as protein S activity when patients are receiving warfarin. The latter intervention would have prevented 16% of tests (on 44% of the patients) performed in the Cox et al study. Other promising efforts include embedding guidelines into order sets and requiring the provider to choose a guideline-based reason before being allowed to order such a test. Finally, eliminating thrombophilia “panels” may reduce unnecessary duplicate testing and avoid giving a false sense of clinical validation to ordering providers who may not be familiar with the indications or nuances of each individual test.

In light of mounting evidence, including the 2 important studies discussed above, it is no longer appropriate or wise to allow unfettered access to thrombophilia testing in hospitalized patients. The evidence suggests that these tests are often ordered without regard to expense, utility, or accuracy in hospital-based settings. Deimplementation efforts that provide hard stops, education, and limited access to such testing in the electronic medical ordering system when ordering thrombophilia workups now appear necessary.

Disclosure

Lauren Heidemann and Christopher Petrilli have no conflicts of interest to report. Geoffrey Barnes reports the following conflicts of interest: Research funding from NIH/NHLBI (K01 HL135392), Blue Cross-Blue Shield of Michigan, and BMS/Pfizer. Consulting from BMS/Pfizer and Portola.

Thrombotic disorders, such as venous thromboembolism (VTE) and acute ischemic stroke, are highly prevalent,¹ morbid, and anxiety-provoking conditions for patients, their families, and providers.² Often, a clear cause for these thrombotic events cannot be found, leading to diagnoses of “cryptogenic stroke” or “idiopathic VTE.” In response, many patients and clinicians search for a cause with thrombophilia testing.

However, evaluation for thrombophilia is rarely clinically useful in hospitalized patients. Test results are often inaccurate in the setting of acute thrombosis or active anticoagulation. Even when thrombophilia results are reliable, they seldom alter immediate management of the underlying condition, especially for the inherited forms.³ An important exception is when there is high clinical suspicion for the antiphospholipid syndrome (APS), because APS test results may affect both short-term and long-term drug choices and international normalized ratio target range. Despite the broad recommendations against routine use of thrombophilia testing (including the Choosing Wisely campaign),⁴ patterns and cost of testing for inpatient thrombophilia evaluation have not been well reported.

In this issue of Journal of Hospital Medicine, Cox et al.⁵ and Mou et al.⁶ retrospectively review the appropriateness and impact of inpatient thrombophilia testing at 2 academic centers. In the report by Mou and colleagues, nearly half of all thrombophilia tests were felt to be inappropriate at an excess cost of over $40,000. Cox and colleagues identified that 77% of patients received 1 or more thrombophilia tests with minimal clinical utility. Perhaps most striking, Cox and colleagues report that management was affected in only 2 of 163 patients (1.2%) that received thrombophilia testing; both had cryptogenic stroke and both were started on anticoagulation after testing positive for multiple coagulation defects.

These studies confirm 2 key findings: first, that 43%-63% of tests are potentially inaccurate or of low utility, and second, that inpatient thrombophilia testing can be costly. Importantly, the costs of inappropriate testing were likely underestimated. For example, Mou et al. excluded 16.6% of tests that were performed for reasons that could not always be easily justified—such as “tests ordered with no documentation or justification” or “work-up sent solely on suspicion of possible thrombotic event without diagnostic confirmation.” Additionally, Mou et al. defined appropriateness more generously than current guidelines; for example, “recurrent provoked VTE” was listed as an appropriate indication for thrombophilia testing, although this is not supported by current guidelines for inherited thrombophilia evaluation. Similarly, Cox et al included cryptogenic stroke as an appropriate indication to perform thrombophilia testing; however, current American Heart Association and American Stroke Association guidelines state that usefulness of screening for hypercoagulable states in such patients is unknown.⁷ Furthermore, APS testing is not recommended in all cases of cryptogenic stroke in the absence of other clinical manifestations of APS.⁷

It remains puzzling why physicians continue to order inpatient thrombophilia testing despite their low clinical utility and inaccurate results. Cox and colleagues suggested that a lack of clinician and patient education may explain part of this reason. Likewise, easy access to “thrombophilia panels” make it easy for any clinician to order a number of tests that appear to be expert endorsed due to their inclusion in the panel. Cox et al. found that 79% of all thrombophilia tests were ordered as a part of a panel. Finally, patients and clinicians are continually searching for a reason why the thromboembolic event occurred. The thrombophilia test results (even if potentially inaccurate), may lead to a false sense of relief for both parties, no matter the results. If a thrombophilia is found, then patients and clinicians often have a sense for why the thrombotic event occurred. If the testing is negative, there may be a false sense of reassurance that “no genetic” cause for thrombosis exists.⁸

How can we improve care in this regard? Given the magnitude of financial and psychological cost of inappropriate inpatient thrombophilia testing,⁹ a robust deimplementation effort is needed.^10,11 Electronic-medical-record–based solutions may be the most effective tool to educate physicians at the point of care while simultaneously deterring inappropriate ordering. Examples include eliminating tests without evidence of clinical utility in the inpatient setting (ie, methylenetetrahydrofolate reductase); using hard stops to prevent unintentional duplicative tests¹²; and preventing providers from ordering tests that are not reliable in certain settings—such as protein S activity when patients are receiving warfarin. The latter intervention would have prevented 16% of tests (on 44% of the patients) performed in the Cox et al study. Other promising efforts include embedding guidelines into order sets and requiring the provider to choose a guideline-based reason before being allowed to order such a test. Finally, eliminating thrombophilia “panels” may reduce unnecessary duplicate testing and avoid giving a false sense of clinical validation to ordering providers who may not be familiar with the indications or nuances of each individual test.

In light of mounting evidence, including the 2 important studies discussed above, it is no longer appropriate or wise to allow unfettered access to thrombophilia testing in hospitalized patients. The evidence suggests that these tests are often ordered without regard to expense, utility, or accuracy in hospital-based settings. Deimplementation efforts that provide hard stops, education, and limited access to such testing in the electronic medical ordering system when ordering thrombophilia workups now appear necessary.

Disclosure

Lauren Heidemann and Christopher Petrilli have no conflicts of interest to report. Geoffrey Barnes reports the following conflicts of interest: Research funding from NIH/NHLBI (K01 HL135392), Blue Cross-Blue Shield of Michigan, and BMS/Pfizer. Consulting from BMS/Pfizer and Portola.

Any conversation about point-of-care ultrasound (POCUS) inevitably brings up discussion about credentialing, privileging, and certification. While credentialing and privileging are institution-specific processes, competency certification can be extramural through a national board or intramural through an institutional process.

Disclosure

Nilam Soni receives support from the U.S. Department of Veterans Affairs, Quality Enhancement Research Initiative (QUERI) Partnered Evaluation Initiative Grant (HX002263-01A1). Brian P. Lucas receives support from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, National Center for Translational Science (UL1TR001086). The contents of this publication do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Any conversation about point-of-care ultrasound (POCUS) inevitably brings up discussion about credentialing, privileging, and certification. While credentialing and privileging are institution-specific processes, competency certification can be extramural through a national board or intramural through an institutional process.

Disclosure

Nilam Soni receives support from the U.S. Department of Veterans Affairs, Quality Enhancement Research Initiative (QUERI) Partnered Evaluation Initiative Grant (HX002263-01A1). Brian P. Lucas receives support from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, National Center for Translational Science (UL1TR001086). The contents of this publication do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Any conversation about point-of-care ultrasound (POCUS) inevitably brings up discussion about credentialing, privileging, and certification. While credentialing and privileging are institution-specific processes, competency certification can be extramural through a national board or intramural through an institutional process.

Disclosure

Nilam Soni receives support from the U.S. Department of Veterans Affairs, Quality Enhancement Research Initiative (QUERI) Partnered Evaluation Initiative Grant (HX002263-01A1). Brian P. Lucas receives support from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, National Center for Translational Science (UL1TR001086). The contents of this publication do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

There is no doubt about the importance of assessing, documenting, and honoring patient wishes regarding care. For hospitalized patients, code status is a critical treatment preference to document given that the need for cardiopulmonary resuscitation (CPR) arises suddenly, outcomes are often poor, and the default is for patients to receive the treatment unless they actively decline it. Hospitalists are expected to document code status for every hospitalized patient, but admission code status conversations are often brief—and that might be all right. A code status discussion for a 70-year-old man with no chronic medical problems and excellent functional status who has been admitted for pain after a motor vehicle accident may require only an introduction to the concept of advance care planning, the importance of having a surrogate, and confirmation of full code status. On the other hand, a 45-year-old woman with metastatic pancreatic cancer would likely benefit from a family meeting in which the hospitalist could review her disease course and prognosis, assess her values and priorities in the context of her advanced illness, make treatment recommendations—including code status—that are consistent with her values, and elicit questions.^1,2 We need to free up hospitalists from spending time discussing code status with every patient so that they can spend more time in quality goals of care discussions with seriously ill patients. The paradigm of the one doctor—one patient admission code status conversation for every patient is no longer realistic.

As reported by Merino and colleagues in this issue of JHM, video decision aids about CPR for hospitalized patients can offer an innovative solution to determining code status for hospitalized patients.³ The authors conducted a prospective, randomized controlled trial, which enrolled older adults admitted to the hospital medicine service at the Veteran’s Administration (VA) Hospital in Minneapolis. Participants (N = 119) were randomized to usual care or to watch a 6-minute video that explained code status options, used a mannequin to illustrate a mock code, and provided information about potential complications and survival rates. Patients who watched the video were more likely to choose do not resuscitate/do not intubate status, with a large effect size (56% in the intervention group vs. 17% in the control group, P < 0.00001).

This study adds to a growing body of literature about this powerful modality to assist with advanced care planning. Over the past 10 years, studies—conducted primarily by Volandes, El-Jawahri, and colleagues—have demonstrated how video decision aids impact the care that patients want in the setting of cancer, heart failure, serious illness with short prognosis, and future dementia.^4-9 This literature has also shown that video decision aids can increase patients’ knowledge about CPR and increase the stability of decisions over time. Further, video decision aids have been well accepted by patients, who report that they would recommended such videos to others. This body of evidence underscores the potential of video decision aids to improve concordance between patient preferences and care provided, which is key given the longstanding and widespread concern about patients receiving care that is inconsistent with their values at the end of life.¹⁰ In short, video decision aids work.

Merino and colleagues are the first to examine the use of a video decision aid about code status in a general population of older adults on a hospital medicine service and the second to integrate such a video into usual inpatient care, which are important advancements.^2,3 There are several issues that warrant further consideration prior to widely disseminating such a video, however. As the authors note, the participants in this VA study were overwhelmingly white men and their average age was 75. Further, the authors found a nonsignificant trend towards patients in the intervention group having less trust that “my doctors and healthcare team want what is best for me” (76% in the intervention group vs. 93% in the control group; P = 0.083). Decision making about life-sustaining therapies and reactions to communication about serious illness are heavily influenced by cultural and socioeconomic factors, including health literacy.¹¹ It will be important to seek feedback from a diverse group of patients and families to ensure that the video decision aid is interpreted accurately, renders decisions that are consistent with patients’ values, and does not negatively impact the clinician-patient relationship.¹² Additionally, as the above cases illustrate, code status discussions should be tailored to patient factors, including illness severity and point in the disease course. Hospitalists will ultimately benefit from having access to multiple different videos about a range of advance care planning topics that can be used when appropriate.

In addition to selecting the right video for the right patient, the next challenge for hospitalists and health systems will be how to implement them within real-world clinical care and a broader approach to advance care planning. There are technical and logistical challenges to displaying videos in hospital rooms, and more significant challenges in ensuring timely follow-up discussions, communication of patients’ dynamic care preferences to their surrogates, changes to inpatient orders, documentation in the electronic medical record where it can be easily found in the future, and completion of advance directives and Physician Orders for Life Sustaining Treatment forms to communicate patients’ goals of care beyond the hospital and health system. Each of these steps is critical and is supported through videos and activities in the free, patient-facing, PREPARE web-based tool (https://www.prepareforyourcare.org/).^2,13,14

The ubiquitous presence of videos in our lives speaks to their power to engage and affect us. Video decision aids provide detailed explanations and vivid images that convey more than words can alone. While there is more work to be done to ensure videos are appropriate for all hospitalized patients and support rather than detract from patient-doctor relationships, this study and others like it show that video decision aids are potent tools to promote better decision-making and higher value, more efficient care.

Disclosures

The authors have nothing to disclose.

There is no doubt about the importance of assessing, documenting, and honoring patient wishes regarding care. For hospitalized patients, code status is a critical treatment preference to document given that the need for cardiopulmonary resuscitation (CPR) arises suddenly, outcomes are often poor, and the default is for patients to receive the treatment unless they actively decline it. Hospitalists are expected to document code status for every hospitalized patient, but admission code status conversations are often brief—and that might be all right. A code status discussion for a 70-year-old man with no chronic medical problems and excellent functional status who has been admitted for pain after a motor vehicle accident may require only an introduction to the concept of advance care planning, the importance of having a surrogate, and confirmation of full code status. On the other hand, a 45-year-old woman with metastatic pancreatic cancer would likely benefit from a family meeting in which the hospitalist could review her disease course and prognosis, assess her values and priorities in the context of her advanced illness, make treatment recommendations—including code status—that are consistent with her values, and elicit questions.^1,2 We need to free up hospitalists from spending time discussing code status with every patient so that they can spend more time in quality goals of care discussions with seriously ill patients. The paradigm of the one doctor—one patient admission code status conversation for every patient is no longer realistic.

As reported by Merino and colleagues in this issue of JHM, video decision aids about CPR for hospitalized patients can offer an innovative solution to determining code status for hospitalized patients.³ The authors conducted a prospective, randomized controlled trial, which enrolled older adults admitted to the hospital medicine service at the Veteran’s Administration (VA) Hospital in Minneapolis. Participants (N = 119) were randomized to usual care or to watch a 6-minute video that explained code status options, used a mannequin to illustrate a mock code, and provided information about potential complications and survival rates. Patients who watched the video were more likely to choose do not resuscitate/do not intubate status, with a large effect size (56% in the intervention group vs. 17% in the control group, P < 0.00001).

This study adds to a growing body of literature about this powerful modality to assist with advanced care planning. Over the past 10 years, studies—conducted primarily by Volandes, El-Jawahri, and colleagues—have demonstrated how video decision aids impact the care that patients want in the setting of cancer, heart failure, serious illness with short prognosis, and future dementia.^4-9 This literature has also shown that video decision aids can increase patients’ knowledge about CPR and increase the stability of decisions over time. Further, video decision aids have been well accepted by patients, who report that they would recommended such videos to others. This body of evidence underscores the potential of video decision aids to improve concordance between patient preferences and care provided, which is key given the longstanding and widespread concern about patients receiving care that is inconsistent with their values at the end of life.¹⁰ In short, video decision aids work.

Merino and colleagues are the first to examine the use of a video decision aid about code status in a general population of older adults on a hospital medicine service and the second to integrate such a video into usual inpatient care, which are important advancements.^2,3 There are several issues that warrant further consideration prior to widely disseminating such a video, however. As the authors note, the participants in this VA study were overwhelmingly white men and their average age was 75. Further, the authors found a nonsignificant trend towards patients in the intervention group having less trust that “my doctors and healthcare team want what is best for me” (76% in the intervention group vs. 93% in the control group; P = 0.083). Decision making about life-sustaining therapies and reactions to communication about serious illness are heavily influenced by cultural and socioeconomic factors, including health literacy.¹¹ It will be important to seek feedback from a diverse group of patients and families to ensure that the video decision aid is interpreted accurately, renders decisions that are consistent with patients’ values, and does not negatively impact the clinician-patient relationship.¹² Additionally, as the above cases illustrate, code status discussions should be tailored to patient factors, including illness severity and point in the disease course. Hospitalists will ultimately benefit from having access to multiple different videos about a range of advance care planning topics that can be used when appropriate.

In addition to selecting the right video for the right patient, the next challenge for hospitalists and health systems will be how to implement them within real-world clinical care and a broader approach to advance care planning. There are technical and logistical challenges to displaying videos in hospital rooms, and more significant challenges in ensuring timely follow-up discussions, communication of patients’ dynamic care preferences to their surrogates, changes to inpatient orders, documentation in the electronic medical record where it can be easily found in the future, and completion of advance directives and Physician Orders for Life Sustaining Treatment forms to communicate patients’ goals of care beyond the hospital and health system. Each of these steps is critical and is supported through videos and activities in the free, patient-facing, PREPARE web-based tool (https://www.prepareforyourcare.org/).^2,13,14

The ubiquitous presence of videos in our lives speaks to their power to engage and affect us. Video decision aids provide detailed explanations and vivid images that convey more than words can alone. While there is more work to be done to ensure videos are appropriate for all hospitalized patients and support rather than detract from patient-doctor relationships, this study and others like it show that video decision aids are potent tools to promote better decision-making and higher value, more efficient care.

Disclosures

The authors have nothing to disclose.

There is no doubt about the importance of assessing, documenting, and honoring patient wishes regarding care. For hospitalized patients, code status is a critical treatment preference to document given that the need for cardiopulmonary resuscitation (CPR) arises suddenly, outcomes are often poor, and the default is for patients to receive the treatment unless they actively decline it. Hospitalists are expected to document code status for every hospitalized patient, but admission code status conversations are often brief—and that might be all right. A code status discussion for a 70-year-old man with no chronic medical problems and excellent functional status who has been admitted for pain after a motor vehicle accident may require only an introduction to the concept of advance care planning, the importance of having a surrogate, and confirmation of full code status. On the other hand, a 45-year-old woman with metastatic pancreatic cancer would likely benefit from a family meeting in which the hospitalist could review her disease course and prognosis, assess her values and priorities in the context of her advanced illness, make treatment recommendations—including code status—that are consistent with her values, and elicit questions.^1,2 We need to free up hospitalists from spending time discussing code status with every patient so that they can spend more time in quality goals of care discussions with seriously ill patients. The paradigm of the one doctor—one patient admission code status conversation for every patient is no longer realistic.

As reported by Merino and colleagues in this issue of JHM, video decision aids about CPR for hospitalized patients can offer an innovative solution to determining code status for hospitalized patients.³ The authors conducted a prospective, randomized controlled trial, which enrolled older adults admitted to the hospital medicine service at the Veteran’s Administration (VA) Hospital in Minneapolis. Participants (N = 119) were randomized to usual care or to watch a 6-minute video that explained code status options, used a mannequin to illustrate a mock code, and provided information about potential complications and survival rates. Patients who watched the video were more likely to choose do not resuscitate/do not intubate status, with a large effect size (56% in the intervention group vs. 17% in the control group, P < 0.00001).

This study adds to a growing body of literature about this powerful modality to assist with advanced care planning. Over the past 10 years, studies—conducted primarily by Volandes, El-Jawahri, and colleagues—have demonstrated how video decision aids impact the care that patients want in the setting of cancer, heart failure, serious illness with short prognosis, and future dementia.^4-9 This literature has also shown that video decision aids can increase patients’ knowledge about CPR and increase the stability of decisions over time. Further, video decision aids have been well accepted by patients, who report that they would recommended such videos to others. This body of evidence underscores the potential of video decision aids to improve concordance between patient preferences and care provided, which is key given the longstanding and widespread concern about patients receiving care that is inconsistent with their values at the end of life.¹⁰ In short, video decision aids work.

Merino and colleagues are the first to examine the use of a video decision aid about code status in a general population of older adults on a hospital medicine service and the second to integrate such a video into usual inpatient care, which are important advancements.^2,3 There are several issues that warrant further consideration prior to widely disseminating such a video, however. As the authors note, the participants in this VA study were overwhelmingly white men and their average age was 75. Further, the authors found a nonsignificant trend towards patients in the intervention group having less trust that “my doctors and healthcare team want what is best for me” (76% in the intervention group vs. 93% in the control group; P = 0.083). Decision making about life-sustaining therapies and reactions to communication about serious illness are heavily influenced by cultural and socioeconomic factors, including health literacy.¹¹ It will be important to seek feedback from a diverse group of patients and families to ensure that the video decision aid is interpreted accurately, renders decisions that are consistent with patients’ values, and does not negatively impact the clinician-patient relationship.¹² Additionally, as the above cases illustrate, code status discussions should be tailored to patient factors, including illness severity and point in the disease course. Hospitalists will ultimately benefit from having access to multiple different videos about a range of advance care planning topics that can be used when appropriate.

In addition to selecting the right video for the right patient, the next challenge for hospitalists and health systems will be how to implement them within real-world clinical care and a broader approach to advance care planning. There are technical and logistical challenges to displaying videos in hospital rooms, and more significant challenges in ensuring timely follow-up discussions, communication of patients’ dynamic care preferences to their surrogates, changes to inpatient orders, documentation in the electronic medical record where it can be easily found in the future, and completion of advance directives and Physician Orders for Life Sustaining Treatment forms to communicate patients’ goals of care beyond the hospital and health system. Each of these steps is critical and is supported through videos and activities in the free, patient-facing, PREPARE web-based tool (https://www.prepareforyourcare.org/).^2,13,14

The ubiquitous presence of videos in our lives speaks to their power to engage and affect us. Video decision aids provide detailed explanations and vivid images that convey more than words can alone. While there is more work to be done to ensure videos are appropriate for all hospitalized patients and support rather than detract from patient-doctor relationships, this study and others like it show that video decision aids are potent tools to promote better decision-making and higher value, more efficient care.

Disclosures

The authors have nothing to disclose.

Ultrasound has been used for decades by radiology, obstetrics-gynecology, and cardiology departments within a comprehensive paradigm in which a physician enters an order, then a trained sonographer performs the study, followed by a physician evaluating and interpreting the images.¹ Unlike the traditional comprehensive paradigm, point-of-care ultrasound (POCUS) is a focused study that is both performed and interpreted by the bedside provider.² POCUS has been demonstrated to improve diagnosis and clinical management in multiple studies.^3-15

The scope of practice in POCUS differs by specialty, as POCUS is done to achieve specific procedural aims (eg, direct the needle to the correct location) or answer focused questions (eg, does the patient have a distended bladder?) related to the specialty. POCUS in hospital medicine (HM) provides immediate answers, without the delay and potential risk of transportation to other hospital areas. It may be used to diagnose pleural effusion, pneumonia, hydronephrosis, heart failure, deep vein thrombosis, and many other pathologies.^5-15 It is important to understand that POCUS performed by HM is a limited study and is not a substitute for more complete ultrasound examinations conducted in the radiology suite or in the echocardiography lab.

POCUS should not be used exclusively in medical decision making, but rather in conjunction with the greater clinical context of each patient, building on established principles of diagnosis and management.

• Credentialing: An umbrella term, which incorporates licensure, education, and certification.
• Privileging: Used to define the scope authorized for a provider by a healthcare organization based on an evaluation of the individual’s credentials and performance.
• Competency: An observable ability of a provider, integrating multiple components, such as knowledge and skills. Since competencies are observable, they can be measured and assessed to ensure their acquisition.
• Certification: The process by which an association grants recognition to a provider who has met certain predetermined qualifications specified by the association. Competence is distinguished from certification, which is defined as the process by which competence is recognized by an external agency.

All of the above mechanisms work together to provide the highest quality of reliability that a practitioner is providing safe, competent care.^16-18

Acknowledging that there are no published guidelines in the realm of HM POCUS, the development of the credentialing process at our institution is consistent with published guidelines by Emergency Medicine societies (the most established physician users of POCUS) and the American Medical Association (AMA).^19-21

The use of emergency ultrasound by physicians in the emergency department is endorsed by the American College of Emergency Physicians (ACEP).¹⁹ ACEP, along with the Society of Academic Emergency Medicine (SAEM), recommends that training in the performance and interpretation of ultrasound imaging be included during residency.²⁰ ACEP and SAEM add that the availability of equivalent training should be made available to practicing physicians. The American Society of Echocardiography has supported the use of POCUS and sees this modality as part of the continuum of care.^23,24

The AMA has also recognized that POCUS is within the scope of practice of trained physicians.²² The AMA further recommended hospital staff create their own criteria for granting ultrasound privileges based on the background and training of the physician and in accordance with the standards set within specific specialties.^22,23

The provision of clinical privileges in HM is governed by the rules and regulations of the department and institution for which privileges are sought. In detailing our policies and procedures above, we intend to provide an example for HM departments at other institutions that are attempting to create a POCUS credentialing program.

An interdisciplinary approach was created by our institution to address training, competency, and ongoing quality assurance (QA) concerns due to the increasing popularity of POCUS and variability in its use. We developed a hospital-wide POCUS committee with, among others, members from HM, emergency medicine, critical care, radiology, and cardiology, with a charter to standardize POCUS across departments. After review of the literature,^{16-18, 20, 21, 23-74} baseline training requirements were established for credentialing and developing a unified delineation of privileges for hospital-wide POCUS. The data support the use of a variety of assessments to ensure a provider has developed competence (portfolio development, knowledge-based examination, skills-based assessment, ongoing QA process). The POCUS committee identified which exams could be performed at bedside for credentialed providers, delineated imaging requirements for each exam, and set up the information technology infrastructure to support ordering and reporting through electronic health records (EHR). While the POCUS committee delineated this process for all hospital providers, we will focus our discussion on the credentialing policy and procedure in HM.

The credentialing requirements at our institution include one of the the following basic education pathways and minimal formal training:

Residency/Fellowship Based Pathway

Completed training in an Accreditation Council for Graduate Medical Education–approved program that provided opportunities for 20 hours of POCUS training with at least 6 hours of hands-on ultrasound scanning, 5 proctored limited cardiac ultrasound cases and portfolio development.

Practice Based Pathway

Completed 20 hours of POCUS continuing medical education (CME) with at least 6 hours of hands-on ultrasound scanning and has completed 5 proctored limited cardiac ultrasound cases (as part of CME).

The majority of HM providers had little formal residency training in POCUS, so a training program needed to be developed. Our training program, modeled after the American College of Chest Physicians’ CHEST certificate of completion,⁸⁶ utilizes didactic training, hands-on instruction, and portfolio development that fulfills the minimal formal requirements in the practice-based pathway.

After satisfactory completion of the minimal formal training, applicants need to provide documentation of a set number of cases. To aid this requirement, our HM department developed the portfolio guidelines in the Table. These are minimum requirements, and because of the varying training curves of learning,^76-80 1 hospitalist may need to submit 300 files for review to meet the standards, while another may need to submit 500 files. Submissions are not accepted unless they yield high-quality video files with meticulous attention to gain, depth, and appropriate topographic planes. The portfolio development monitors hospitalists’ progression during their deliberate practice, providing objective assessments, feedback, and mentorship.^81,82

A final knowledge exam with case-based image interpretation and hands-on examination is also provided. The passing score for the written examination is 85% and was based on the Angoff methodology.⁷⁵ Providers who meet these requirements are then able to apply for POCUS credentialing in HM. Providers who do not pass the final assessments are required to participate in further training before they reattempt the assessments. There is uniformity in training outcomes but diversity in training time for POCUS providers.

Candidates who complete the portfolio and satisfactorily pass the final assessments are credentialed after review by the POCUS committee. Credentialed physicians are then able to perform POCUS and to integrate the findings into patient care.

Documentation

After credentialing is obtained, all POCUS studies used in patient care are included in the EHR following a clearly defined workflow. The study is ordered through the EHR and is retrieved wirelessly on the ultrasound machine. After performing the ultrasound, all images are wirelessly transferred to the radiology Picture Archiving and Communication System server. Standardized text reports are used to distinguish focused POCUS from traditional diagnostic ultrasound studies. Documentation is optimized using electronic drop-down menus for documenting ultrasound findings in the EHR.

Minimum Number of Examinations

Maintenance of credentials will require that each hospitalist perform 10 documented ultrasounds per year for each cardiac and noncardiac application for which credentials are requested. If these numbers are not met, then all the studies performed during the previous year will be reviewed by the ultrasound committee, and providers will be provided with opportunities to meet the minimum benchmark (supervised scanning sessions).

Quality Assurance

Establishing scope of practice, developing curricula, and credentialing criteria are important steps toward assuring provider competence.^16,17,22,74 To be confident that providers are using POCUS appropriately, there must also be a development of standards of periodic assessment that encompass both examination performance and interpretation. The objective of a QA process is to evaluate the POCUS cases for technical competence and the interpretations for clinical accuracy, and to provide feedback to improve performance of providers.

QA is maintained through the interdisciplinary POCUS committee and is described in the Figure.

After initial credentialing, continued QA of HM POCUS is done for a proportion of ongoing exams (10% as per recommendations by ACEP) to document continued competency.² Credentialed POCUS providers perform and document their exam and interpretations. Ultrasound interpretations are reviewed by the POCUS committee (every case by 2 physicians, 1 hospitalist, and 1 radiologist or cardiologist depending on the study type) at appropriate intervals based on volume (at minimum, quarterly). A standardized review form is used to grade images and interpretations. This is the same general rubric used with the portfolio for initial credentialing. Each case is scored on a scale of 1 to 6, with 1 representing high image quality and support for diagnosis and 6 representing studies limited by patient factors. All scores rated 4 or 5 are reviewed at the larger quarterly POCUS committee meetings. For any provider scoring a 4 or 5, the ultrasound committee will recommend a focused professional practice evaluation as it pertains to POCUS. The committee will also make recommendations on a physician’s continued privileges to the department leaders.⁸³

Coding, billing, and reimbursement for focused ultrasound has been supported through the AMA Physicians’ Current Procedural Terminology (CPT) 2011 codes, which includes CPT code modifiers for POCUS.⁸⁴ There are significant costs associated with building a HM ultrasound program, including the education of hospitalists, ultrasound equipment purchase and maintenance, as well as image archiving and QA. The development of a HM ultrasound billing program can help justify and fund these costs.^19,85

To appropriately bill for POCUS, permanently retrievable images and an interpretation document need to be available for review. HM coders are instructed to only bill if both components are available. Because most insurers will not pay for 2 of the same type of study performed within a 24-hour period, coders do not bill for ultrasounds when a comprehensive ultrasound of the same body region is performed within a 24-hour period. The workflow that we have developed, including ordering, performing, and documenting, allows for easy coding and billing.

While POCUS has a well-established literature base in other specialties like emergency medicine, it has been a relatively recent addition to the HM specialty. As such, there exists a paucity of evidence-based medicine to support its use of POCUS in HM. While it is tempting to extrapolate from the literature of other specialties, this may not be a valid approach.

Training curves in which novice users of ultrasound become competent in specific applications are incompletely understood. Little research describes the rate of progression of learners in ultrasound towards competency. We have recently started the QA process and hope that the data will further guide feedback to the process.

Additionally, with the portfolios, the raters’ expertise may not be stable (develops through experience). We aim to mitigate this by having a group of raters reviewing each file, particularly if there is a question about if a submission is of high image quality. A notable barrier that groups face is support from their leadership regarding POCUS. Our group has had support from the chief medical officer who helped mandate the development of POCUS standards.

We have developed a robust collaborative HM POCUS program. We have noted challenges in motivating all providers to work through this protocol. Development of a POCUS program takes dedicated time, and without a champion, it is at risk for failing. HM departments would be advised to seek out willing collaborators at their institutions. We have seen that it is useful to partner with some experienced emergency medicine providers. Additionally, portfolio development and feedback has been key to demonstrating growth in image acquisition. Deliberate longitudinal practice with feedback and successive refinements with POCUS obtain the highest yield towards competency. We hope our QA data will provide further feedback into the credentialing policy and procedure.

It is important that POCUS users work together to recognize its potential and limitations, teach current and future care providers’ best practices, and create an infrastructure that maximizes quality of care while minimizing patient risk.

We are hopeful that this document will prove beneficial to other HM departments in the development of successful POCUS programs. We feel that it is important to make available to other HM departments a concise protocol that has successfully passed through the credentialing process at a large tertiary care medical system.

Acknowledgments

The authors would like to acknowledge Susan Truman, MD, for her contributions to the success of the POCUS committee at Regions Hospital. The authors would like to acknowledge Kreegan Reierson, MD, Ankit Mehta, MBBS, and Khuong Vuong, MD for their contributions to the success of POCUS within hospital medicine at HealthPartners. The authors would like to acknowledge Sandi Wewerka, MPH, for her review and input of this manuscript.

Disclosure

The authors do not have any relevant financial disclosures to report.

Ultrasound has been used for decades by radiology, obstetrics-gynecology, and cardiology departments within a comprehensive paradigm in which a physician enters an order, then a trained sonographer performs the study, followed by a physician evaluating and interpreting the images.¹ Unlike the traditional comprehensive paradigm, point-of-care ultrasound (POCUS) is a focused study that is both performed and interpreted by the bedside provider.² POCUS has been demonstrated to improve diagnosis and clinical management in multiple studies.^3-15

The scope of practice in POCUS differs by specialty, as POCUS is done to achieve specific procedural aims (eg, direct the needle to the correct location) or answer focused questions (eg, does the patient have a distended bladder?) related to the specialty. POCUS in hospital medicine (HM) provides immediate answers, without the delay and potential risk of transportation to other hospital areas. It may be used to diagnose pleural effusion, pneumonia, hydronephrosis, heart failure, deep vein thrombosis, and many other pathologies.^5-15 It is important to understand that POCUS performed by HM is a limited study and is not a substitute for more complete ultrasound examinations conducted in the radiology suite or in the echocardiography lab.

POCUS should not be used exclusively in medical decision making, but rather in conjunction with the greater clinical context of each patient, building on established principles of diagnosis and management.

• Credentialing: An umbrella term, which incorporates licensure, education, and certification.
• Privileging: Used to define the scope authorized for a provider by a healthcare organization based on an evaluation of the individual’s credentials and performance.
• Competency: An observable ability of a provider, integrating multiple components, such as knowledge and skills. Since competencies are observable, they can be measured and assessed to ensure their acquisition.
• Certification: The process by which an association grants recognition to a provider who has met certain predetermined qualifications specified by the association. Competence is distinguished from certification, which is defined as the process by which competence is recognized by an external agency.

All of the above mechanisms work together to provide the highest quality of reliability that a practitioner is providing safe, competent care.^16-18

Acknowledging that there are no published guidelines in the realm of HM POCUS, the development of the credentialing process at our institution is consistent with published guidelines by Emergency Medicine societies (the most established physician users of POCUS) and the American Medical Association (AMA).^19-21

The use of emergency ultrasound by physicians in the emergency department is endorsed by the American College of Emergency Physicians (ACEP).¹⁹ ACEP, along with the Society of Academic Emergency Medicine (SAEM), recommends that training in the performance and interpretation of ultrasound imaging be included during residency.²⁰ ACEP and SAEM add that the availability of equivalent training should be made available to practicing physicians. The American Society of Echocardiography has supported the use of POCUS and sees this modality as part of the continuum of care.^23,24

The AMA has also recognized that POCUS is within the scope of practice of trained physicians.²² The AMA further recommended hospital staff create their own criteria for granting ultrasound privileges based on the background and training of the physician and in accordance with the standards set within specific specialties.^22,23

The provision of clinical privileges in HM is governed by the rules and regulations of the department and institution for which privileges are sought. In detailing our policies and procedures above, we intend to provide an example for HM departments at other institutions that are attempting to create a POCUS credentialing program.

An interdisciplinary approach was created by our institution to address training, competency, and ongoing quality assurance (QA) concerns due to the increasing popularity of POCUS and variability in its use. We developed a hospital-wide POCUS committee with, among others, members from HM, emergency medicine, critical care, radiology, and cardiology, with a charter to standardize POCUS across departments. After review of the literature,^{16-18, 20, 21, 23-74} baseline training requirements were established for credentialing and developing a unified delineation of privileges for hospital-wide POCUS. The data support the use of a variety of assessments to ensure a provider has developed competence (portfolio development, knowledge-based examination, skills-based assessment, ongoing QA process). The POCUS committee identified which exams could be performed at bedside for credentialed providers, delineated imaging requirements for each exam, and set up the information technology infrastructure to support ordering and reporting through electronic health records (EHR). While the POCUS committee delineated this process for all hospital providers, we will focus our discussion on the credentialing policy and procedure in HM.

The credentialing requirements at our institution include one of the the following basic education pathways and minimal formal training:

Residency/Fellowship Based Pathway

Completed training in an Accreditation Council for Graduate Medical Education–approved program that provided opportunities for 20 hours of POCUS training with at least 6 hours of hands-on ultrasound scanning, 5 proctored limited cardiac ultrasound cases and portfolio development.

Practice Based Pathway

Completed 20 hours of POCUS continuing medical education (CME) with at least 6 hours of hands-on ultrasound scanning and has completed 5 proctored limited cardiac ultrasound cases (as part of CME).

The majority of HM providers had little formal residency training in POCUS, so a training program needed to be developed. Our training program, modeled after the American College of Chest Physicians’ CHEST certificate of completion,⁸⁶ utilizes didactic training, hands-on instruction, and portfolio development that fulfills the minimal formal requirements in the practice-based pathway.

After satisfactory completion of the minimal formal training, applicants need to provide documentation of a set number of cases. To aid this requirement, our HM department developed the portfolio guidelines in the Table. These are minimum requirements, and because of the varying training curves of learning,^76-80 1 hospitalist may need to submit 300 files for review to meet the standards, while another may need to submit 500 files. Submissions are not accepted unless they yield high-quality video files with meticulous attention to gain, depth, and appropriate topographic planes. The portfolio development monitors hospitalists’ progression during their deliberate practice, providing objective assessments, feedback, and mentorship.^81,82

A final knowledge exam with case-based image interpretation and hands-on examination is also provided. The passing score for the written examination is 85% and was based on the Angoff methodology.⁷⁵ Providers who meet these requirements are then able to apply for POCUS credentialing in HM. Providers who do not pass the final assessments are required to participate in further training before they reattempt the assessments. There is uniformity in training outcomes but diversity in training time for POCUS providers.

Candidates who complete the portfolio and satisfactorily pass the final assessments are credentialed after review by the POCUS committee. Credentialed physicians are then able to perform POCUS and to integrate the findings into patient care.

Documentation

After credentialing is obtained, all POCUS studies used in patient care are included in the EHR following a clearly defined workflow. The study is ordered through the EHR and is retrieved wirelessly on the ultrasound machine. After performing the ultrasound, all images are wirelessly transferred to the radiology Picture Archiving and Communication System server. Standardized text reports are used to distinguish focused POCUS from traditional diagnostic ultrasound studies. Documentation is optimized using electronic drop-down menus for documenting ultrasound findings in the EHR.

Minimum Number of Examinations

Maintenance of credentials will require that each hospitalist perform 10 documented ultrasounds per year for each cardiac and noncardiac application for which credentials are requested. If these numbers are not met, then all the studies performed during the previous year will be reviewed by the ultrasound committee, and providers will be provided with opportunities to meet the minimum benchmark (supervised scanning sessions).

Quality Assurance

Establishing scope of practice, developing curricula, and credentialing criteria are important steps toward assuring provider competence.^16,17,22,74 To be confident that providers are using POCUS appropriately, there must also be a development of standards of periodic assessment that encompass both examination performance and interpretation. The objective of a QA process is to evaluate the POCUS cases for technical competence and the interpretations for clinical accuracy, and to provide feedback to improve performance of providers.

QA is maintained through the interdisciplinary POCUS committee and is described in the Figure.

After initial credentialing, continued QA of HM POCUS is done for a proportion of ongoing exams (10% as per recommendations by ACEP) to document continued competency.² Credentialed POCUS providers perform and document their exam and interpretations. Ultrasound interpretations are reviewed by the POCUS committee (every case by 2 physicians, 1 hospitalist, and 1 radiologist or cardiologist depending on the study type) at appropriate intervals based on volume (at minimum, quarterly). A standardized review form is used to grade images and interpretations. This is the same general rubric used with the portfolio for initial credentialing. Each case is scored on a scale of 1 to 6, with 1 representing high image quality and support for diagnosis and 6 representing studies limited by patient factors. All scores rated 4 or 5 are reviewed at the larger quarterly POCUS committee meetings. For any provider scoring a 4 or 5, the ultrasound committee will recommend a focused professional practice evaluation as it pertains to POCUS. The committee will also make recommendations on a physician’s continued privileges to the department leaders.⁸³

Coding, billing, and reimbursement for focused ultrasound has been supported through the AMA Physicians’ Current Procedural Terminology (CPT) 2011 codes, which includes CPT code modifiers for POCUS.⁸⁴ There are significant costs associated with building a HM ultrasound program, including the education of hospitalists, ultrasound equipment purchase and maintenance, as well as image archiving and QA. The development of a HM ultrasound billing program can help justify and fund these costs.^19,85

To appropriately bill for POCUS, permanently retrievable images and an interpretation document need to be available for review. HM coders are instructed to only bill if both components are available. Because most insurers will not pay for 2 of the same type of study performed within a 24-hour period, coders do not bill for ultrasounds when a comprehensive ultrasound of the same body region is performed within a 24-hour period. The workflow that we have developed, including ordering, performing, and documenting, allows for easy coding and billing.

While POCUS has a well-established literature base in other specialties like emergency medicine, it has been a relatively recent addition to the HM specialty. As such, there exists a paucity of evidence-based medicine to support its use of POCUS in HM. While it is tempting to extrapolate from the literature of other specialties, this may not be a valid approach.

Training curves in which novice users of ultrasound become competent in specific applications are incompletely understood. Little research describes the rate of progression of learners in ultrasound towards competency. We have recently started the QA process and hope that the data will further guide feedback to the process.

Additionally, with the portfolios, the raters’ expertise may not be stable (develops through experience). We aim to mitigate this by having a group of raters reviewing each file, particularly if there is a question about if a submission is of high image quality. A notable barrier that groups face is support from their leadership regarding POCUS. Our group has had support from the chief medical officer who helped mandate the development of POCUS standards.

We have developed a robust collaborative HM POCUS program. We have noted challenges in motivating all providers to work through this protocol. Development of a POCUS program takes dedicated time, and without a champion, it is at risk for failing. HM departments would be advised to seek out willing collaborators at their institutions. We have seen that it is useful to partner with some experienced emergency medicine providers. Additionally, portfolio development and feedback has been key to demonstrating growth in image acquisition. Deliberate longitudinal practice with feedback and successive refinements with POCUS obtain the highest yield towards competency. We hope our QA data will provide further feedback into the credentialing policy and procedure.

It is important that POCUS users work together to recognize its potential and limitations, teach current and future care providers’ best practices, and create an infrastructure that maximizes quality of care while minimizing patient risk.

We are hopeful that this document will prove beneficial to other HM departments in the development of successful POCUS programs. We feel that it is important to make available to other HM departments a concise protocol that has successfully passed through the credentialing process at a large tertiary care medical system.

Acknowledgments

The authors would like to acknowledge Susan Truman, MD, for her contributions to the success of the POCUS committee at Regions Hospital. The authors would like to acknowledge Kreegan Reierson, MD, Ankit Mehta, MBBS, and Khuong Vuong, MD for their contributions to the success of POCUS within hospital medicine at HealthPartners. The authors would like to acknowledge Sandi Wewerka, MPH, for her review and input of this manuscript.

Disclosure

The authors do not have any relevant financial disclosures to report.

Ultrasound has been used for decades by radiology, obstetrics-gynecology, and cardiology departments within a comprehensive paradigm in which a physician enters an order, then a trained sonographer performs the study, followed by a physician evaluating and interpreting the images.¹ Unlike the traditional comprehensive paradigm, point-of-care ultrasound (POCUS) is a focused study that is both performed and interpreted by the bedside provider.² POCUS has been demonstrated to improve diagnosis and clinical management in multiple studies.^3-15

The scope of practice in POCUS differs by specialty, as POCUS is done to achieve specific procedural aims (eg, direct the needle to the correct location) or answer focused questions (eg, does the patient have a distended bladder?) related to the specialty. POCUS in hospital medicine (HM) provides immediate answers, without the delay and potential risk of transportation to other hospital areas. It may be used to diagnose pleural effusion, pneumonia, hydronephrosis, heart failure, deep vein thrombosis, and many other pathologies.^5-15 It is important to understand that POCUS performed by HM is a limited study and is not a substitute for more complete ultrasound examinations conducted in the radiology suite or in the echocardiography lab.

POCUS should not be used exclusively in medical decision making, but rather in conjunction with the greater clinical context of each patient, building on established principles of diagnosis and management.

• Credentialing: An umbrella term, which incorporates licensure, education, and certification.
• Privileging: Used to define the scope authorized for a provider by a healthcare organization based on an evaluation of the individual’s credentials and performance.
• Competency: An observable ability of a provider, integrating multiple components, such as knowledge and skills. Since competencies are observable, they can be measured and assessed to ensure their acquisition.
• Certification: The process by which an association grants recognition to a provider who has met certain predetermined qualifications specified by the association. Competence is distinguished from certification, which is defined as the process by which competence is recognized by an external agency.

All of the above mechanisms work together to provide the highest quality of reliability that a practitioner is providing safe, competent care.^16-18

Acknowledging that there are no published guidelines in the realm of HM POCUS, the development of the credentialing process at our institution is consistent with published guidelines by Emergency Medicine societies (the most established physician users of POCUS) and the American Medical Association (AMA).^19-21

The use of emergency ultrasound by physicians in the emergency department is endorsed by the American College of Emergency Physicians (ACEP).¹⁹ ACEP, along with the Society of Academic Emergency Medicine (SAEM), recommends that training in the performance and interpretation of ultrasound imaging be included during residency.²⁰ ACEP and SAEM add that the availability of equivalent training should be made available to practicing physicians. The American Society of Echocardiography has supported the use of POCUS and sees this modality as part of the continuum of care.^23,24

The AMA has also recognized that POCUS is within the scope of practice of trained physicians.²² The AMA further recommended hospital staff create their own criteria for granting ultrasound privileges based on the background and training of the physician and in accordance with the standards set within specific specialties.^22,23

The provision of clinical privileges in HM is governed by the rules and regulations of the department and institution for which privileges are sought. In detailing our policies and procedures above, we intend to provide an example for HM departments at other institutions that are attempting to create a POCUS credentialing program.

An interdisciplinary approach was created by our institution to address training, competency, and ongoing quality assurance (QA) concerns due to the increasing popularity of POCUS and variability in its use. We developed a hospital-wide POCUS committee with, among others, members from HM, emergency medicine, critical care, radiology, and cardiology, with a charter to standardize POCUS across departments. After review of the literature,^{16-18, 20, 21, 23-74} baseline training requirements were established for credentialing and developing a unified delineation of privileges for hospital-wide POCUS. The data support the use of a variety of assessments to ensure a provider has developed competence (portfolio development, knowledge-based examination, skills-based assessment, ongoing QA process). The POCUS committee identified which exams could be performed at bedside for credentialed providers, delineated imaging requirements for each exam, and set up the information technology infrastructure to support ordering and reporting through electronic health records (EHR). While the POCUS committee delineated this process for all hospital providers, we will focus our discussion on the credentialing policy and procedure in HM.

The credentialing requirements at our institution include one of the the following basic education pathways and minimal formal training:

Residency/Fellowship Based Pathway

Completed training in an Accreditation Council for Graduate Medical Education–approved program that provided opportunities for 20 hours of POCUS training with at least 6 hours of hands-on ultrasound scanning, 5 proctored limited cardiac ultrasound cases and portfolio development.

Practice Based Pathway

Completed 20 hours of POCUS continuing medical education (CME) with at least 6 hours of hands-on ultrasound scanning and has completed 5 proctored limited cardiac ultrasound cases (as part of CME).

The majority of HM providers had little formal residency training in POCUS, so a training program needed to be developed. Our training program, modeled after the American College of Chest Physicians’ CHEST certificate of completion,⁸⁶ utilizes didactic training, hands-on instruction, and portfolio development that fulfills the minimal formal requirements in the practice-based pathway.

After satisfactory completion of the minimal formal training, applicants need to provide documentation of a set number of cases. To aid this requirement, our HM department developed the portfolio guidelines in the Table. These are minimum requirements, and because of the varying training curves of learning,^76-80 1 hospitalist may need to submit 300 files for review to meet the standards, while another may need to submit 500 files. Submissions are not accepted unless they yield high-quality video files with meticulous attention to gain, depth, and appropriate topographic planes. The portfolio development monitors hospitalists’ progression during their deliberate practice, providing objective assessments, feedback, and mentorship.^81,82

A final knowledge exam with case-based image interpretation and hands-on examination is also provided. The passing score for the written examination is 85% and was based on the Angoff methodology.⁷⁵ Providers who meet these requirements are then able to apply for POCUS credentialing in HM. Providers who do not pass the final assessments are required to participate in further training before they reattempt the assessments. There is uniformity in training outcomes but diversity in training time for POCUS providers.

Candidates who complete the portfolio and satisfactorily pass the final assessments are credentialed after review by the POCUS committee. Credentialed physicians are then able to perform POCUS and to integrate the findings into patient care.

Documentation

After credentialing is obtained, all POCUS studies used in patient care are included in the EHR following a clearly defined workflow. The study is ordered through the EHR and is retrieved wirelessly on the ultrasound machine. After performing the ultrasound, all images are wirelessly transferred to the radiology Picture Archiving and Communication System server. Standardized text reports are used to distinguish focused POCUS from traditional diagnostic ultrasound studies. Documentation is optimized using electronic drop-down menus for documenting ultrasound findings in the EHR.

Minimum Number of Examinations

Maintenance of credentials will require that each hospitalist perform 10 documented ultrasounds per year for each cardiac and noncardiac application for which credentials are requested. If these numbers are not met, then all the studies performed during the previous year will be reviewed by the ultrasound committee, and providers will be provided with opportunities to meet the minimum benchmark (supervised scanning sessions).

Quality Assurance

Establishing scope of practice, developing curricula, and credentialing criteria are important steps toward assuring provider competence.^16,17,22,74 To be confident that providers are using POCUS appropriately, there must also be a development of standards of periodic assessment that encompass both examination performance and interpretation. The objective of a QA process is to evaluate the POCUS cases for technical competence and the interpretations for clinical accuracy, and to provide feedback to improve performance of providers.

QA is maintained through the interdisciplinary POCUS committee and is described in the Figure.

After initial credentialing, continued QA of HM POCUS is done for a proportion of ongoing exams (10% as per recommendations by ACEP) to document continued competency.² Credentialed POCUS providers perform and document their exam and interpretations. Ultrasound interpretations are reviewed by the POCUS committee (every case by 2 physicians, 1 hospitalist, and 1 radiologist or cardiologist depending on the study type) at appropriate intervals based on volume (at minimum, quarterly). A standardized review form is used to grade images and interpretations. This is the same general rubric used with the portfolio for initial credentialing. Each case is scored on a scale of 1 to 6, with 1 representing high image quality and support for diagnosis and 6 representing studies limited by patient factors. All scores rated 4 or 5 are reviewed at the larger quarterly POCUS committee meetings. For any provider scoring a 4 or 5, the ultrasound committee will recommend a focused professional practice evaluation as it pertains to POCUS. The committee will also make recommendations on a physician’s continued privileges to the department leaders.⁸³

Coding, billing, and reimbursement for focused ultrasound has been supported through the AMA Physicians’ Current Procedural Terminology (CPT) 2011 codes, which includes CPT code modifiers for POCUS.⁸⁴ There are significant costs associated with building a HM ultrasound program, including the education of hospitalists, ultrasound equipment purchase and maintenance, as well as image archiving and QA. The development of a HM ultrasound billing program can help justify and fund these costs.^19,85

To appropriately bill for POCUS, permanently retrievable images and an interpretation document need to be available for review. HM coders are instructed to only bill if both components are available. Because most insurers will not pay for 2 of the same type of study performed within a 24-hour period, coders do not bill for ultrasounds when a comprehensive ultrasound of the same body region is performed within a 24-hour period. The workflow that we have developed, including ordering, performing, and documenting, allows for easy coding and billing.

While POCUS has a well-established literature base in other specialties like emergency medicine, it has been a relatively recent addition to the HM specialty. As such, there exists a paucity of evidence-based medicine to support its use of POCUS in HM. While it is tempting to extrapolate from the literature of other specialties, this may not be a valid approach.

Training curves in which novice users of ultrasound become competent in specific applications are incompletely understood. Little research describes the rate of progression of learners in ultrasound towards competency. We have recently started the QA process and hope that the data will further guide feedback to the process.

Additionally, with the portfolios, the raters’ expertise may not be stable (develops through experience). We aim to mitigate this by having a group of raters reviewing each file, particularly if there is a question about if a submission is of high image quality. A notable barrier that groups face is support from their leadership regarding POCUS. Our group has had support from the chief medical officer who helped mandate the development of POCUS standards.

We have developed a robust collaborative HM POCUS program. We have noted challenges in motivating all providers to work through this protocol. Development of a POCUS program takes dedicated time, and without a champion, it is at risk for failing. HM departments would be advised to seek out willing collaborators at their institutions. We have seen that it is useful to partner with some experienced emergency medicine providers. Additionally, portfolio development and feedback has been key to demonstrating growth in image acquisition. Deliberate longitudinal practice with feedback and successive refinements with POCUS obtain the highest yield towards competency. We hope our QA data will provide further feedback into the credentialing policy and procedure.

It is important that POCUS users work together to recognize its potential and limitations, teach current and future care providers’ best practices, and create an infrastructure that maximizes quality of care while minimizing patient risk.

We are hopeful that this document will prove beneficial to other HM departments in the development of successful POCUS programs. We feel that it is important to make available to other HM departments a concise protocol that has successfully passed through the credentialing process at a large tertiary care medical system.

Acknowledgments

The authors would like to acknowledge Susan Truman, MD, for her contributions to the success of the POCUS committee at Regions Hospital. The authors would like to acknowledge Kreegan Reierson, MD, Ankit Mehta, MBBS, and Khuong Vuong, MD for their contributions to the success of POCUS within hospital medicine at HealthPartners. The authors would like to acknowledge Sandi Wewerka, MPH, for her review and input of this manuscript.

Disclosure

The authors do not have any relevant financial disclosures to report.

The presence of a “weekend effect” (increased mortality rate during Saturday and/or Sunday admissions) for hospitalized inpatients is uncertain. Several observational studies^1-3 suggested a positive correlation between weekend admission and increased mortality, whereas other studies demonstrated no correlation^4-6 or mixed results.^7,8 The majority of studies have been published only within the last decade.

Several possible reasons are cited to explain the weekend effect. Decreased and presence of inexperienced staffing on weekends may contribute to a deficit in care.^7,9,10 Patients admitted during the weekend may be less likely to undergo procedures or have significant delays before receiving needed intervention.^11-13 Another possibility is that there may be differences in severity of illness or comorbidities in patients admitted during the weekend compared with those admitted during the remainder of the week. Due to inconsistency between studies regarding the existence of such an effect, we performed a meta-analysis in hospitalized inpatients to delineate whether or not there is a weekend effect on mortality.

Data Sources and Searches

This study was exempt from institutional review board review, and we utilized the recommendations from the Meta-analysis of Observational Studies in Epidemiology statement. We examined the mortality rate for hospital inpatients admitted during the weekend (weekend death) compared with the mortality rate for those admitted during the workweek (workweek death). We performed a literature search (January 1966−April 2013) of multiple databases, including PubMed, EMBASE, SCOPUS, and the Cochrane library (see Appendix). Two reviewers (LP, RJP) independently evaluated the full article of each abstract. Any disputes were resolved by a third reviewer (CW). Bibliographic references were hand searched for additional literature.

Study Selection

To be included in the systematic review, the study had to provide discrete mortality data on the weekends (including holidays) versus weekdays, include patients who were admitted as inpatients over the weekend, and be published in the English language. We excluded studies that combined weekend with weekday “off hours” (eg, weekday night shift) data, which could not be extracted or analyzed separately.

Data Extraction and Quality Assessment

Once an article was accepted to be included for the systematic review, the authors extracted relevant data if available, including study location, number and type of patients studied, patient comorbidity data, procedure-related data (type of procedure, difference in rate of procedure and time to procedure performed for both weekday and weekends), any stated and/or implied differences in staffing patterns between weekend and weekdays, and definition of mortality. We used the Newcastle-Ottawa Quality Assessment Scale to assess the quality of methodological reporting of the study.¹⁴ The definition of weekend and extraction and classification of data (weekend versus weekday) was based on the original study definition. We made no attempt to impose a universal definition of “weekend” on all studies. Similarly, the definition of mortality (eg, 3-/7-/30-day) was based according to the original study definition. Death from a patient admitted on the weekend was defined as a “weekend death” (regardless of ultimate time of death) and similarly, death from a patient admitted on a weekday was defined as a “weekday death.” Although some articles provided specific information on healthcare worker staffing patterns between weekends and weekdays, differences in weekend versus weekday staffing were implied in many articles. In these studies, staffing paradigms were considered to be different between weekend and weekdays if there were specific descriptions of the type of hospitals (urban versus rural, teaching versus nonteaching, large versus small) in the database, which would imply a typical routine staffing pattern as currently occurs in most hospitals (ie, generally less healthcare worker staff on weekends). We only included data that provided times (mean minutes/hours) from admission to the specific intervention and that provided actual rates of intervention performed for both weekend and weekday patients. We only included data that provided an actual rate of intervention performed for both weekend and weekday patients. With regard to patient comorbidities or illness severity index, we used the original studies classification (defined by the original manuscripts), which might include widely accepted global indices or a listing of specific comorbidities and/or physiologic parameters present on admission.

Data Synthesis and Analysis

We used a random effects meta-analysis approach for estimating an overall relative risk (RR) and risk differences of mortality for weekends versus weekdays, as well as subgroup specific estimates, and for computing confidence limits. The DerSimonian and Laird approach was used to estimate the random effects. Within each of the 4 subgroups (weekend staffing, procedure rates and delays, illness severity), we grouped each qualified individual study by the presence of a difference (ie, difference, no difference, or mixed) and then pooled the mortality rates for all of the studies in that group. For instance, in the subgroup of staffing, we sorted available studies by whether weekend staffing was the same or decreased versus weekday staffing, then pooled the mortality rates for studies where staffing levels were the same (versus weekday) and also separately pooled studies where staffing levels were decreased (versus weekday). Data were managed with Stata 13 (Stata Statistical Software: Release 13; StataCorp. 2013, College Station, TX) and R, and all meta-analyses were performed with the metafor package in R.¹⁵ Pooled estimated are presented as RR (95% confidence intervals [CI]).

A literature search retrieved a total of 594 unique citations. A review of the bibliographic references yielded an additional 20 articles. Upon evaluation, 97 studies (N = 51,114,109 patients) met inclusion criteria (Figure 1). The articles were published between 2001–2012; the kappa statistic comparing interrater reliability in the selection of articles was 0.86. Supplementary Tables 1 and 2 present a summary of study characteristics and outcomes of the accepted articles. A summary of accepted studies is in Supplementary Table 1. When summing the total number of subjects across all 97 articles, 76% were classified as weekday and 24% were weekend patients.

Weekend Admission/Inpatient Status and Mortality

The definition of the weekend varied among the included studies. The weekend time period was delineated as Friday midnight to Sunday midnight in 66% (65/99) of the studies. The remaining studies typically defined the weekend to be between Friday evening and Monday morning although studies from the Middle East generally defined the weekend as Wednesday/Thursday through Saturday. The definition of mortality also varied among researchers with most studies describing death rate as hospital inpatient mortality although some studies also examined multiple definitions of mortality (eg, 30-day all-cause mortality and hospital inpatient mortality). Not all studies provided a specific timeframe for mortality.

Weekend Effect Factors

We also performed subgroup analyses to investigate the overall weekend effect by hospital level factors (weekend staffing, procedure rates and delays, illness severity). Complete data were not available for all studies (staffing levels = 73 studies, time to intervention = 18 studies, rate of intervention = 30 studies, illness severity = 64 studies). Patients admitted on the weekends consistently had higher mortality than those admitted during the week, regardless of the levels of weekend/weekday differences in staffing, procedure rates and delays, illness severity (Figure 3). Analysis of studies that included staffing data for weekends revealed that decreased staffing levels on the weekends was associated with a higher mortality for weekend patients (RR = 1.16; 95% CI, 1.12-1.20; I² = 99%; Figure 3). There was no difference in mortality for weekend patients when staffing was similar to that for the weekdays (RR = 1.21; 95% CI, 0.91-1.63; I² = 99%).

Analysis for weekend data revealed that longer times to interventions on weekends were associated with significantly higher mortality rates (RR = 1.11; 95% CI, 1.08-1.15; I² = 0%; Figure 3). When there were no delays to weekend procedure/interventions, there was no difference in mortality between weekend and weekday procedures/interventions (RR = 1.04; 95% CI, 0.96-1.13; I² = 55%; Figure 3). Some articles included several procedures with “mixed” results (some procedures were “positive,” while other were “negative” for increased mortality). In studies that showed a mixed result for time to intervention, there was a significant increase in mortality (RR = 1.16; 95% CI, 1.06-1.27; I² = 42%) for weekend patients (Figure 3).

Analyses showed a higher mortality rate on the weekends regardless of whether the rate of intervention/procedures was lower (RR=1.12; 95% CI, 1.07-1.17; I² = 79%) or the same between weekend and weekdays (RR = 1.08; 95% CI, 1.01-1.16; I² = 90%; Figure 3). Analyses showed a higher mortality rate on the weekends regardless of whether the illness severity was higher on the weekends (RR = 1.21; 95% CI, 1.07-1.38; I² = 99%) or the same (RR = 1.21; 95% CI, 1.14-1.28; I² = 99%) versus that for weekday patients (Figure 3). An inverse funnel plot for publication bias is shown in Figure 4.

We have presented one of the first meta-analyses to examine the mortality rate for hospital inpatients admitted during the weekend compared with those admitted during the workweek. We found that patients admitted on the weekends had a significantly higher overall mortality (RR = 1.19; 95% CI, 1.14-1.23; risk difference = 0.014; 95% CI, 0.013-0.016). This association was not modified by differences in weekday and weekend staffing patterns, and other hospital characteristics. Previous systematic reviews have been exclusive to the intensive care unit setting¹⁶ or did not specifically examine weekend mortality, which was a component of “off-shift” and/or “after-hours” care.¹⁷

These findings should be placed in the context of the recently published literature.^18,19 A meta-analysis of cohort studies found that off-hour admission was associated with increased mortality for 28 diseases although the associations varied considerably for different diseases.¹⁸ Likewise, a meta-analysis of 21 cohort studies noted that off-hour presentation for patients with acute ischemic stroke was associated with significantly higher short-term mortality.¹⁹ Our results of increased weekend mortality corroborate that found in these two meta-analyses. However, our study differs in that we specifically examined only weekend mortality and did not include after-hours care on weekdays, which was included in the off-hour mortality in the other meta-analyses.^18,19

Differences in healthcare worker staffing between weekends and weekdays have been proposed to contribute to the observed increase in mortality.^7,16,20 Data indicate that lower levels of nursing are associated with increased mortality.^10,21-23 The presence of less experienced and/or fewer physician specialists may contribute to increases in mortality.^24-26 Fewer or less experienced staff during weekends may contribute to inadequacies in patient handovers and/or handoffs, delays in patient assessment and/or interventions, and overall continuity of care for newly admitted patients.^27-33

Our data show little conclusive evidence that the weekend mortality versus weekday mortality vary by staffing level differences. While the estimated RR of mortality differs in magnitude for facilities with no difference in weekend and weekday staffing versus those that have a difference in staffing levels, both estimate an increased mortality on weekends, and the difference in these effects is not statistically significant. It should be noted that there was no difference in mortality for weekend (versus weekday) patients where there was no difference between weekend and weekday staffing; these studies were typically in high acuity units or centers where the general expectation is for 24/7/365 uniform staffing coverage.

A decrease in the use of interventions and/or procedures on weekends has been suggested to contribute to increases in mortality for patients admitted on the weekends.³⁴ Several studies have associated lower weekend rates to higher mortality for a variety of interventions,^13,35-37 although some other studies have suggested that lower procedure rates on weekends have no effect on mortality.^38-40 Lower diagnostic procedure weekend rates linked to higher mortality rates may exacerbate underlying healthcare disparities.⁴¹ Our results do not conclusively show that a decrease rate of intervention and/or procedures for weekends patients is associated with a higher risk of mortality for weekends compared to weekdays.

Delays in intervention and/or procedure on weekends have also been suggested to contribute to increases in mortality.^34,42 Similar to that seen with lower rates of diagnostic or therapeutic intervention and/or procedure performed on weekends, delays in potentially critical intervention and/or procedures might ultimately manifest as an increase in mortality.⁴³ Patients admitted to the hospital on weekends and requiring an early procedure were less likely to receive it within 2 days of admission.⁴² Several studies have shown an association between delays in diagnostic or therapeutic intervention and/or procedure on weekends to a higher hospital inpatient mortality^35,42,44,45; however, some data suggested that a delay in time to procedure on weekends may not always be associated with increased mortality.⁴⁶ Depending on the procedure, there may be a threshold below which the effect of reducing delay times will have no effect on mortality rates.^47,48

Patients admitted on the weekends may be different (in the severity of illness and/or comorbidities) than those admitted during the workweek and these potential differences may be a factor for increases in mortality for weekend patients. Whether there is a selection bias for weekend versus weekday patients is not clear.³⁴ This is a complex issue as there is significant heterogeneity in patient case mix depending on the specific disease or condition studied. For instance, one would expect that weekend trauma patients would be different than those seen during the regular workweek.⁴⁹ Some large scale studies suggest that weekend patients may not be more sick than weekday patients and that any increase in weekend mortality is probably not due to factors such as severity of illness.^1,7 Although we were unable to determine if there was an overall difference in illness severity between weekend and weekday patients due to the wide variety of assessments used for illness severity, our results showed statistically comparable higher mortality rate on the weekends regardless of whether the illness severity was higher, the same, or mixed between weekend and weekday patients, suggesting that general illness severity per se may not be as important as the weekend effect on mortality; however, illness severity may still have an important effect on mortality for more specific subgroups (eg, trauma).⁴⁹

There are several implications of our results. We found a mean increased RR mortality of approximately 19% for patients admitted on the weekends, a number similar to one of the largest published observational studies containing almost 5 million subjects.² Even if we took a more conservative estimate of 10% increased risk of weekend mortality, this would be equivalent to an excess of 25,000 preventable deaths per year. If the weekend effect were to be placed in context of a public health issue, the weekend effect would be the number 8 cause of death below the 29,000 deaths due to gun violence, but above the 20,000 deaths resulting from sexual behavior (sexual transmitted diseases) in 2000.^{3, 50,51} Although our data suggest that staffing shortfalls and decreases or delays for procedures on weekends may be associated with an increased mortality for patients admitted on the weekends, further large-scale studies are needed to confirm these findings. Increasing nurse and physician staffing levels and skill mix to cover any potential shortfall on weekends may be expensive, although theoretically, there may be savings accrued from reduced adverse events and shorter length of stay.^26,52 Changes to weekend care might only benefit daytime hospitalizations because some studies have shown increased mortality during nighttime regardless of weekend or weekday admission.⁵³

Several methodologic points in our study need to be clarified. We excluded many studies which examined the relationship of off-hours or after-hours admissions and mortality as off-hours studies typically combined weekend and after-hours weekday data. Some studies suggest that off-hour admission may be associated with increased mortality and delays in time for critical procedures during off-hours.^18,19 This is a complex topic, but it is clear that the risks of hospitalization vary not just by the day of the week but also by time of the day.⁵⁴ The use of meta-analyses of nonrandomized trials has been somewhat controversial,^55,56 and there may be significant bias or confounding in the pooling of highly varied studies. It is important to keep in mind that there are very different definitions of weekends, populations studied, and measures of mortality rates, even as the pooled statistic suggests a homogeneity among the studies that does not exist.

There are several limitations to our study. Our systematic review may be seen as limited as we included only English language papers. In addition, we did not search nontraditional sources and abstracts. We accepted the definition of a weekend as defined by the original study, which resulted in varied definitions of weekend time period and mortality. There was a lack of specific data on staffing patterns and procedures in many studies, particularly those using databases. We were not able to further subdivide our analysis by admitting service. We were not able to undertake a subgroup analysis by country or continent, which may have implications on the effect of different healthcare systems on healthcare quality. It is unclear whether correlations in our study are a direct consequence of poorer weekend care or are the result of other unknown or unexamined differences between weekend and weekday patient populations.^34,57 For instance, there may be other global factors (higher rates of medical errors, higher hospital volumes) which may not be specifically related to weekend care and therefore not been accounted for in many of the studies we examined.^10,27,58-61 There may be potential bias of patient phenotypes (are weekend patients different than weekday patients?) admitted on the weekend. Holidays were included in the weekend data and it is not clear how this would affect our findings as some data suggest that there is a significantly higher mortality rate on holidays (versus weekends or weekdays),⁶¹ while other data do not.⁶² There was no universal definition for the timeframe for a weekend and as such, we had to rely on the original article for their determination and definition of weekend versus weekday death.

In summary, our meta-analysis suggests that hospital inpatients admitted during the weekend have a significantly increased mortality compared with those admitted on weekday. While none of our subgroup analyses showed strong evidence on effect modification, the interpretation of these results is hampered by the relatively small number of studies. Further research should be directed to determine the presence of causality between various factors purported to affect mortality and it is possible that we ultimately find that the weekend effect may exist for some but not all patients.

Acknowledgments

The authors would like to acknowledge Jaime Blanck, MLIS, MPA, AHIP, Clinical Informationist, Welch Medical Library, for her invaluable assistance in undertaking the literature searches for this manuscript.

Disclosure

This manuscript has been supported by the Department of Anesthesiology and Critical Care Medicine; The Johns Hopkins School of Medicine; Baltimore, Maryland. There are no relevant conflicts of interests.

The presence of a “weekend effect” (increased mortality rate during Saturday and/or Sunday admissions) for hospitalized inpatients is uncertain. Several observational studies^1-3 suggested a positive correlation between weekend admission and increased mortality, whereas other studies demonstrated no correlation^4-6 or mixed results.^7,8 The majority of studies have been published only within the last decade.

Several possible reasons are cited to explain the weekend effect. Decreased and presence of inexperienced staffing on weekends may contribute to a deficit in care.^7,9,10 Patients admitted during the weekend may be less likely to undergo procedures or have significant delays before receiving needed intervention.^11-13 Another possibility is that there may be differences in severity of illness or comorbidities in patients admitted during the weekend compared with those admitted during the remainder of the week. Due to inconsistency between studies regarding the existence of such an effect, we performed a meta-analysis in hospitalized inpatients to delineate whether or not there is a weekend effect on mortality.

Data Sources and Searches

This study was exempt from institutional review board review, and we utilized the recommendations from the Meta-analysis of Observational Studies in Epidemiology statement. We examined the mortality rate for hospital inpatients admitted during the weekend (weekend death) compared with the mortality rate for those admitted during the workweek (workweek death). We performed a literature search (January 1966−April 2013) of multiple databases, including PubMed, EMBASE, SCOPUS, and the Cochrane library (see Appendix). Two reviewers (LP, RJP) independently evaluated the full article of each abstract. Any disputes were resolved by a third reviewer (CW). Bibliographic references were hand searched for additional literature.

Study Selection

To be included in the systematic review, the study had to provide discrete mortality data on the weekends (including holidays) versus weekdays, include patients who were admitted as inpatients over the weekend, and be published in the English language. We excluded studies that combined weekend with weekday “off hours” (eg, weekday night shift) data, which could not be extracted or analyzed separately.

Data Extraction and Quality Assessment

Once an article was accepted to be included for the systematic review, the authors extracted relevant data if available, including study location, number and type of patients studied, patient comorbidity data, procedure-related data (type of procedure, difference in rate of procedure and time to procedure performed for both weekday and weekends), any stated and/or implied differences in staffing patterns between weekend and weekdays, and definition of mortality. We used the Newcastle-Ottawa Quality Assessment Scale to assess the quality of methodological reporting of the study.¹⁴ The definition of weekend and extraction and classification of data (weekend versus weekday) was based on the original study definition. We made no attempt to impose a universal definition of “weekend” on all studies. Similarly, the definition of mortality (eg, 3-/7-/30-day) was based according to the original study definition. Death from a patient admitted on the weekend was defined as a “weekend death” (regardless of ultimate time of death) and similarly, death from a patient admitted on a weekday was defined as a “weekday death.” Although some articles provided specific information on healthcare worker staffing patterns between weekends and weekdays, differences in weekend versus weekday staffing were implied in many articles. In these studies, staffing paradigms were considered to be different between weekend and weekdays if there were specific descriptions of the type of hospitals (urban versus rural, teaching versus nonteaching, large versus small) in the database, which would imply a typical routine staffing pattern as currently occurs in most hospitals (ie, generally less healthcare worker staff on weekends). We only included data that provided times (mean minutes/hours) from admission to the specific intervention and that provided actual rates of intervention performed for both weekend and weekday patients. We only included data that provided an actual rate of intervention performed for both weekend and weekday patients. With regard to patient comorbidities or illness severity index, we used the original studies classification (defined by the original manuscripts), which might include widely accepted global indices or a listing of specific comorbidities and/or physiologic parameters present on admission.

Data Synthesis and Analysis

We used a random effects meta-analysis approach for estimating an overall relative risk (RR) and risk differences of mortality for weekends versus weekdays, as well as subgroup specific estimates, and for computing confidence limits. The DerSimonian and Laird approach was used to estimate the random effects. Within each of the 4 subgroups (weekend staffing, procedure rates and delays, illness severity), we grouped each qualified individual study by the presence of a difference (ie, difference, no difference, or mixed) and then pooled the mortality rates for all of the studies in that group. For instance, in the subgroup of staffing, we sorted available studies by whether weekend staffing was the same or decreased versus weekday staffing, then pooled the mortality rates for studies where staffing levels were the same (versus weekday) and also separately pooled studies where staffing levels were decreased (versus weekday). Data were managed with Stata 13 (Stata Statistical Software: Release 13; StataCorp. 2013, College Station, TX) and R, and all meta-analyses were performed with the metafor package in R.¹⁵ Pooled estimated are presented as RR (95% confidence intervals [CI]).

A literature search retrieved a total of 594 unique citations. A review of the bibliographic references yielded an additional 20 articles. Upon evaluation, 97 studies (N = 51,114,109 patients) met inclusion criteria (Figure 1). The articles were published between 2001–2012; the kappa statistic comparing interrater reliability in the selection of articles was 0.86. Supplementary Tables 1 and 2 present a summary of study characteristics and outcomes of the accepted articles. A summary of accepted studies is in Supplementary Table 1. When summing the total number of subjects across all 97 articles, 76% were classified as weekday and 24% were weekend patients.

Weekend Admission/Inpatient Status and Mortality

The definition of the weekend varied among the included studies. The weekend time period was delineated as Friday midnight to Sunday midnight in 66% (65/99) of the studies. The remaining studies typically defined the weekend to be between Friday evening and Monday morning although studies from the Middle East generally defined the weekend as Wednesday/Thursday through Saturday. The definition of mortality also varied among researchers with most studies describing death rate as hospital inpatient mortality although some studies also examined multiple definitions of mortality (eg, 30-day all-cause mortality and hospital inpatient mortality). Not all studies provided a specific timeframe for mortality.

Weekend Effect Factors

We also performed subgroup analyses to investigate the overall weekend effect by hospital level factors (weekend staffing, procedure rates and delays, illness severity). Complete data were not available for all studies (staffing levels = 73 studies, time to intervention = 18 studies, rate of intervention = 30 studies, illness severity = 64 studies). Patients admitted on the weekends consistently had higher mortality than those admitted during the week, regardless of the levels of weekend/weekday differences in staffing, procedure rates and delays, illness severity (Figure 3). Analysis of studies that included staffing data for weekends revealed that decreased staffing levels on the weekends was associated with a higher mortality for weekend patients (RR = 1.16; 95% CI, 1.12-1.20; I² = 99%; Figure 3). There was no difference in mortality for weekend patients when staffing was similar to that for the weekdays (RR = 1.21; 95% CI, 0.91-1.63; I² = 99%).

Analysis for weekend data revealed that longer times to interventions on weekends were associated with significantly higher mortality rates (RR = 1.11; 95% CI, 1.08-1.15; I² = 0%; Figure 3). When there were no delays to weekend procedure/interventions, there was no difference in mortality between weekend and weekday procedures/interventions (RR = 1.04; 95% CI, 0.96-1.13; I² = 55%; Figure 3). Some articles included several procedures with “mixed” results (some procedures were “positive,” while other were “negative” for increased mortality). In studies that showed a mixed result for time to intervention, there was a significant increase in mortality (RR = 1.16; 95% CI, 1.06-1.27; I² = 42%) for weekend patients (Figure 3).

Analyses showed a higher mortality rate on the weekends regardless of whether the rate of intervention/procedures was lower (RR=1.12; 95% CI, 1.07-1.17; I² = 79%) or the same between weekend and weekdays (RR = 1.08; 95% CI, 1.01-1.16; I² = 90%; Figure 3). Analyses showed a higher mortality rate on the weekends regardless of whether the illness severity was higher on the weekends (RR = 1.21; 95% CI, 1.07-1.38; I² = 99%) or the same (RR = 1.21; 95% CI, 1.14-1.28; I² = 99%) versus that for weekday patients (Figure 3). An inverse funnel plot for publication bias is shown in Figure 4.

We have presented one of the first meta-analyses to examine the mortality rate for hospital inpatients admitted during the weekend compared with those admitted during the workweek. We found that patients admitted on the weekends had a significantly higher overall mortality (RR = 1.19; 95% CI, 1.14-1.23; risk difference = 0.014; 95% CI, 0.013-0.016). This association was not modified by differences in weekday and weekend staffing patterns, and other hospital characteristics. Previous systematic reviews have been exclusive to the intensive care unit setting¹⁶ or did not specifically examine weekend mortality, which was a component of “off-shift” and/or “after-hours” care.¹⁷

These findings should be placed in the context of the recently published literature.^18,19 A meta-analysis of cohort studies found that off-hour admission was associated with increased mortality for 28 diseases although the associations varied considerably for different diseases.¹⁸ Likewise, a meta-analysis of 21 cohort studies noted that off-hour presentation for patients with acute ischemic stroke was associated with significantly higher short-term mortality.¹⁹ Our results of increased weekend mortality corroborate that found in these two meta-analyses. However, our study differs in that we specifically examined only weekend mortality and did not include after-hours care on weekdays, which was included in the off-hour mortality in the other meta-analyses.^18,19

Differences in healthcare worker staffing between weekends and weekdays have been proposed to contribute to the observed increase in mortality.^7,16,20 Data indicate that lower levels of nursing are associated with increased mortality.^10,21-23 The presence of less experienced and/or fewer physician specialists may contribute to increases in mortality.^24-26 Fewer or less experienced staff during weekends may contribute to inadequacies in patient handovers and/or handoffs, delays in patient assessment and/or interventions, and overall continuity of care for newly admitted patients.^27-33

Our data show little conclusive evidence that the weekend mortality versus weekday mortality vary by staffing level differences. While the estimated RR of mortality differs in magnitude for facilities with no difference in weekend and weekday staffing versus those that have a difference in staffing levels, both estimate an increased mortality on weekends, and the difference in these effects is not statistically significant. It should be noted that there was no difference in mortality for weekend (versus weekday) patients where there was no difference between weekend and weekday staffing; these studies were typically in high acuity units or centers where the general expectation is for 24/7/365 uniform staffing coverage.

A decrease in the use of interventions and/or procedures on weekends has been suggested to contribute to increases in mortality for patients admitted on the weekends.³⁴ Several studies have associated lower weekend rates to higher mortality for a variety of interventions,^13,35-37 although some other studies have suggested that lower procedure rates on weekends have no effect on mortality.^38-40 Lower diagnostic procedure weekend rates linked to higher mortality rates may exacerbate underlying healthcare disparities.⁴¹ Our results do not conclusively show that a decrease rate of intervention and/or procedures for weekends patients is associated with a higher risk of mortality for weekends compared to weekdays.

Delays in intervention and/or procedure on weekends have also been suggested to contribute to increases in mortality.^34,42 Similar to that seen with lower rates of diagnostic or therapeutic intervention and/or procedure performed on weekends, delays in potentially critical intervention and/or procedures might ultimately manifest as an increase in mortality.⁴³ Patients admitted to the hospital on weekends and requiring an early procedure were less likely to receive it within 2 days of admission.⁴² Several studies have shown an association between delays in diagnostic or therapeutic intervention and/or procedure on weekends to a higher hospital inpatient mortality^35,42,44,45; however, some data suggested that a delay in time to procedure on weekends may not always be associated with increased mortality.⁴⁶ Depending on the procedure, there may be a threshold below which the effect of reducing delay times will have no effect on mortality rates.^47,48

Patients admitted on the weekends may be different (in the severity of illness and/or comorbidities) than those admitted during the workweek and these potential differences may be a factor for increases in mortality for weekend patients. Whether there is a selection bias for weekend versus weekday patients is not clear.³⁴ This is a complex issue as there is significant heterogeneity in patient case mix depending on the specific disease or condition studied. For instance, one would expect that weekend trauma patients would be different than those seen during the regular workweek.⁴⁹ Some large scale studies suggest that weekend patients may not be more sick than weekday patients and that any increase in weekend mortality is probably not due to factors such as severity of illness.^1,7 Although we were unable to determine if there was an overall difference in illness severity between weekend and weekday patients due to the wide variety of assessments used for illness severity, our results showed statistically comparable higher mortality rate on the weekends regardless of whether the illness severity was higher, the same, or mixed between weekend and weekday patients, suggesting that general illness severity per se may not be as important as the weekend effect on mortality; however, illness severity may still have an important effect on mortality for more specific subgroups (eg, trauma).⁴⁹

There are several implications of our results. We found a mean increased RR mortality of approximately 19% for patients admitted on the weekends, a number similar to one of the largest published observational studies containing almost 5 million subjects.² Even if we took a more conservative estimate of 10% increased risk of weekend mortality, this would be equivalent to an excess of 25,000 preventable deaths per year. If the weekend effect were to be placed in context of a public health issue, the weekend effect would be the number 8 cause of death below the 29,000 deaths due to gun violence, but above the 20,000 deaths resulting from sexual behavior (sexual transmitted diseases) in 2000.^{3, 50,51} Although our data suggest that staffing shortfalls and decreases or delays for procedures on weekends may be associated with an increased mortality for patients admitted on the weekends, further large-scale studies are needed to confirm these findings. Increasing nurse and physician staffing levels and skill mix to cover any potential shortfall on weekends may be expensive, although theoretically, there may be savings accrued from reduced adverse events and shorter length of stay.^26,52 Changes to weekend care might only benefit daytime hospitalizations because some studies have shown increased mortality during nighttime regardless of weekend or weekday admission.⁵³

Several methodologic points in our study need to be clarified. We excluded many studies which examined the relationship of off-hours or after-hours admissions and mortality as off-hours studies typically combined weekend and after-hours weekday data. Some studies suggest that off-hour admission may be associated with increased mortality and delays in time for critical procedures during off-hours.^18,19 This is a complex topic, but it is clear that the risks of hospitalization vary not just by the day of the week but also by time of the day.⁵⁴ The use of meta-analyses of nonrandomized trials has been somewhat controversial,^55,56 and there may be significant bias or confounding in the pooling of highly varied studies. It is important to keep in mind that there are very different definitions of weekends, populations studied, and measures of mortality rates, even as the pooled statistic suggests a homogeneity among the studies that does not exist.

There are several limitations to our study. Our systematic review may be seen as limited as we included only English language papers. In addition, we did not search nontraditional sources and abstracts. We accepted the definition of a weekend as defined by the original study, which resulted in varied definitions of weekend time period and mortality. There was a lack of specific data on staffing patterns and procedures in many studies, particularly those using databases. We were not able to further subdivide our analysis by admitting service. We were not able to undertake a subgroup analysis by country or continent, which may have implications on the effect of different healthcare systems on healthcare quality. It is unclear whether correlations in our study are a direct consequence of poorer weekend care or are the result of other unknown or unexamined differences between weekend and weekday patient populations.^34,57 For instance, there may be other global factors (higher rates of medical errors, higher hospital volumes) which may not be specifically related to weekend care and therefore not been accounted for in many of the studies we examined.^10,27,58-61 There may be potential bias of patient phenotypes (are weekend patients different than weekday patients?) admitted on the weekend. Holidays were included in the weekend data and it is not clear how this would affect our findings as some data suggest that there is a significantly higher mortality rate on holidays (versus weekends or weekdays),⁶¹ while other data do not.⁶² There was no universal definition for the timeframe for a weekend and as such, we had to rely on the original article for their determination and definition of weekend versus weekday death.

In summary, our meta-analysis suggests that hospital inpatients admitted during the weekend have a significantly increased mortality compared with those admitted on weekday. While none of our subgroup analyses showed strong evidence on effect modification, the interpretation of these results is hampered by the relatively small number of studies. Further research should be directed to determine the presence of causality between various factors purported to affect mortality and it is possible that we ultimately find that the weekend effect may exist for some but not all patients.

Acknowledgments

The authors would like to acknowledge Jaime Blanck, MLIS, MPA, AHIP, Clinical Informationist, Welch Medical Library, for her invaluable assistance in undertaking the literature searches for this manuscript.

Disclosure

This manuscript has been supported by the Department of Anesthesiology and Critical Care Medicine; The Johns Hopkins School of Medicine; Baltimore, Maryland. There are no relevant conflicts of interests.

The presence of a “weekend effect” (increased mortality rate during Saturday and/or Sunday admissions) for hospitalized inpatients is uncertain. Several observational studies^1-3 suggested a positive correlation between weekend admission and increased mortality, whereas other studies demonstrated no correlation^4-6 or mixed results.^7,8 The majority of studies have been published only within the last decade.

Several possible reasons are cited to explain the weekend effect. Decreased and presence of inexperienced staffing on weekends may contribute to a deficit in care.^7,9,10 Patients admitted during the weekend may be less likely to undergo procedures or have significant delays before receiving needed intervention.^11-13 Another possibility is that there may be differences in severity of illness or comorbidities in patients admitted during the weekend compared with those admitted during the remainder of the week. Due to inconsistency between studies regarding the existence of such an effect, we performed a meta-analysis in hospitalized inpatients to delineate whether or not there is a weekend effect on mortality.

Data Sources and Searches

This study was exempt from institutional review board review, and we utilized the recommendations from the Meta-analysis of Observational Studies in Epidemiology statement. We examined the mortality rate for hospital inpatients admitted during the weekend (weekend death) compared with the mortality rate for those admitted during the workweek (workweek death). We performed a literature search (January 1966−April 2013) of multiple databases, including PubMed, EMBASE, SCOPUS, and the Cochrane library (see Appendix). Two reviewers (LP, RJP) independently evaluated the full article of each abstract. Any disputes were resolved by a third reviewer (CW). Bibliographic references were hand searched for additional literature.

Study Selection

To be included in the systematic review, the study had to provide discrete mortality data on the weekends (including holidays) versus weekdays, include patients who were admitted as inpatients over the weekend, and be published in the English language. We excluded studies that combined weekend with weekday “off hours” (eg, weekday night shift) data, which could not be extracted or analyzed separately.

Data Extraction and Quality Assessment

Once an article was accepted to be included for the systematic review, the authors extracted relevant data if available, including study location, number and type of patients studied, patient comorbidity data, procedure-related data (type of procedure, difference in rate of procedure and time to procedure performed for both weekday and weekends), any stated and/or implied differences in staffing patterns between weekend and weekdays, and definition of mortality. We used the Newcastle-Ottawa Quality Assessment Scale to assess the quality of methodological reporting of the study.¹⁴ The definition of weekend and extraction and classification of data (weekend versus weekday) was based on the original study definition. We made no attempt to impose a universal definition of “weekend” on all studies. Similarly, the definition of mortality (eg, 3-/7-/30-day) was based according to the original study definition. Death from a patient admitted on the weekend was defined as a “weekend death” (regardless of ultimate time of death) and similarly, death from a patient admitted on a weekday was defined as a “weekday death.” Although some articles provided specific information on healthcare worker staffing patterns between weekends and weekdays, differences in weekend versus weekday staffing were implied in many articles. In these studies, staffing paradigms were considered to be different between weekend and weekdays if there were specific descriptions of the type of hospitals (urban versus rural, teaching versus nonteaching, large versus small) in the database, which would imply a typical routine staffing pattern as currently occurs in most hospitals (ie, generally less healthcare worker staff on weekends). We only included data that provided times (mean minutes/hours) from admission to the specific intervention and that provided actual rates of intervention performed for both weekend and weekday patients. We only included data that provided an actual rate of intervention performed for both weekend and weekday patients. With regard to patient comorbidities or illness severity index, we used the original studies classification (defined by the original manuscripts), which might include widely accepted global indices or a listing of specific comorbidities and/or physiologic parameters present on admission.

Data Synthesis and Analysis

We used a random effects meta-analysis approach for estimating an overall relative risk (RR) and risk differences of mortality for weekends versus weekdays, as well as subgroup specific estimates, and for computing confidence limits. The DerSimonian and Laird approach was used to estimate the random effects. Within each of the 4 subgroups (weekend staffing, procedure rates and delays, illness severity), we grouped each qualified individual study by the presence of a difference (ie, difference, no difference, or mixed) and then pooled the mortality rates for all of the studies in that group. For instance, in the subgroup of staffing, we sorted available studies by whether weekend staffing was the same or decreased versus weekday staffing, then pooled the mortality rates for studies where staffing levels were the same (versus weekday) and also separately pooled studies where staffing levels were decreased (versus weekday). Data were managed with Stata 13 (Stata Statistical Software: Release 13; StataCorp. 2013, College Station, TX) and R, and all meta-analyses were performed with the metafor package in R.¹⁵ Pooled estimated are presented as RR (95% confidence intervals [CI]).

A literature search retrieved a total of 594 unique citations. A review of the bibliographic references yielded an additional 20 articles. Upon evaluation, 97 studies (N = 51,114,109 patients) met inclusion criteria (Figure 1). The articles were published between 2001–2012; the kappa statistic comparing interrater reliability in the selection of articles was 0.86. Supplementary Tables 1 and 2 present a summary of study characteristics and outcomes of the accepted articles. A summary of accepted studies is in Supplementary Table 1. When summing the total number of subjects across all 97 articles, 76% were classified as weekday and 24% were weekend patients.

Weekend Admission/Inpatient Status and Mortality

The definition of the weekend varied among the included studies. The weekend time period was delineated as Friday midnight to Sunday midnight in 66% (65/99) of the studies. The remaining studies typically defined the weekend to be between Friday evening and Monday morning although studies from the Middle East generally defined the weekend as Wednesday/Thursday through Saturday. The definition of mortality also varied among researchers with most studies describing death rate as hospital inpatient mortality although some studies also examined multiple definitions of mortality (eg, 30-day all-cause mortality and hospital inpatient mortality). Not all studies provided a specific timeframe for mortality.

Weekend Effect Factors

We also performed subgroup analyses to investigate the overall weekend effect by hospital level factors (weekend staffing, procedure rates and delays, illness severity). Complete data were not available for all studies (staffing levels = 73 studies, time to intervention = 18 studies, rate of intervention = 30 studies, illness severity = 64 studies). Patients admitted on the weekends consistently had higher mortality than those admitted during the week, regardless of the levels of weekend/weekday differences in staffing, procedure rates and delays, illness severity (Figure 3). Analysis of studies that included staffing data for weekends revealed that decreased staffing levels on the weekends was associated with a higher mortality for weekend patients (RR = 1.16; 95% CI, 1.12-1.20; I² = 99%; Figure 3). There was no difference in mortality for weekend patients when staffing was similar to that for the weekdays (RR = 1.21; 95% CI, 0.91-1.63; I² = 99%).

Analysis for weekend data revealed that longer times to interventions on weekends were associated with significantly higher mortality rates (RR = 1.11; 95% CI, 1.08-1.15; I² = 0%; Figure 3). When there were no delays to weekend procedure/interventions, there was no difference in mortality between weekend and weekday procedures/interventions (RR = 1.04; 95% CI, 0.96-1.13; I² = 55%; Figure 3). Some articles included several procedures with “mixed” results (some procedures were “positive,” while other were “negative” for increased mortality). In studies that showed a mixed result for time to intervention, there was a significant increase in mortality (RR = 1.16; 95% CI, 1.06-1.27; I² = 42%) for weekend patients (Figure 3).

Analyses showed a higher mortality rate on the weekends regardless of whether the rate of intervention/procedures was lower (RR=1.12; 95% CI, 1.07-1.17; I² = 79%) or the same between weekend and weekdays (RR = 1.08; 95% CI, 1.01-1.16; I² = 90%; Figure 3). Analyses showed a higher mortality rate on the weekends regardless of whether the illness severity was higher on the weekends (RR = 1.21; 95% CI, 1.07-1.38; I² = 99%) or the same (RR = 1.21; 95% CI, 1.14-1.28; I² = 99%) versus that for weekday patients (Figure 3). An inverse funnel plot for publication bias is shown in Figure 4.

We have presented one of the first meta-analyses to examine the mortality rate for hospital inpatients admitted during the weekend compared with those admitted during the workweek. We found that patients admitted on the weekends had a significantly higher overall mortality (RR = 1.19; 95% CI, 1.14-1.23; risk difference = 0.014; 95% CI, 0.013-0.016). This association was not modified by differences in weekday and weekend staffing patterns, and other hospital characteristics. Previous systematic reviews have been exclusive to the intensive care unit setting¹⁶ or did not specifically examine weekend mortality, which was a component of “off-shift” and/or “after-hours” care.¹⁷

These findings should be placed in the context of the recently published literature.^18,19 A meta-analysis of cohort studies found that off-hour admission was associated with increased mortality for 28 diseases although the associations varied considerably for different diseases.¹⁸ Likewise, a meta-analysis of 21 cohort studies noted that off-hour presentation for patients with acute ischemic stroke was associated with significantly higher short-term mortality.¹⁹ Our results of increased weekend mortality corroborate that found in these two meta-analyses. However, our study differs in that we specifically examined only weekend mortality and did not include after-hours care on weekdays, which was included in the off-hour mortality in the other meta-analyses.^18,19

Differences in healthcare worker staffing between weekends and weekdays have been proposed to contribute to the observed increase in mortality.^7,16,20 Data indicate that lower levels of nursing are associated with increased mortality.^10,21-23 The presence of less experienced and/or fewer physician specialists may contribute to increases in mortality.^24-26 Fewer or less experienced staff during weekends may contribute to inadequacies in patient handovers and/or handoffs, delays in patient assessment and/or interventions, and overall continuity of care for newly admitted patients.^27-33

Our data show little conclusive evidence that the weekend mortality versus weekday mortality vary by staffing level differences. While the estimated RR of mortality differs in magnitude for facilities with no difference in weekend and weekday staffing versus those that have a difference in staffing levels, both estimate an increased mortality on weekends, and the difference in these effects is not statistically significant. It should be noted that there was no difference in mortality for weekend (versus weekday) patients where there was no difference between weekend and weekday staffing; these studies were typically in high acuity units or centers where the general expectation is for 24/7/365 uniform staffing coverage.

A decrease in the use of interventions and/or procedures on weekends has been suggested to contribute to increases in mortality for patients admitted on the weekends.³⁴ Several studies have associated lower weekend rates to higher mortality for a variety of interventions,^13,35-37 although some other studies have suggested that lower procedure rates on weekends have no effect on mortality.^38-40 Lower diagnostic procedure weekend rates linked to higher mortality rates may exacerbate underlying healthcare disparities.⁴¹ Our results do not conclusively show that a decrease rate of intervention and/or procedures for weekends patients is associated with a higher risk of mortality for weekends compared to weekdays.

Delays in intervention and/or procedure on weekends have also been suggested to contribute to increases in mortality.^34,42 Similar to that seen with lower rates of diagnostic or therapeutic intervention and/or procedure performed on weekends, delays in potentially critical intervention and/or procedures might ultimately manifest as an increase in mortality.⁴³ Patients admitted to the hospital on weekends and requiring an early procedure were less likely to receive it within 2 days of admission.⁴² Several studies have shown an association between delays in diagnostic or therapeutic intervention and/or procedure on weekends to a higher hospital inpatient mortality^35,42,44,45; however, some data suggested that a delay in time to procedure on weekends may not always be associated with increased mortality.⁴⁶ Depending on the procedure, there may be a threshold below which the effect of reducing delay times will have no effect on mortality rates.^47,48

Patients admitted on the weekends may be different (in the severity of illness and/or comorbidities) than those admitted during the workweek and these potential differences may be a factor for increases in mortality for weekend patients. Whether there is a selection bias for weekend versus weekday patients is not clear.³⁴ This is a complex issue as there is significant heterogeneity in patient case mix depending on the specific disease or condition studied. For instance, one would expect that weekend trauma patients would be different than those seen during the regular workweek.⁴⁹ Some large scale studies suggest that weekend patients may not be more sick than weekday patients and that any increase in weekend mortality is probably not due to factors such as severity of illness.^1,7 Although we were unable to determine if there was an overall difference in illness severity between weekend and weekday patients due to the wide variety of assessments used for illness severity, our results showed statistically comparable higher mortality rate on the weekends regardless of whether the illness severity was higher, the same, or mixed between weekend and weekday patients, suggesting that general illness severity per se may not be as important as the weekend effect on mortality; however, illness severity may still have an important effect on mortality for more specific subgroups (eg, trauma).⁴⁹

There are several implications of our results. We found a mean increased RR mortality of approximately 19% for patients admitted on the weekends, a number similar to one of the largest published observational studies containing almost 5 million subjects.² Even if we took a more conservative estimate of 10% increased risk of weekend mortality, this would be equivalent to an excess of 25,000 preventable deaths per year. If the weekend effect were to be placed in context of a public health issue, the weekend effect would be the number 8 cause of death below the 29,000 deaths due to gun violence, but above the 20,000 deaths resulting from sexual behavior (sexual transmitted diseases) in 2000.^{3, 50,51} Although our data suggest that staffing shortfalls and decreases or delays for procedures on weekends may be associated with an increased mortality for patients admitted on the weekends, further large-scale studies are needed to confirm these findings. Increasing nurse and physician staffing levels and skill mix to cover any potential shortfall on weekends may be expensive, although theoretically, there may be savings accrued from reduced adverse events and shorter length of stay.^26,52 Changes to weekend care might only benefit daytime hospitalizations because some studies have shown increased mortality during nighttime regardless of weekend or weekday admission.⁵³

Several methodologic points in our study need to be clarified. We excluded many studies which examined the relationship of off-hours or after-hours admissions and mortality as off-hours studies typically combined weekend and after-hours weekday data. Some studies suggest that off-hour admission may be associated with increased mortality and delays in time for critical procedures during off-hours.^18,19 This is a complex topic, but it is clear that the risks of hospitalization vary not just by the day of the week but also by time of the day.⁵⁴ The use of meta-analyses of nonrandomized trials has been somewhat controversial,^55,56 and there may be significant bias or confounding in the pooling of highly varied studies. It is important to keep in mind that there are very different definitions of weekends, populations studied, and measures of mortality rates, even as the pooled statistic suggests a homogeneity among the studies that does not exist.

There are several limitations to our study. Our systematic review may be seen as limited as we included only English language papers. In addition, we did not search nontraditional sources and abstracts. We accepted the definition of a weekend as defined by the original study, which resulted in varied definitions of weekend time period and mortality. There was a lack of specific data on staffing patterns and procedures in many studies, particularly those using databases. We were not able to further subdivide our analysis by admitting service. We were not able to undertake a subgroup analysis by country or continent, which may have implications on the effect of different healthcare systems on healthcare quality. It is unclear whether correlations in our study are a direct consequence of poorer weekend care or are the result of other unknown or unexamined differences between weekend and weekday patient populations.^34,57 For instance, there may be other global factors (higher rates of medical errors, higher hospital volumes) which may not be specifically related to weekend care and therefore not been accounted for in many of the studies we examined.^10,27,58-61 There may be potential bias of patient phenotypes (are weekend patients different than weekday patients?) admitted on the weekend. Holidays were included in the weekend data and it is not clear how this would affect our findings as some data suggest that there is a significantly higher mortality rate on holidays (versus weekends or weekdays),⁶¹ while other data do not.⁶² There was no universal definition for the timeframe for a weekend and as such, we had to rely on the original article for their determination and definition of weekend versus weekday death.

In summary, our meta-analysis suggests that hospital inpatients admitted during the weekend have a significantly increased mortality compared with those admitted on weekday. While none of our subgroup analyses showed strong evidence on effect modification, the interpretation of these results is hampered by the relatively small number of studies. Further research should be directed to determine the presence of causality between various factors purported to affect mortality and it is possible that we ultimately find that the weekend effect may exist for some but not all patients.

Acknowledgments

The authors would like to acknowledge Jaime Blanck, MLIS, MPA, AHIP, Clinical Informationist, Welch Medical Library, for her invaluable assistance in undertaking the literature searches for this manuscript.

Disclosure

This manuscript has been supported by the Department of Anesthesiology and Critical Care Medicine; The Johns Hopkins School of Medicine; Baltimore, Maryland. There are no relevant conflicts of interests.

A 58-year-old Danish man presented to an urgent care center due to several months of gradually worsening fatigue, weight loss, abdominal pain, and changes in vision . His abdominal pain was diffuse, constant, and moderate in severity. There was no association with meals, and he reported no nausea, vomiting, or change in bowel movements. He also said his vision in both eyes was blurry, but denied diplopia and said the blurring did not improve when either eye w as closed. He denied dysphagia, headache, focal weakness, or sensitivity to bright lights.

Fatigue and weight loss in a middle-aged man are nonspecific complaints that mainly help to alert the clinician that there may be a serious, systemic process lurking. Constant abdominal pain without nausea, vomiting, or change in bowel movements makes intestinal obstruction or a motility disorder less likely. Given that the pain is diffuse, it raises the possibility of an intraperitoneal process or a process within an organ that is irritating the peritoneum.

Worsening of vision can result from disorders anywhere along the visual pathway, including the cornea (keratitis or corneal edema from glaucoma), anterior chamber (uveitis or hyphema), lens (cataracts, dislocations, hyperglycemia), vitreous humor (uveitis), retina (infections, ischemia, detachment, diabetic retinopathy), macula (degenerative disease), optic nerve (optic neuritis), optic chiasm, and the visual projections through the hemispheres to the occipital lobes. To narrow the differential diagnosis, it would be important to inquire about prior eye problems, to measure visual acuity and intraocular pressure, to perform fundoscopic and slit-lamp exams to detect retinal and anterior chamber disorders, respectively, and to assess visual fields. An afferent pupillary defect would suggest optic nerve pathology.

Disorders that could unify the constitutional, abdominal, and visual symptoms include systemic inflammatory diseases, such as sarcoidosis (which has an increased incidence among Northern Europeans), tuberculosis, or cancer. While diabetes mellitus could explain his visual problems, weight loss, and fatigue, the absence of polyuria, polydipsia, or polyphagia argues against this possibility.

The patient had hypercholesterolemia and type 2 diabetes mellitus. Medications were metformin, atorvastatin, and glimepiride. He was a former smoker with 23 pack-years and had quit over 5 years prior. He had not traveled outside of Denmark in 2 years and had no pets at home. He reported being monogamous with his same-sex partner for the past 25 years. He had no significant family history, and he worked at a local hospital as a nurse. He denied any previous ocular history.

On examination, the pulse was 67 beats per minute, temperature was 36.7 degrees Celsius, respiratory rate was 16 breaths per minute, oxygen saturation was 99% while breathing ambient air, and blood pressure was 132/78. Oropharynx demonstrated no thrush or other lesions. The heart rhythm was regular and there were no murmurs. Lungs were clear to auscultation bilaterally. Abdominal exam was normal except for mild tenderness upon palpation in all quadrants, but no masses, organomegaly, rigidity, or rebound tenderness were present. Skin examination revealed several subcutaneous nodules measuring up to 0.5 cm in diameter overlying the right and left posterolateral chest walls. T he nodules were rubbery, pink, nontender, and not warm nor fluctuant. Visual acuity was reduced in both eyes. Extraocular movements were intact, and the pupils reacted to light and accommodated appropriately. The sclerae were injected bilaterally. The remainder of the cranial nerves and neurologic exam were normal. Due to the vision loss , the patient was referred to an ophthalmologist who diagnosed bilateral anterior uveitis.

Though monogamous with his male partner for many years, it is mandatory to consider complications of human immunodeficiency virus infection (HIV ). The absence of oral lesions indicative of a low CD4 count, such as oral hairy leukoplakia or thrush, does not rule out HIV disease. Additional history about his work as a nurse might shed light on his risk of infection, such as airborne exposure to tuberculosis or acquisition of blood-borne pathogens through a needle stick injury. His unremarkable vital signs support the chronicity of his medical condition.

Uveitis can result from numerous causes. When confined to the eye, uncommon hereditary and acquired causes are less likely . In many patients, uveitis arises in the setting of systemic infection or inflammation. The numerous infectious causes of uveitis include syphilis, tuberculosis, toxoplasmosis, cat scratch disease, and viruses such as HIV, West Nile, and Ebola. Among the inflammatory diseases that can cause uveitis are sarcoidosis, inflammatory bowel disease, systemic lupus erythematosus, Behçet disease, and Sjogren syndrome.

Several of these conditions, including tuberculosis and syphilis, may also cause subcutaneous nodules. Both tuberculosis and syphilis can cause skin and gastrointestinal disease. Sarcoidosis could involve the skin, peritoneum, and uvea, and is a possibility in this patient. The dermatologic conditions associated with sarcoidosis are protean and include granulomatous inflammation and nongranulomatous processes such as erythema nodosum. Usually the nodules of erythema nodosum are tender, red or purple, and located on the lower extremities. The lack of tenderness points away from erythema nodosum in this patient. Metastatic cancer can disseminate to the subcutaneous tissue, and the patient’s smoking history and age mandate we consider malignancy. However, skin metastases tend to be hard, not rubbery.

A cost-effective evaluation at this point would include syphilis serologies, HIV testing, testing for tuberculosis with either a purified protein derivative test or interferon gamma release assay, chest radiography, and biopsy of 1 of the lesions on his back.

Laboratory data showed 12,400 white blood cells per cubic milliliter (64% neutrophils, 24% lymphocytes, 9% monocytes, 2% eosinophils, 1% basophils), hemoglobin 7.9 g/dL, mean corpuscular volume 85 fL, platelets 476,000 per cubic milliliter , C-reactive protein 43 mg/ d L (normal < 8 mg/L), gamma-glutamyl-transferase 554 IU/L (normal range 0-45), alkaline phosphatase 865 U/L (normal range 60-200), and erythrocyte sedimentation rate (ESR) 71 mm per hour. International normalized ratio was 1.0, albumin was 3.0 mg/dL, activated partial thromboplastin time was 32 seconds (normal 22 to 35 seconds), and bilirubin was 0.3 mg/dL. Antibodies to HIV , hepatitis C, and hepatitis B surface antigen were not detectable. Electrocardiography ( ECG ) was normal. Plain radiograph of the chest demonstrated multiple nodular lesions bilaterally measuring up to 1 cm with no cavitation. There was a left pleural effusion.

The history and exam findings indicate a serious inflammatory condition affecting his lungs, pleura, eyes, skin, liver, and possibly his peritoneum. In this context, the elevated C-reactive protein and ESR are not helpful in differentiating inflammatory from infectious causes. The constellation of uveitis, pulmonary and cutaneous nodules, and marked abnormalities of liver tests in a middle-aged man of Northern European origin points us toward sarcoidosis. Pleural effusions are not common with sarcoidosis but may occur. However, to avoid premature closure, it is important to consider other possibilities.

Metastatic cancer, including lymphoma, could cause pulmonary and cutaneous nodules and liver involvement, but the chronic time course and uveitis are not consistent with malignancy. Tuberculosis is still a consideration, though one would have expected him to report fevers, night sweats, and, perhaps, exposure to patients with pulmonary tuberculosis in his job as a nurse. Multiple solid pulmonary nodules are also uncommon with pulmonary tuberculosis. Fungal infections such as histoplasmosis can cause skin lesions and pulmonary nodules but do not fit well with uveitis.

At this point, “ tissue is the issue.” A skin nodule would be the easiest site to biopsy. If skin biopsy was not diagnostic, computed tomography (CT) of his chest and abdomen should be performed to identify the next most accessible site for biopsy.

Esophagogastroduodenoscopy (EGD) and colonoscopy showed normal findings, and random biopsies from the stomach and colon were normal. CT of the chest, abdomen, and pelvis performed with the administration of intravenous contrast showed multiple solid opacities in both lung fields up to 1 cm, with enlarged mediastinal and retroperitoneal lymph nodes measuring 1 to 3 cm in diameter, a left pleural effusion, wall thickening in the right colon, and several nonspecific hypodensities in the liver. A punch biopsy taken from the right chest wall lesion demonstrated chronic inflammation without granulomas. The patient underwent CT-guided biopsy of 1 of the right-sided lung nodules, which revealed noncaseating granulomatous inflammation, fibrosis, and necrosis. Neither biopsy contained malignant cells, and additional stains revealed no bacteria, fungi, or acid fast bacilli.

The retroperitoneal and mediastinal adenopathy are indicative of a widely disseminated inflammatory process. Lymphoma continues to be a concern, though uveitis as an initial presenting problem would very unusual. Although biopsy of the chest wall lesion failed to demonstrate granulomatous inflammation, the most parsimonious explanation is that the skin and lung nodules are both related to a single systemic process.

Granulomas form in an attempt to wall off offending agents, whether foreign antigens (talc, certain medications), infectious agents, or self-antigens. Review of histopathology and microbiologic studies are useful first steps. Stains for bacteria, fungi, or acid-fast organisms may diagnose an infectious cause, such as tuberculosis, leprosy, syphilis, fungi, or cat scratch disease. Granulomas in association with vascular inflammation would indicate vasculitis. Other autoimmune considerations include sarcoidosis and Crohn disease. Noncaseating granulomas are typically found in sarcoidosis, cat scratch disease, syphilis, leprosy, or Crohn disease, but do not entirely exclude tuberculosis.

The negative infectious studies and lack of classic features of Crohn disease or other autoimmune diseases further point to sarcoidosis as the etiology of this patient’s illness. A Norwegian dermatologist first described the pathology of sarcoidosis based upon specimens taken from skin nodules. He thought the lesions were sarcoma and described them as, “ multiple benign sarcoid of the skin,” which is where the name “ sarcoidosis” originated.

Diagnosing sarcoidosis requires excluding other mimickers. Additional testing should include syphilis serologies, rheumatoid factor, and antineutrophilic cytoplasmic antibodies. The latter is associated with granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, either of which may produce granulomatous inflammation of the lungs, skin, and uvea.

A

Syphilis is a sexually transmitted disease with increasing incidence worldwide. Untreated infection progresses through 3 stages. The primary stage is characterized by the appearance of a painless chancre after an incubation period of 2 to 3 weeks. Four to 8 weeks later, the secondary stage emerges as a systemic infection, often heralded by a maculopapular rash with desquamation, frequently involving the soles and palms. Hepatitis, iridocyclitis, and early neurosyphilis may also be seen at this stage. Subsequently, syphilis becomes latent. One-third of patients with untreated latent syphilis will develop tertiary syphilis, typified by late neurosyphilis (tabes dorsalis and general paresis), cardiovascular disease (aortitis), or gummatous disease. ¹

Gummas are destructive granulomatous lesions that typically present indolently, may occur singly or multiply, and may involve almost any organ. It has been suggested that gummas are the immune system’s defense to slow the bacteria after attempts to kill it have failed. Histologically, gummas are hyalinized nodules with surrounding granulomatous infiltrate of lymphocytes, plasma cells, and multinucleated giant cells with or without necrosis . In the preantibiotic era, gummas were seen in approximately 15% of infected patients, with a latency of 1 to 46 years after primary infection. ² Penicillin led to a drastic reduction in gummas until the HIV epidemic, which led to the resurgence of gummas at a drastically shortened interval following primary syphilis. ³

Most commonly, gummas affect the skin and bones. In the skin , lesions may be superficial or deep and may progress into ulcerative nodules. In the bones, destructive gummas have a characteristic “moth-eaten” appearance. Less common sequelae of gummas incude gummatous hepatitis, perforated nasal septum (saddle nose deformity), or hard palate erosions. ^2,4 R arely, syphilis involves the lungs, appearing as nodules, infiltrates, or pleural effusion. ⁵

Ocular manifestations occur in approximately 5% of patients with syphilis, more often in secondary and tertiary stages, and are strongly associated with a spread to the central nervous system. Syphilis may affect any structure of the eye, with anterior uveitis as the most frequent manifestation. Partial or complete vision loss is identified in approximately half of the patients with ocular syphilis and may be completely reversed by appropriate treatment. Ophthalmologic findings such as optic neuritis and papilledema imply advanced illness , as do Argyll-Robertson pupils (small pupils that are poorly reactive to light , but with preserved accommodation and convergence). ^6,7 The treatment of ocular syphilis is identical to that of neurosyphilis. The Centers for Disease Control and Prevention recommends CSF analysis in any patient with ocular syphilis. Abnormal results should prompt repeat lumbar puncture every 3 to 6 months following treatment until the CSF results normalize. ⁸

The diagnosis of syphilis relies on indirect serologic tests. T. pallidum cannot be cultured in vitro, and techniques to identify spirochetes directly by using darkfield microscopy or DNA amplification via polymerase chain reaction are limited by availability or by poor sensitivity in advanced syphilis. ¹ Imaging modalities including PET cannot reliably differentiate syphilis from other infectious and noninfectious mimickers. ⁹ F ortunately, syphilis infection can be diagnosed accurately based on reactive treponemal and nontreponemal serum tests. Nontreponemal tests, such as the RPR and Venereal Disease Research Laboratory, have traditionally been utilized as first-line evaluation, followed by a confirmatory treponemal test. However, nontreponemal tests may be nonreactive in a few settings: very early or very late in infection, and in individuals previously treated for syphilis. Thus, newer “reverse testing” algorithms utilize more sensitive and less expensive treponemal tests as the first test, followed by nontreponemal tests if the initial treponemal test is reactive. ⁸ Regardless of the testing sequence, in patients with no prior history of syphilis, reactive results on both treponemal and nontreponemal assays firmly establish a diagnosis of syphilis, obviating the need for more invasive and costly testing.

In patients with unexplained systemic illness, clinicians should have a low threshold to test for syphilis. Testing should be extended to certain asymptomatic individuals at higher risk of infection, including men who have sex with men, sexual partners of patients infected with syphilis, individuals with HIV or sexually-transmitted diseases, and others with high-risk sexual behavior or a history of sexually-transmitted diseases. ⁸ As the discussant points out, earlier consideration of and testing for syphilis would have spared the patient from unnecessary and costly EGD, colonoscopy, PET-CT scanning, and 3 biopsies.

Syphilis has been known to be a horribly destructive disease for centuries, earning the moniker “morbo serpentino” (serpentine disease) from the Spanish physician Ruiz Diaz de Isla in the 1500s. ¹⁰ In the modern era, physicians must remember to consider the diagnosis of syphilis in order to effectively mitigate the harm from this resurgent disease when it attacks our patients.

• Syphilis, the great imposter, is rising in incidence and should be on the differential diagnosis in all patients with unexplained multisystem inflammatory disease.
• A cost-effective diagnostic approach to syphilis entails serologic testing with treponemal and nontreponemal assays.
• Unexplained granulomas, especially in the skin, bone, or liver, should prompt consideration of gummatous syphilis.
• Ocular syphilis may involve any part of the visual tract and is treated the same as neurosyphilis.

Disclosure

Dr. Weinreich has received payment for lectures from Boehringer er Ingelheim, Astra Zeneca, TEVA and Novartis in 2016. All other contributors have nothing to report.

A 58-year-old Danish man presented to an urgent care center due to several months of gradually worsening fatigue, weight loss, abdominal pain, and changes in vision . His abdominal pain was diffuse, constant, and moderate in severity. There was no association with meals, and he reported no nausea, vomiting, or change in bowel movements. He also said his vision in both eyes was blurry, but denied diplopia and said the blurring did not improve when either eye w as closed. He denied dysphagia, headache, focal weakness, or sensitivity to bright lights.

Fatigue and weight loss in a middle-aged man are nonspecific complaints that mainly help to alert the clinician that there may be a serious, systemic process lurking. Constant abdominal pain without nausea, vomiting, or change in bowel movements makes intestinal obstruction or a motility disorder less likely. Given that the pain is diffuse, it raises the possibility of an intraperitoneal process or a process within an organ that is irritating the peritoneum.

Worsening of vision can result from disorders anywhere along the visual pathway, including the cornea (keratitis or corneal edema from glaucoma), anterior chamber (uveitis or hyphema), lens (cataracts, dislocations, hyperglycemia), vitreous humor (uveitis), retina (infections, ischemia, detachment, diabetic retinopathy), macula (degenerative disease), optic nerve (optic neuritis), optic chiasm, and the visual projections through the hemispheres to the occipital lobes. To narrow the differential diagnosis, it would be important to inquire about prior eye problems, to measure visual acuity and intraocular pressure, to perform fundoscopic and slit-lamp exams to detect retinal and anterior chamber disorders, respectively, and to assess visual fields. An afferent pupillary defect would suggest optic nerve pathology.

Disorders that could unify the constitutional, abdominal, and visual symptoms include systemic inflammatory diseases, such as sarcoidosis (which has an increased incidence among Northern Europeans), tuberculosis, or cancer. While diabetes mellitus could explain his visual problems, weight loss, and fatigue, the absence of polyuria, polydipsia, or polyphagia argues against this possibility.

The patient had hypercholesterolemia and type 2 diabetes mellitus. Medications were metformin, atorvastatin, and glimepiride. He was a former smoker with 23 pack-years and had quit over 5 years prior. He had not traveled outside of Denmark in 2 years and had no pets at home. He reported being monogamous with his same-sex partner for the past 25 years. He had no significant family history, and he worked at a local hospital as a nurse. He denied any previous ocular history.

On examination, the pulse was 67 beats per minute, temperature was 36.7 degrees Celsius, respiratory rate was 16 breaths per minute, oxygen saturation was 99% while breathing ambient air, and blood pressure was 132/78. Oropharynx demonstrated no thrush or other lesions. The heart rhythm was regular and there were no murmurs. Lungs were clear to auscultation bilaterally. Abdominal exam was normal except for mild tenderness upon palpation in all quadrants, but no masses, organomegaly, rigidity, or rebound tenderness were present. Skin examination revealed several subcutaneous nodules measuring up to 0.5 cm in diameter overlying the right and left posterolateral chest walls. T he nodules were rubbery, pink, nontender, and not warm nor fluctuant. Visual acuity was reduced in both eyes. Extraocular movements were intact, and the pupils reacted to light and accommodated appropriately. The sclerae were injected bilaterally. The remainder of the cranial nerves and neurologic exam were normal. Due to the vision loss , the patient was referred to an ophthalmologist who diagnosed bilateral anterior uveitis.

Though monogamous with his male partner for many years, it is mandatory to consider complications of human immunodeficiency virus infection (HIV ). The absence of oral lesions indicative of a low CD4 count, such as oral hairy leukoplakia or thrush, does not rule out HIV disease. Additional history about his work as a nurse might shed light on his risk of infection, such as airborne exposure to tuberculosis or acquisition of blood-borne pathogens through a needle stick injury. His unremarkable vital signs support the chronicity of his medical condition.

Uveitis can result from numerous causes. When confined to the eye, uncommon hereditary and acquired causes are less likely . In many patients, uveitis arises in the setting of systemic infection or inflammation. The numerous infectious causes of uveitis include syphilis, tuberculosis, toxoplasmosis, cat scratch disease, and viruses such as HIV, West Nile, and Ebola. Among the inflammatory diseases that can cause uveitis are sarcoidosis, inflammatory bowel disease, systemic lupus erythematosus, Behçet disease, and Sjogren syndrome.

Several of these conditions, including tuberculosis and syphilis, may also cause subcutaneous nodules. Both tuberculosis and syphilis can cause skin and gastrointestinal disease. Sarcoidosis could involve the skin, peritoneum, and uvea, and is a possibility in this patient. The dermatologic conditions associated with sarcoidosis are protean and include granulomatous inflammation and nongranulomatous processes such as erythema nodosum. Usually the nodules of erythema nodosum are tender, red or purple, and located on the lower extremities. The lack of tenderness points away from erythema nodosum in this patient. Metastatic cancer can disseminate to the subcutaneous tissue, and the patient’s smoking history and age mandate we consider malignancy. However, skin metastases tend to be hard, not rubbery.

A cost-effective evaluation at this point would include syphilis serologies, HIV testing, testing for tuberculosis with either a purified protein derivative test or interferon gamma release assay, chest radiography, and biopsy of 1 of the lesions on his back.

Laboratory data showed 12,400 white blood cells per cubic milliliter (64% neutrophils, 24% lymphocytes, 9% monocytes, 2% eosinophils, 1% basophils), hemoglobin 7.9 g/dL, mean corpuscular volume 85 fL, platelets 476,000 per cubic milliliter , C-reactive protein 43 mg/ d L (normal < 8 mg/L), gamma-glutamyl-transferase 554 IU/L (normal range 0-45), alkaline phosphatase 865 U/L (normal range 60-200), and erythrocyte sedimentation rate (ESR) 71 mm per hour. International normalized ratio was 1.0, albumin was 3.0 mg/dL, activated partial thromboplastin time was 32 seconds (normal 22 to 35 seconds), and bilirubin was 0.3 mg/dL. Antibodies to HIV , hepatitis C, and hepatitis B surface antigen were not detectable. Electrocardiography ( ECG ) was normal. Plain radiograph of the chest demonstrated multiple nodular lesions bilaterally measuring up to 1 cm with no cavitation. There was a left pleural effusion.

The history and exam findings indicate a serious inflammatory condition affecting his lungs, pleura, eyes, skin, liver, and possibly his peritoneum. In this context, the elevated C-reactive protein and ESR are not helpful in differentiating inflammatory from infectious causes. The constellation of uveitis, pulmonary and cutaneous nodules, and marked abnormalities of liver tests in a middle-aged man of Northern European origin points us toward sarcoidosis. Pleural effusions are not common with sarcoidosis but may occur. However, to avoid premature closure, it is important to consider other possibilities.

Metastatic cancer, including lymphoma, could cause pulmonary and cutaneous nodules and liver involvement, but the chronic time course and uveitis are not consistent with malignancy. Tuberculosis is still a consideration, though one would have expected him to report fevers, night sweats, and, perhaps, exposure to patients with pulmonary tuberculosis in his job as a nurse. Multiple solid pulmonary nodules are also uncommon with pulmonary tuberculosis. Fungal infections such as histoplasmosis can cause skin lesions and pulmonary nodules but do not fit well with uveitis.

At this point, “ tissue is the issue.” A skin nodule would be the easiest site to biopsy. If skin biopsy was not diagnostic, computed tomography (CT) of his chest and abdomen should be performed to identify the next most accessible site for biopsy.

Esophagogastroduodenoscopy (EGD) and colonoscopy showed normal findings, and random biopsies from the stomach and colon were normal. CT of the chest, abdomen, and pelvis performed with the administration of intravenous contrast showed multiple solid opacities in both lung fields up to 1 cm, with enlarged mediastinal and retroperitoneal lymph nodes measuring 1 to 3 cm in diameter, a left pleural effusion, wall thickening in the right colon, and several nonspecific hypodensities in the liver. A punch biopsy taken from the right chest wall lesion demonstrated chronic inflammation without granulomas. The patient underwent CT-guided biopsy of 1 of the right-sided lung nodules, which revealed noncaseating granulomatous inflammation, fibrosis, and necrosis. Neither biopsy contained malignant cells, and additional stains revealed no bacteria, fungi, or acid fast bacilli.

The retroperitoneal and mediastinal adenopathy are indicative of a widely disseminated inflammatory process. Lymphoma continues to be a concern, though uveitis as an initial presenting problem would very unusual. Although biopsy of the chest wall lesion failed to demonstrate granulomatous inflammation, the most parsimonious explanation is that the skin and lung nodules are both related to a single systemic process.

Granulomas form in an attempt to wall off offending agents, whether foreign antigens (talc, certain medications), infectious agents, or self-antigens. Review of histopathology and microbiologic studies are useful first steps. Stains for bacteria, fungi, or acid-fast organisms may diagnose an infectious cause, such as tuberculosis, leprosy, syphilis, fungi, or cat scratch disease. Granulomas in association with vascular inflammation would indicate vasculitis. Other autoimmune considerations include sarcoidosis and Crohn disease. Noncaseating granulomas are typically found in sarcoidosis, cat scratch disease, syphilis, leprosy, or Crohn disease, but do not entirely exclude tuberculosis.

The negative infectious studies and lack of classic features of Crohn disease or other autoimmune diseases further point to sarcoidosis as the etiology of this patient’s illness. A Norwegian dermatologist first described the pathology of sarcoidosis based upon specimens taken from skin nodules. He thought the lesions were sarcoma and described them as, “ multiple benign sarcoid of the skin,” which is where the name “ sarcoidosis” originated.

Diagnosing sarcoidosis requires excluding other mimickers. Additional testing should include syphilis serologies, rheumatoid factor, and antineutrophilic cytoplasmic antibodies. The latter is associated with granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, either of which may produce granulomatous inflammation of the lungs, skin, and uvea.

A

Syphilis is a sexually transmitted disease with increasing incidence worldwide. Untreated infection progresses through 3 stages. The primary stage is characterized by the appearance of a painless chancre after an incubation period of 2 to 3 weeks. Four to 8 weeks later, the secondary stage emerges as a systemic infection, often heralded by a maculopapular rash with desquamation, frequently involving the soles and palms. Hepatitis, iridocyclitis, and early neurosyphilis may also be seen at this stage. Subsequently, syphilis becomes latent. One-third of patients with untreated latent syphilis will develop tertiary syphilis, typified by late neurosyphilis (tabes dorsalis and general paresis), cardiovascular disease (aortitis), or gummatous disease. ¹

Gummas are destructive granulomatous lesions that typically present indolently, may occur singly or multiply, and may involve almost any organ. It has been suggested that gummas are the immune system’s defense to slow the bacteria after attempts to kill it have failed. Histologically, gummas are hyalinized nodules with surrounding granulomatous infiltrate of lymphocytes, plasma cells, and multinucleated giant cells with or without necrosis . In the preantibiotic era, gummas were seen in approximately 15% of infected patients, with a latency of 1 to 46 years after primary infection. ² Penicillin led to a drastic reduction in gummas until the HIV epidemic, which led to the resurgence of gummas at a drastically shortened interval following primary syphilis. ³

Most commonly, gummas affect the skin and bones. In the skin , lesions may be superficial or deep and may progress into ulcerative nodules. In the bones, destructive gummas have a characteristic “moth-eaten” appearance. Less common sequelae of gummas incude gummatous hepatitis, perforated nasal septum (saddle nose deformity), or hard palate erosions. ^2,4 R arely, syphilis involves the lungs, appearing as nodules, infiltrates, or pleural effusion. ⁵

Ocular manifestations occur in approximately 5% of patients with syphilis, more often in secondary and tertiary stages, and are strongly associated with a spread to the central nervous system. Syphilis may affect any structure of the eye, with anterior uveitis as the most frequent manifestation. Partial or complete vision loss is identified in approximately half of the patients with ocular syphilis and may be completely reversed by appropriate treatment. Ophthalmologic findings such as optic neuritis and papilledema imply advanced illness , as do Argyll-Robertson pupils (small pupils that are poorly reactive to light , but with preserved accommodation and convergence). ^6,7 The treatment of ocular syphilis is identical to that of neurosyphilis. The Centers for Disease Control and Prevention recommends CSF analysis in any patient with ocular syphilis. Abnormal results should prompt repeat lumbar puncture every 3 to 6 months following treatment until the CSF results normalize. ⁸

The diagnosis of syphilis relies on indirect serologic tests. T. pallidum cannot be cultured in vitro, and techniques to identify spirochetes directly by using darkfield microscopy or DNA amplification via polymerase chain reaction are limited by availability or by poor sensitivity in advanced syphilis. ¹ Imaging modalities including PET cannot reliably differentiate syphilis from other infectious and noninfectious mimickers. ⁹ F ortunately, syphilis infection can be diagnosed accurately based on reactive treponemal and nontreponemal serum tests. Nontreponemal tests, such as the RPR and Venereal Disease Research Laboratory, have traditionally been utilized as first-line evaluation, followed by a confirmatory treponemal test. However, nontreponemal tests may be nonreactive in a few settings: very early or very late in infection, and in individuals previously treated for syphilis. Thus, newer “reverse testing” algorithms utilize more sensitive and less expensive treponemal tests as the first test, followed by nontreponemal tests if the initial treponemal test is reactive. ⁸ Regardless of the testing sequence, in patients with no prior history of syphilis, reactive results on both treponemal and nontreponemal assays firmly establish a diagnosis of syphilis, obviating the need for more invasive and costly testing.

In patients with unexplained systemic illness, clinicians should have a low threshold to test for syphilis. Testing should be extended to certain asymptomatic individuals at higher risk of infection, including men who have sex with men, sexual partners of patients infected with syphilis, individuals with HIV or sexually-transmitted diseases, and others with high-risk sexual behavior or a history of sexually-transmitted diseases. ⁸ As the discussant points out, earlier consideration of and testing for syphilis would have spared the patient from unnecessary and costly EGD, colonoscopy, PET-CT scanning, and 3 biopsies.

Syphilis has been known to be a horribly destructive disease for centuries, earning the moniker “morbo serpentino” (serpentine disease) from the Spanish physician Ruiz Diaz de Isla in the 1500s. ¹⁰ In the modern era, physicians must remember to consider the diagnosis of syphilis in order to effectively mitigate the harm from this resurgent disease when it attacks our patients.

• Syphilis, the great imposter, is rising in incidence and should be on the differential diagnosis in all patients with unexplained multisystem inflammatory disease.
• A cost-effective diagnostic approach to syphilis entails serologic testing with treponemal and nontreponemal assays.
• Unexplained granulomas, especially in the skin, bone, or liver, should prompt consideration of gummatous syphilis.
• Ocular syphilis may involve any part of the visual tract and is treated the same as neurosyphilis.

Disclosure

Dr. Weinreich has received payment for lectures from Boehringer er Ingelheim, Astra Zeneca, TEVA and Novartis in 2016. All other contributors have nothing to report.

A 58-year-old Danish man presented to an urgent care center due to several months of gradually worsening fatigue, weight loss, abdominal pain, and changes in vision . His abdominal pain was diffuse, constant, and moderate in severity. There was no association with meals, and he reported no nausea, vomiting, or change in bowel movements. He also said his vision in both eyes was blurry, but denied diplopia and said the blurring did not improve when either eye w as closed. He denied dysphagia, headache, focal weakness, or sensitivity to bright lights.

Fatigue and weight loss in a middle-aged man are nonspecific complaints that mainly help to alert the clinician that there may be a serious, systemic process lurking. Constant abdominal pain without nausea, vomiting, or change in bowel movements makes intestinal obstruction or a motility disorder less likely. Given that the pain is diffuse, it raises the possibility of an intraperitoneal process or a process within an organ that is irritating the peritoneum.

Worsening of vision can result from disorders anywhere along the visual pathway, including the cornea (keratitis or corneal edema from glaucoma), anterior chamber (uveitis or hyphema), lens (cataracts, dislocations, hyperglycemia), vitreous humor (uveitis), retina (infections, ischemia, detachment, diabetic retinopathy), macula (degenerative disease), optic nerve (optic neuritis), optic chiasm, and the visual projections through the hemispheres to the occipital lobes. To narrow the differential diagnosis, it would be important to inquire about prior eye problems, to measure visual acuity and intraocular pressure, to perform fundoscopic and slit-lamp exams to detect retinal and anterior chamber disorders, respectively, and to assess visual fields. An afferent pupillary defect would suggest optic nerve pathology.

Disorders that could unify the constitutional, abdominal, and visual symptoms include systemic inflammatory diseases, such as sarcoidosis (which has an increased incidence among Northern Europeans), tuberculosis, or cancer. While diabetes mellitus could explain his visual problems, weight loss, and fatigue, the absence of polyuria, polydipsia, or polyphagia argues against this possibility.

The patient had hypercholesterolemia and type 2 diabetes mellitus. Medications were metformin, atorvastatin, and glimepiride. He was a former smoker with 23 pack-years and had quit over 5 years prior. He had not traveled outside of Denmark in 2 years and had no pets at home. He reported being monogamous with his same-sex partner for the past 25 years. He had no significant family history, and he worked at a local hospital as a nurse. He denied any previous ocular history.

On examination, the pulse was 67 beats per minute, temperature was 36.7 degrees Celsius, respiratory rate was 16 breaths per minute, oxygen saturation was 99% while breathing ambient air, and blood pressure was 132/78. Oropharynx demonstrated no thrush or other lesions. The heart rhythm was regular and there were no murmurs. Lungs were clear to auscultation bilaterally. Abdominal exam was normal except for mild tenderness upon palpation in all quadrants, but no masses, organomegaly, rigidity, or rebound tenderness were present. Skin examination revealed several subcutaneous nodules measuring up to 0.5 cm in diameter overlying the right and left posterolateral chest walls. T he nodules were rubbery, pink, nontender, and not warm nor fluctuant. Visual acuity was reduced in both eyes. Extraocular movements were intact, and the pupils reacted to light and accommodated appropriately. The sclerae were injected bilaterally. The remainder of the cranial nerves and neurologic exam were normal. Due to the vision loss , the patient was referred to an ophthalmologist who diagnosed bilateral anterior uveitis.

Though monogamous with his male partner for many years, it is mandatory to consider complications of human immunodeficiency virus infection (HIV ). The absence of oral lesions indicative of a low CD4 count, such as oral hairy leukoplakia or thrush, does not rule out HIV disease. Additional history about his work as a nurse might shed light on his risk of infection, such as airborne exposure to tuberculosis or acquisition of blood-borne pathogens through a needle stick injury. His unremarkable vital signs support the chronicity of his medical condition.

Uveitis can result from numerous causes. When confined to the eye, uncommon hereditary and acquired causes are less likely . In many patients, uveitis arises in the setting of systemic infection or inflammation. The numerous infectious causes of uveitis include syphilis, tuberculosis, toxoplasmosis, cat scratch disease, and viruses such as HIV, West Nile, and Ebola. Among the inflammatory diseases that can cause uveitis are sarcoidosis, inflammatory bowel disease, systemic lupus erythematosus, Behçet disease, and Sjogren syndrome.

Several of these conditions, including tuberculosis and syphilis, may also cause subcutaneous nodules. Both tuberculosis and syphilis can cause skin and gastrointestinal disease. Sarcoidosis could involve the skin, peritoneum, and uvea, and is a possibility in this patient. The dermatologic conditions associated with sarcoidosis are protean and include granulomatous inflammation and nongranulomatous processes such as erythema nodosum. Usually the nodules of erythema nodosum are tender, red or purple, and located on the lower extremities. The lack of tenderness points away from erythema nodosum in this patient. Metastatic cancer can disseminate to the subcutaneous tissue, and the patient’s smoking history and age mandate we consider malignancy. However, skin metastases tend to be hard, not rubbery.

A cost-effective evaluation at this point would include syphilis serologies, HIV testing, testing for tuberculosis with either a purified protein derivative test or interferon gamma release assay, chest radiography, and biopsy of 1 of the lesions on his back.

Laboratory data showed 12,400 white blood cells per cubic milliliter (64% neutrophils, 24% lymphocytes, 9% monocytes, 2% eosinophils, 1% basophils), hemoglobin 7.9 g/dL, mean corpuscular volume 85 fL, platelets 476,000 per cubic milliliter , C-reactive protein 43 mg/ d L (normal < 8 mg/L), gamma-glutamyl-transferase 554 IU/L (normal range 0-45), alkaline phosphatase 865 U/L (normal range 60-200), and erythrocyte sedimentation rate (ESR) 71 mm per hour. International normalized ratio was 1.0, albumin was 3.0 mg/dL, activated partial thromboplastin time was 32 seconds (normal 22 to 35 seconds), and bilirubin was 0.3 mg/dL. Antibodies to HIV , hepatitis C, and hepatitis B surface antigen were not detectable. Electrocardiography ( ECG ) was normal. Plain radiograph of the chest demonstrated multiple nodular lesions bilaterally measuring up to 1 cm with no cavitation. There was a left pleural effusion.

The history and exam findings indicate a serious inflammatory condition affecting his lungs, pleura, eyes, skin, liver, and possibly his peritoneum. In this context, the elevated C-reactive protein and ESR are not helpful in differentiating inflammatory from infectious causes. The constellation of uveitis, pulmonary and cutaneous nodules, and marked abnormalities of liver tests in a middle-aged man of Northern European origin points us toward sarcoidosis. Pleural effusions are not common with sarcoidosis but may occur. However, to avoid premature closure, it is important to consider other possibilities.

Metastatic cancer, including lymphoma, could cause pulmonary and cutaneous nodules and liver involvement, but the chronic time course and uveitis are not consistent with malignancy. Tuberculosis is still a consideration, though one would have expected him to report fevers, night sweats, and, perhaps, exposure to patients with pulmonary tuberculosis in his job as a nurse. Multiple solid pulmonary nodules are also uncommon with pulmonary tuberculosis. Fungal infections such as histoplasmosis can cause skin lesions and pulmonary nodules but do not fit well with uveitis.

At this point, “ tissue is the issue.” A skin nodule would be the easiest site to biopsy. If skin biopsy was not diagnostic, computed tomography (CT) of his chest and abdomen should be performed to identify the next most accessible site for biopsy.

Esophagogastroduodenoscopy (EGD) and colonoscopy showed normal findings, and random biopsies from the stomach and colon were normal. CT of the chest, abdomen, and pelvis performed with the administration of intravenous contrast showed multiple solid opacities in both lung fields up to 1 cm, with enlarged mediastinal and retroperitoneal lymph nodes measuring 1 to 3 cm in diameter, a left pleural effusion, wall thickening in the right colon, and several nonspecific hypodensities in the liver. A punch biopsy taken from the right chest wall lesion demonstrated chronic inflammation without granulomas. The patient underwent CT-guided biopsy of 1 of the right-sided lung nodules, which revealed noncaseating granulomatous inflammation, fibrosis, and necrosis. Neither biopsy contained malignant cells, and additional stains revealed no bacteria, fungi, or acid fast bacilli.

The retroperitoneal and mediastinal adenopathy are indicative of a widely disseminated inflammatory process. Lymphoma continues to be a concern, though uveitis as an initial presenting problem would very unusual. Although biopsy of the chest wall lesion failed to demonstrate granulomatous inflammation, the most parsimonious explanation is that the skin and lung nodules are both related to a single systemic process.

Granulomas form in an attempt to wall off offending agents, whether foreign antigens (talc, certain medications), infectious agents, or self-antigens. Review of histopathology and microbiologic studies are useful first steps. Stains for bacteria, fungi, or acid-fast organisms may diagnose an infectious cause, such as tuberculosis, leprosy, syphilis, fungi, or cat scratch disease. Granulomas in association with vascular inflammation would indicate vasculitis. Other autoimmune considerations include sarcoidosis and Crohn disease. Noncaseating granulomas are typically found in sarcoidosis, cat scratch disease, syphilis, leprosy, or Crohn disease, but do not entirely exclude tuberculosis.

The negative infectious studies and lack of classic features of Crohn disease or other autoimmune diseases further point to sarcoidosis as the etiology of this patient’s illness. A Norwegian dermatologist first described the pathology of sarcoidosis based upon specimens taken from skin nodules. He thought the lesions were sarcoma and described them as, “ multiple benign sarcoid of the skin,” which is where the name “ sarcoidosis” originated.

Diagnosing sarcoidosis requires excluding other mimickers. Additional testing should include syphilis serologies, rheumatoid factor, and antineutrophilic cytoplasmic antibodies. The latter is associated with granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, either of which may produce granulomatous inflammation of the lungs, skin, and uvea.

A

Syphilis is a sexually transmitted disease with increasing incidence worldwide. Untreated infection progresses through 3 stages. The primary stage is characterized by the appearance of a painless chancre after an incubation period of 2 to 3 weeks. Four to 8 weeks later, the secondary stage emerges as a systemic infection, often heralded by a maculopapular rash with desquamation, frequently involving the soles and palms. Hepatitis, iridocyclitis, and early neurosyphilis may also be seen at this stage. Subsequently, syphilis becomes latent. One-third of patients with untreated latent syphilis will develop tertiary syphilis, typified by late neurosyphilis (tabes dorsalis and general paresis), cardiovascular disease (aortitis), or gummatous disease. ¹

Gummas are destructive granulomatous lesions that typically present indolently, may occur singly or multiply, and may involve almost any organ. It has been suggested that gummas are the immune system’s defense to slow the bacteria after attempts to kill it have failed. Histologically, gummas are hyalinized nodules with surrounding granulomatous infiltrate of lymphocytes, plasma cells, and multinucleated giant cells with or without necrosis . In the preantibiotic era, gummas were seen in approximately 15% of infected patients, with a latency of 1 to 46 years after primary infection. ² Penicillin led to a drastic reduction in gummas until the HIV epidemic, which led to the resurgence of gummas at a drastically shortened interval following primary syphilis. ³

Most commonly, gummas affect the skin and bones. In the skin , lesions may be superficial or deep and may progress into ulcerative nodules. In the bones, destructive gummas have a characteristic “moth-eaten” appearance. Less common sequelae of gummas incude gummatous hepatitis, perforated nasal septum (saddle nose deformity), or hard palate erosions. ^2,4 R arely, syphilis involves the lungs, appearing as nodules, infiltrates, or pleural effusion. ⁵

Ocular manifestations occur in approximately 5% of patients with syphilis, more often in secondary and tertiary stages, and are strongly associated with a spread to the central nervous system. Syphilis may affect any structure of the eye, with anterior uveitis as the most frequent manifestation. Partial or complete vision loss is identified in approximately half of the patients with ocular syphilis and may be completely reversed by appropriate treatment. Ophthalmologic findings such as optic neuritis and papilledema imply advanced illness , as do Argyll-Robertson pupils (small pupils that are poorly reactive to light , but with preserved accommodation and convergence). ^6,7 The treatment of ocular syphilis is identical to that of neurosyphilis. The Centers for Disease Control and Prevention recommends CSF analysis in any patient with ocular syphilis. Abnormal results should prompt repeat lumbar puncture every 3 to 6 months following treatment until the CSF results normalize. ⁸

The diagnosis of syphilis relies on indirect serologic tests. T. pallidum cannot be cultured in vitro, and techniques to identify spirochetes directly by using darkfield microscopy or DNA amplification via polymerase chain reaction are limited by availability or by poor sensitivity in advanced syphilis. ¹ Imaging modalities including PET cannot reliably differentiate syphilis from other infectious and noninfectious mimickers. ⁹ F ortunately, syphilis infection can be diagnosed accurately based on reactive treponemal and nontreponemal serum tests. Nontreponemal tests, such as the RPR and Venereal Disease Research Laboratory, have traditionally been utilized as first-line evaluation, followed by a confirmatory treponemal test. However, nontreponemal tests may be nonreactive in a few settings: very early or very late in infection, and in individuals previously treated for syphilis. Thus, newer “reverse testing” algorithms utilize more sensitive and less expensive treponemal tests as the first test, followed by nontreponemal tests if the initial treponemal test is reactive. ⁸ Regardless of the testing sequence, in patients with no prior history of syphilis, reactive results on both treponemal and nontreponemal assays firmly establish a diagnosis of syphilis, obviating the need for more invasive and costly testing.

In patients with unexplained systemic illness, clinicians should have a low threshold to test for syphilis. Testing should be extended to certain asymptomatic individuals at higher risk of infection, including men who have sex with men, sexual partners of patients infected with syphilis, individuals with HIV or sexually-transmitted diseases, and others with high-risk sexual behavior or a history of sexually-transmitted diseases. ⁸ As the discussant points out, earlier consideration of and testing for syphilis would have spared the patient from unnecessary and costly EGD, colonoscopy, PET-CT scanning, and 3 biopsies.

Syphilis has been known to be a horribly destructive disease for centuries, earning the moniker “morbo serpentino” (serpentine disease) from the Spanish physician Ruiz Diaz de Isla in the 1500s. ¹⁰ In the modern era, physicians must remember to consider the diagnosis of syphilis in order to effectively mitigate the harm from this resurgent disease when it attacks our patients.

• Syphilis, the great imposter, is rising in incidence and should be on the differential diagnosis in all patients with unexplained multisystem inflammatory disease.
• A cost-effective diagnostic approach to syphilis entails serologic testing with treponemal and nontreponemal assays.
• Unexplained granulomas, especially in the skin, bone, or liver, should prompt consideration of gummatous syphilis.
• Ocular syphilis may involve any part of the visual tract and is treated the same as neurosyphilis.

Disclosure

Dr. Weinreich has received payment for lectures from Boehringer er Ingelheim, Astra Zeneca, TEVA and Novartis in 2016. All other contributors have nothing to report.

A 57-year-old woman presented to the emergency department of a community hospital with a 2-week history of dizziness, blurred vision, and poor coordination following a flu-like illness. Symptoms were initially attributed to complications from a presumed viral illness, but when they persisted for 2 weeks, she underwent magnetic resonance imaging (MRI) of the brain, which was reported as showing a 2.4 x 2.3 x 1.9 cm right frontal lobe mass with mild mass effect and contrast enhancement (Figure 1). She was discharged home at her request with plans for outpatient follow-up.

Brain masses are usually neoplastic, infectious, or less commonly, inflammatory. The isolated lesion in the right frontal lobe is unlikely to explain her symptoms, which are more suggestive of multifocal disease or elevated intracranial pressure. Although the frontal eye fields could be affected by the mass, such lesions usually cause tonic eye deviation, not blurry vision; furthermore, coordination, which is impaired here, is not governed by the frontal lobe.

Two weeks later, she returned to the same emergency department with worsening symptoms and new bilateral upper extremity dystonia, confusion, and visual hallucinations. Cerebrospinal fluid (CSF) analysis revealed clear, nonxanthochromic fluid with 4 nucleated cells (a differential was not performed), 113 red blood cells, glucose of 80 mg/dL (normal range, 50-80 mg/dL), and protein of 52 mg/dL (normal range, 15-45 mg/dL).

Confusion is generally caused by a metabolic, infectious, structural, or toxic etiology. Standard CSF test results are usually normal with most toxic or metabolic encephalopathies. The absence of significant CSF inflammation argues against infectious encephalitis; paraneoplastic and autoimmune encephalitis, however, are still possible. The CSF red blood cells were likely due to a mildly traumatic tap, but also may have arisen from the frontal lobe mass or a more diffuse invasive process, although the lack of xanthochromia argues against this. Delirium and red blood cells in the CSF should trigger consideration of herpes simplex virus (HSV) encephalitis, although the time course is a bit too protracted and the reported MRI findings do not suggest typical medial temporal lobe involvement.

The disparate neurologic findings suggest a multifocal process, perhaps embolic (eg, endocarditis), ischemic (eg, intravascular lymphoma), infiltrative (eg, malignancy, neurosarcoidosis), or demyelinating (eg, postinfectious acute disseminated encephalomyelitis, multiple sclerosis). However, most of these would have been detected on the initial MRI. Upper extremity dystonia would likely localize to the basal ganglia, whereas confusion and visual hallucinations are more global. The combination of a movement disorder and visual hallucinations is seen in Lewy body dementia, but this tempo is not typical.

Although the CSF does not have pleocytosis, her original symptoms were flu-like; therefore, CSF testing for viruses (eg, enterovirus) is reasonable. Bacterial, mycobacteria, and fungal studies are apt to be unrevealing, but CSF cytology, IgG index, and oligoclonal bands may be useful. Should the encephalopathy progress further and the general medical evaluation prove to be normal, then tests for autoimmune disorders (eg, antinuclear antibodies, NMDAR, paraneoplastic disorders) and rare causes of rapidly progressive dementias (eg, prion diseases) should be sent.

Additional CSF studies including HSV polymerase chain reaction (PCR), West Nile PCR, Lyme antibody, paraneoplastic antibodies, and cytology were sent. Intravenous acyclovir was administered. The above studies, as well as Gram stain, acid-fast bacillus stain, fungal stain, and cultures, were negative. She was started on levetiracetam for seizure prevention due to the mass lesion. An electroencephalogram (EEG) was reported as showing diffuse background slowing with superimposed semiperiodic sharp waves with a right hemispheric emphasis. Intravenous immunoglobulin (IVIG) 0.4 mg/kg/day over 5 days was administered with no improvement. The patient was transferred to an academic medical center for further evaluation.

The EEG reflects encephalopathy without pointing to a specific diagnosis. Prophylactic antiepileptic medications are not indicated for CNS mass lesions without clinical or electrophysiologic seizure activity. IVIG is often administered when an autoimmune encephalitis is suspected, but the lack of response does not rule out an autoimmune condition.

Her medical history included bilateral cataract extraction, right leg fracture, tonsillectomy, and total abdominal hysterectomy. She had a 25-year smoking history and a family history of lung cancer. She had no history of drug or alcohol use. On examination, her temperature was 37.9°C, blood pressure of 144/98 mm Hg, respiratory rate of 18 breaths per minute, a heart rate of 121 beats per minute, and oxygen saturation of 97% on ambient air. Her eyes were open but she was nonverbal. Her chest was clear to auscultation. Heart sounds were distinct and rhythm was regular. Abdomen was soft and nontender with no organomegaly. Skin examination revealed no rash. Her pupils were equal, round, and reactive to light. She did not follow verbal or gestural commands and intermittently tracked with her eyes, but not consistently enough to characterize extraocular movements. Her face was symmetric. She had a normal gag and blink reflex and an increased jaw jerk reflex. Her arms were flexed with increased tone. She had a positive palmo-mental reflex. She had spontaneous movement of all extremities. She had symmetric, 3+ reflexes of the patella and Achilles tendon with a bilateral Babinski’s sign. Sensation was intact only to withdrawal from noxious stimuli.

The physical exam does not localize to a specific brain region, but suggests a diffuse brain process. There are multiple signs of upper motor neuron involvement, including increased tone, hyperreflexia, and Babinski (plantar flexion) reflexes. A palmo-mental reflex signifies pathology in the cerebrum. Although cranial nerve testing is limited, there are no features of cranial neuropathy; similarly, no pyramidal weakness or sensory deficit has been demonstrated on limited testing. The differential diagnosis of her rapidly progressive encephalopathy includes autoimmune or paraneoplastic encephalitis, diffuse infiltrative malignancy, metabolic diseases (eg, porphyria, heavy metal intoxication), and prion disease.

Her family history of lung cancer and her smoking increases the possibility of paraneoplastic encephalitis, which often has subacute behavioral changes that precede complete neurologic impairment. Inflammatory or hemorrhagic CSF is seen with Balamuthia amoebic infection, which causes a granulomatous encephalitis and is characteristically associated with a mass lesion. Toxoplasmosis causes encephalitis that can be profound, but patients are usually immunocompromised and there are typically multiple lesions.

Laboratory results showed a normal white blood cell count and differential, basic metabolic profile and liver function tests, and C-reactive protein. Human immunodeficiency virus antibody testing was negative. Chest radiography and computed tomography of chest, abdomen, and pelvis were normal. A repeat MRI of the brain with contrast was reported as showing a 2.4 x 2.3 x 1.9 cm heterogeneously enhancing mass in the right frontal lobe with an enhancing dural tail and underlying hyperostosis consistent with a meningioma, and blooming within the mass consistent with prior hemorrhage. No mass effect was present.

The meningioma was resected 3 days after admission but her symptoms did not improve. Routine postoperative MRI was reported to show expected postsurgical changes but no infarct. Brain biopsy at the time of the operation was reported as meningioma and mild gliosis without encephalitis.

The reported MRI findings showing unchanged size and overall appearance of the mass, its connection to the dura and skull, and the pathology results all suggest that the mass is a meningioma. There is no evidence of disease outside of the CNS. Some cancers that provoke a paraneoplastic response can be quite small yet may incite an immune encephalitis; anti-NMDAR-mediated encephalitis can occur with malignancy (often ovarian), although it also arises in the absence of any tumor. Any inclination to definitively exclude conditions not seen on the brain biopsy must be tempered by the limited sensitivity of brain histology examination. Still, what was not seen warrants mention: vascular inflammation suggestive of CNS vasculitis, granulomas that might point to neurosarcoidosis, malignant cells of an infiltrating lymphoma or glioma, or inflammatory cells suggestive of encephalitis. Prion encephalopathy remains possible.

The patient remained unresponsive. A repeat EEG showed bilateral generalized periodic epileptiform discharges with accompanying twitching of the head, face, and left arm, which were suppressed with intravenous propofol and levetiracetam. Three weeks following meningioma resection, a new MRI was read as showing new abnormal signal in the right basal ganglia, abnormality of the cortex on the diffusion weighted images, and progressive generalized volume loss.

Among the aforementioned diagnoses, focal or diffuse periodic epileptiform discharges at 1-2 hertz are most characteristic of prion disease. Striatal and cortical transverse relaxation time (T2)-weighted and diffusion-weighted imaging (DWI) hyperintensities with corresponding restricted diffusion is characteristic of Creutzfeldt-Jakob disease (CJD), although metabolic disorders, seizures, and encephalitis can very rarely show similar MRI findings. The clinical course, the MRI and EEG findings, and nondiagnostic biopsy results, which were initially not assessed for prion disease, collectively point to prion disease. Detection of abnormal prion protein in the brain tissue by immunohistochemistry or molecular methods would confirm the diagnosis.

Review of the original right frontal cortex biopsy specimen at the National Prion Disease Pathology Surveillance Center, including immunostaining with 3F4, a monoclonal antibody to the prion protein, revealed granular deposits typical of prion disease. This finding established a diagnosis of prion disease, likely sporadic CJD. The patient was transitioned to palliative care and died shortly thereafter.

Brain autopsy showed regions with transcortical vacuolation (spongiform change), other cortical regions with varying degrees of vacuolation, abundant reactive astrocytes, paucity of neurons, and dark shrunken neurons. Vacuolation and gliosis were observed in the striatum and were most pronounced in the thalamus. There was no evidence of an inflammatory infiltrate or a neoplastic process. These findings with the positive 3F4 immunohistochemistry and positive Western blot from brain autopsy, as well as the absence of a mutation in the prion protein gene, were diagnostic for CJD.

An investigation was initiated to track the nondisposable surgical instruments used in the meningioma resection that may have been subsequently used in other patients. It was determined that 52 neurosurgical patients may have been exposed to prion-contaminated instruments. The instruments were subsequently processed specifically for prion decontamination. After 7 years, no cases of CJD have been diagnosed in the potentially exposed patients.

CJD is a rare neurodegenerative condition¹ classified as one of the transmissible spongiform encephalopathies, so called because of the characteristic spongiform pattern (vacuolation) seen on histology, as well as the presence of neuronal loss, reactive gliosis in the gray matter, and the accumulation of the abnormal isoform of the cellular prion protein.² It affects about one person in every one million people per year worldwide; in the United States there are about 300 cases per year. The most common form of human prion disease, sporadic CJD, is relentlessly progressive and invariably fatal, and in most cases, death occurs less than 5 months from onset.³ There is no cure, although temporizing treatments for symptoms can be helpful.

Sporadic CJD, which accounts for approximately 85% of all cases of prion disease in humans, typically manifests with rapidly progressive dementia and myoclonus after a prolonged incubation period in persons between 55 and 75 years of age. Genetic forms account for approximately 15% and acquired forms less than 1% of human prion diseases.¹ Prion diseases have a broad spectrum of clinical manifestations, including dementia, ataxia, parkinsonism, myoclonus, insomnia, paresthesias, and abnormal or changed behavior.⁴ Given the protean clinical manifestations of prion diseases and rarity, the diagnosis is challenging to make antemortem. One recent study showed that most patients receive about 4 misdiagnoses and are often two-thirds of the way through their disease course before the correct diagnosis of sporadic CJD is made.⁵

• Rapidly progressive dementias (RPD) are characterized by cognitive decline over weeks to months. The RPD differential diagnosis includes fulminant forms of common neurodegenerative disorders (eg, Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia spectrum), autoimmune encephalidites, CNS cancers, and prion disease.
• Sporadic CJD is the most common human prion disease. It is a rare neurodegenerative condition with onset usually between the ages of 50 and 70 years, and most commonly manifests with rapidly progressive dementia, ataxia, and myoclonus.
• Because of its protean manifestations, the diagnosis of CJD is difficult to make antemortem, and diagnosis is often delayed. Specialist evaluation of brain MRI DWI sequences and new CSF diagnostic tests may allow for earlier diagnosis, which has management and infection control implications.

Disclosure

Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr Geschwind’s institution has received R01 grant funding from NIH/NIA; and Alliance Biosecure and the Michael J Homer Family Fund as paid money to his institution, Dr Geschwind has received consulting fees or honoraria from Best Doctors, Kendall Brill & Kelly, CJD Foundation, and Tau Consortium; Dr Geschwind is a consultant for Gerson Lehrman Group, Biohaven Pharmaceuticals, and Advance Medical, outside the submitted work; has grants/grantspending with Quest, Cure PSP, and Tau Consortium, and received payment for lectures from Multiple Grand Rounds Lectures, outside the submitted work. Dr Saint is on a medical advisory board of Doximity, has received honorarium for being a member of the medical advisory board; he is also on the scientifice advisory board of Jvion. Dr Safdar’s institution has received a grant from the VA Patient Safety Center.

A 57-year-old woman presented to the emergency department of a community hospital with a 2-week history of dizziness, blurred vision, and poor coordination following a flu-like illness. Symptoms were initially attributed to complications from a presumed viral illness, but when they persisted for 2 weeks, she underwent magnetic resonance imaging (MRI) of the brain, which was reported as showing a 2.4 x 2.3 x 1.9 cm right frontal lobe mass with mild mass effect and contrast enhancement (Figure 1). She was discharged home at her request with plans for outpatient follow-up.

Brain masses are usually neoplastic, infectious, or less commonly, inflammatory. The isolated lesion in the right frontal lobe is unlikely to explain her symptoms, which are more suggestive of multifocal disease or elevated intracranial pressure. Although the frontal eye fields could be affected by the mass, such lesions usually cause tonic eye deviation, not blurry vision; furthermore, coordination, which is impaired here, is not governed by the frontal lobe.

Two weeks later, she returned to the same emergency department with worsening symptoms and new bilateral upper extremity dystonia, confusion, and visual hallucinations. Cerebrospinal fluid (CSF) analysis revealed clear, nonxanthochromic fluid with 4 nucleated cells (a differential was not performed), 113 red blood cells, glucose of 80 mg/dL (normal range, 50-80 mg/dL), and protein of 52 mg/dL (normal range, 15-45 mg/dL).

Confusion is generally caused by a metabolic, infectious, structural, or toxic etiology. Standard CSF test results are usually normal with most toxic or metabolic encephalopathies. The absence of significant CSF inflammation argues against infectious encephalitis; paraneoplastic and autoimmune encephalitis, however, are still possible. The CSF red blood cells were likely due to a mildly traumatic tap, but also may have arisen from the frontal lobe mass or a more diffuse invasive process, although the lack of xanthochromia argues against this. Delirium and red blood cells in the CSF should trigger consideration of herpes simplex virus (HSV) encephalitis, although the time course is a bit too protracted and the reported MRI findings do not suggest typical medial temporal lobe involvement.

The disparate neurologic findings suggest a multifocal process, perhaps embolic (eg, endocarditis), ischemic (eg, intravascular lymphoma), infiltrative (eg, malignancy, neurosarcoidosis), or demyelinating (eg, postinfectious acute disseminated encephalomyelitis, multiple sclerosis). However, most of these would have been detected on the initial MRI. Upper extremity dystonia would likely localize to the basal ganglia, whereas confusion and visual hallucinations are more global. The combination of a movement disorder and visual hallucinations is seen in Lewy body dementia, but this tempo is not typical.

Although the CSF does not have pleocytosis, her original symptoms were flu-like; therefore, CSF testing for viruses (eg, enterovirus) is reasonable. Bacterial, mycobacteria, and fungal studies are apt to be unrevealing, but CSF cytology, IgG index, and oligoclonal bands may be useful. Should the encephalopathy progress further and the general medical evaluation prove to be normal, then tests for autoimmune disorders (eg, antinuclear antibodies, NMDAR, paraneoplastic disorders) and rare causes of rapidly progressive dementias (eg, prion diseases) should be sent.

Additional CSF studies including HSV polymerase chain reaction (PCR), West Nile PCR, Lyme antibody, paraneoplastic antibodies, and cytology were sent. Intravenous acyclovir was administered. The above studies, as well as Gram stain, acid-fast bacillus stain, fungal stain, and cultures, were negative. She was started on levetiracetam for seizure prevention due to the mass lesion. An electroencephalogram (EEG) was reported as showing diffuse background slowing with superimposed semiperiodic sharp waves with a right hemispheric emphasis. Intravenous immunoglobulin (IVIG) 0.4 mg/kg/day over 5 days was administered with no improvement. The patient was transferred to an academic medical center for further evaluation.

The EEG reflects encephalopathy without pointing to a specific diagnosis. Prophylactic antiepileptic medications are not indicated for CNS mass lesions without clinical or electrophysiologic seizure activity. IVIG is often administered when an autoimmune encephalitis is suspected, but the lack of response does not rule out an autoimmune condition.

Her medical history included bilateral cataract extraction, right leg fracture, tonsillectomy, and total abdominal hysterectomy. She had a 25-year smoking history and a family history of lung cancer. She had no history of drug or alcohol use. On examination, her temperature was 37.9°C, blood pressure of 144/98 mm Hg, respiratory rate of 18 breaths per minute, a heart rate of 121 beats per minute, and oxygen saturation of 97% on ambient air. Her eyes were open but she was nonverbal. Her chest was clear to auscultation. Heart sounds were distinct and rhythm was regular. Abdomen was soft and nontender with no organomegaly. Skin examination revealed no rash. Her pupils were equal, round, and reactive to light. She did not follow verbal or gestural commands and intermittently tracked with her eyes, but not consistently enough to characterize extraocular movements. Her face was symmetric. She had a normal gag and blink reflex and an increased jaw jerk reflex. Her arms were flexed with increased tone. She had a positive palmo-mental reflex. She had spontaneous movement of all extremities. She had symmetric, 3+ reflexes of the patella and Achilles tendon with a bilateral Babinski’s sign. Sensation was intact only to withdrawal from noxious stimuli.

The physical exam does not localize to a specific brain region, but suggests a diffuse brain process. There are multiple signs of upper motor neuron involvement, including increased tone, hyperreflexia, and Babinski (plantar flexion) reflexes. A palmo-mental reflex signifies pathology in the cerebrum. Although cranial nerve testing is limited, there are no features of cranial neuropathy; similarly, no pyramidal weakness or sensory deficit has been demonstrated on limited testing. The differential diagnosis of her rapidly progressive encephalopathy includes autoimmune or paraneoplastic encephalitis, diffuse infiltrative malignancy, metabolic diseases (eg, porphyria, heavy metal intoxication), and prion disease.

Her family history of lung cancer and her smoking increases the possibility of paraneoplastic encephalitis, which often has subacute behavioral changes that precede complete neurologic impairment. Inflammatory or hemorrhagic CSF is seen with Balamuthia amoebic infection, which causes a granulomatous encephalitis and is characteristically associated with a mass lesion. Toxoplasmosis causes encephalitis that can be profound, but patients are usually immunocompromised and there are typically multiple lesions.

Laboratory results showed a normal white blood cell count and differential, basic metabolic profile and liver function tests, and C-reactive protein. Human immunodeficiency virus antibody testing was negative. Chest radiography and computed tomography of chest, abdomen, and pelvis were normal. A repeat MRI of the brain with contrast was reported as showing a 2.4 x 2.3 x 1.9 cm heterogeneously enhancing mass in the right frontal lobe with an enhancing dural tail and underlying hyperostosis consistent with a meningioma, and blooming within the mass consistent with prior hemorrhage. No mass effect was present.

The meningioma was resected 3 days after admission but her symptoms did not improve. Routine postoperative MRI was reported to show expected postsurgical changes but no infarct. Brain biopsy at the time of the operation was reported as meningioma and mild gliosis without encephalitis.

The reported MRI findings showing unchanged size and overall appearance of the mass, its connection to the dura and skull, and the pathology results all suggest that the mass is a meningioma. There is no evidence of disease outside of the CNS. Some cancers that provoke a paraneoplastic response can be quite small yet may incite an immune encephalitis; anti-NMDAR-mediated encephalitis can occur with malignancy (often ovarian), although it also arises in the absence of any tumor. Any inclination to definitively exclude conditions not seen on the brain biopsy must be tempered by the limited sensitivity of brain histology examination. Still, what was not seen warrants mention: vascular inflammation suggestive of CNS vasculitis, granulomas that might point to neurosarcoidosis, malignant cells of an infiltrating lymphoma or glioma, or inflammatory cells suggestive of encephalitis. Prion encephalopathy remains possible.

The patient remained unresponsive. A repeat EEG showed bilateral generalized periodic epileptiform discharges with accompanying twitching of the head, face, and left arm, which were suppressed with intravenous propofol and levetiracetam. Three weeks following meningioma resection, a new MRI was read as showing new abnormal signal in the right basal ganglia, abnormality of the cortex on the diffusion weighted images, and progressive generalized volume loss.

Among the aforementioned diagnoses, focal or diffuse periodic epileptiform discharges at 1-2 hertz are most characteristic of prion disease. Striatal and cortical transverse relaxation time (T2)-weighted and diffusion-weighted imaging (DWI) hyperintensities with corresponding restricted diffusion is characteristic of Creutzfeldt-Jakob disease (CJD), although metabolic disorders, seizures, and encephalitis can very rarely show similar MRI findings. The clinical course, the MRI and EEG findings, and nondiagnostic biopsy results, which were initially not assessed for prion disease, collectively point to prion disease. Detection of abnormal prion protein in the brain tissue by immunohistochemistry or molecular methods would confirm the diagnosis.

Review of the original right frontal cortex biopsy specimen at the National Prion Disease Pathology Surveillance Center, including immunostaining with 3F4, a monoclonal antibody to the prion protein, revealed granular deposits typical of prion disease. This finding established a diagnosis of prion disease, likely sporadic CJD. The patient was transitioned to palliative care and died shortly thereafter.

Brain autopsy showed regions with transcortical vacuolation (spongiform change), other cortical regions with varying degrees of vacuolation, abundant reactive astrocytes, paucity of neurons, and dark shrunken neurons. Vacuolation and gliosis were observed in the striatum and were most pronounced in the thalamus. There was no evidence of an inflammatory infiltrate or a neoplastic process. These findings with the positive 3F4 immunohistochemistry and positive Western blot from brain autopsy, as well as the absence of a mutation in the prion protein gene, were diagnostic for CJD.

An investigation was initiated to track the nondisposable surgical instruments used in the meningioma resection that may have been subsequently used in other patients. It was determined that 52 neurosurgical patients may have been exposed to prion-contaminated instruments. The instruments were subsequently processed specifically for prion decontamination. After 7 years, no cases of CJD have been diagnosed in the potentially exposed patients.

CJD is a rare neurodegenerative condition¹ classified as one of the transmissible spongiform encephalopathies, so called because of the characteristic spongiform pattern (vacuolation) seen on histology, as well as the presence of neuronal loss, reactive gliosis in the gray matter, and the accumulation of the abnormal isoform of the cellular prion protein.² It affects about one person in every one million people per year worldwide; in the United States there are about 300 cases per year. The most common form of human prion disease, sporadic CJD, is relentlessly progressive and invariably fatal, and in most cases, death occurs less than 5 months from onset.³ There is no cure, although temporizing treatments for symptoms can be helpful.

Sporadic CJD, which accounts for approximately 85% of all cases of prion disease in humans, typically manifests with rapidly progressive dementia and myoclonus after a prolonged incubation period in persons between 55 and 75 years of age. Genetic forms account for approximately 15% and acquired forms less than 1% of human prion diseases.¹ Prion diseases have a broad spectrum of clinical manifestations, including dementia, ataxia, parkinsonism, myoclonus, insomnia, paresthesias, and abnormal or changed behavior.⁴ Given the protean clinical manifestations of prion diseases and rarity, the diagnosis is challenging to make antemortem. One recent study showed that most patients receive about 4 misdiagnoses and are often two-thirds of the way through their disease course before the correct diagnosis of sporadic CJD is made.⁵

• Rapidly progressive dementias (RPD) are characterized by cognitive decline over weeks to months. The RPD differential diagnosis includes fulminant forms of common neurodegenerative disorders (eg, Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia spectrum), autoimmune encephalidites, CNS cancers, and prion disease.
• Sporadic CJD is the most common human prion disease. It is a rare neurodegenerative condition with onset usually between the ages of 50 and 70 years, and most commonly manifests with rapidly progressive dementia, ataxia, and myoclonus.
• Because of its protean manifestations, the diagnosis of CJD is difficult to make antemortem, and diagnosis is often delayed. Specialist evaluation of brain MRI DWI sequences and new CSF diagnostic tests may allow for earlier diagnosis, which has management and infection control implications.

Disclosure

Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr Geschwind’s institution has received R01 grant funding from NIH/NIA; and Alliance Biosecure and the Michael J Homer Family Fund as paid money to his institution, Dr Geschwind has received consulting fees or honoraria from Best Doctors, Kendall Brill & Kelly, CJD Foundation, and Tau Consortium; Dr Geschwind is a consultant for Gerson Lehrman Group, Biohaven Pharmaceuticals, and Advance Medical, outside the submitted work; has grants/grantspending with Quest, Cure PSP, and Tau Consortium, and received payment for lectures from Multiple Grand Rounds Lectures, outside the submitted work. Dr Saint is on a medical advisory board of Doximity, has received honorarium for being a member of the medical advisory board; he is also on the scientifice advisory board of Jvion. Dr Safdar’s institution has received a grant from the VA Patient Safety Center.

A 57-year-old woman presented to the emergency department of a community hospital with a 2-week history of dizziness, blurred vision, and poor coordination following a flu-like illness. Symptoms were initially attributed to complications from a presumed viral illness, but when they persisted for 2 weeks, she underwent magnetic resonance imaging (MRI) of the brain, which was reported as showing a 2.4 x 2.3 x 1.9 cm right frontal lobe mass with mild mass effect and contrast enhancement (Figure 1). She was discharged home at her request with plans for outpatient follow-up.

Brain masses are usually neoplastic, infectious, or less commonly, inflammatory. The isolated lesion in the right frontal lobe is unlikely to explain her symptoms, which are more suggestive of multifocal disease or elevated intracranial pressure. Although the frontal eye fields could be affected by the mass, such lesions usually cause tonic eye deviation, not blurry vision; furthermore, coordination, which is impaired here, is not governed by the frontal lobe.

Two weeks later, she returned to the same emergency department with worsening symptoms and new bilateral upper extremity dystonia, confusion, and visual hallucinations. Cerebrospinal fluid (CSF) analysis revealed clear, nonxanthochromic fluid with 4 nucleated cells (a differential was not performed), 113 red blood cells, glucose of 80 mg/dL (normal range, 50-80 mg/dL), and protein of 52 mg/dL (normal range, 15-45 mg/dL).

Confusion is generally caused by a metabolic, infectious, structural, or toxic etiology. Standard CSF test results are usually normal with most toxic or metabolic encephalopathies. The absence of significant CSF inflammation argues against infectious encephalitis; paraneoplastic and autoimmune encephalitis, however, are still possible. The CSF red blood cells were likely due to a mildly traumatic tap, but also may have arisen from the frontal lobe mass or a more diffuse invasive process, although the lack of xanthochromia argues against this. Delirium and red blood cells in the CSF should trigger consideration of herpes simplex virus (HSV) encephalitis, although the time course is a bit too protracted and the reported MRI findings do not suggest typical medial temporal lobe involvement.

The disparate neurologic findings suggest a multifocal process, perhaps embolic (eg, endocarditis), ischemic (eg, intravascular lymphoma), infiltrative (eg, malignancy, neurosarcoidosis), or demyelinating (eg, postinfectious acute disseminated encephalomyelitis, multiple sclerosis). However, most of these would have been detected on the initial MRI. Upper extremity dystonia would likely localize to the basal ganglia, whereas confusion and visual hallucinations are more global. The combination of a movement disorder and visual hallucinations is seen in Lewy body dementia, but this tempo is not typical.

Although the CSF does not have pleocytosis, her original symptoms were flu-like; therefore, CSF testing for viruses (eg, enterovirus) is reasonable. Bacterial, mycobacteria, and fungal studies are apt to be unrevealing, but CSF cytology, IgG index, and oligoclonal bands may be useful. Should the encephalopathy progress further and the general medical evaluation prove to be normal, then tests for autoimmune disorders (eg, antinuclear antibodies, NMDAR, paraneoplastic disorders) and rare causes of rapidly progressive dementias (eg, prion diseases) should be sent.

Additional CSF studies including HSV polymerase chain reaction (PCR), West Nile PCR, Lyme antibody, paraneoplastic antibodies, and cytology were sent. Intravenous acyclovir was administered. The above studies, as well as Gram stain, acid-fast bacillus stain, fungal stain, and cultures, were negative. She was started on levetiracetam for seizure prevention due to the mass lesion. An electroencephalogram (EEG) was reported as showing diffuse background slowing with superimposed semiperiodic sharp waves with a right hemispheric emphasis. Intravenous immunoglobulin (IVIG) 0.4 mg/kg/day over 5 days was administered with no improvement. The patient was transferred to an academic medical center for further evaluation.

The EEG reflects encephalopathy without pointing to a specific diagnosis. Prophylactic antiepileptic medications are not indicated for CNS mass lesions without clinical or electrophysiologic seizure activity. IVIG is often administered when an autoimmune encephalitis is suspected, but the lack of response does not rule out an autoimmune condition.

Her medical history included bilateral cataract extraction, right leg fracture, tonsillectomy, and total abdominal hysterectomy. She had a 25-year smoking history and a family history of lung cancer. She had no history of drug or alcohol use. On examination, her temperature was 37.9°C, blood pressure of 144/98 mm Hg, respiratory rate of 18 breaths per minute, a heart rate of 121 beats per minute, and oxygen saturation of 97% on ambient air. Her eyes were open but she was nonverbal. Her chest was clear to auscultation. Heart sounds were distinct and rhythm was regular. Abdomen was soft and nontender with no organomegaly. Skin examination revealed no rash. Her pupils were equal, round, and reactive to light. She did not follow verbal or gestural commands and intermittently tracked with her eyes, but not consistently enough to characterize extraocular movements. Her face was symmetric. She had a normal gag and blink reflex and an increased jaw jerk reflex. Her arms were flexed with increased tone. She had a positive palmo-mental reflex. She had spontaneous movement of all extremities. She had symmetric, 3+ reflexes of the patella and Achilles tendon with a bilateral Babinski’s sign. Sensation was intact only to withdrawal from noxious stimuli.

The physical exam does not localize to a specific brain region, but suggests a diffuse brain process. There are multiple signs of upper motor neuron involvement, including increased tone, hyperreflexia, and Babinski (plantar flexion) reflexes. A palmo-mental reflex signifies pathology in the cerebrum. Although cranial nerve testing is limited, there are no features of cranial neuropathy; similarly, no pyramidal weakness or sensory deficit has been demonstrated on limited testing. The differential diagnosis of her rapidly progressive encephalopathy includes autoimmune or paraneoplastic encephalitis, diffuse infiltrative malignancy, metabolic diseases (eg, porphyria, heavy metal intoxication), and prion disease.

Her family history of lung cancer and her smoking increases the possibility of paraneoplastic encephalitis, which often has subacute behavioral changes that precede complete neurologic impairment. Inflammatory or hemorrhagic CSF is seen with Balamuthia amoebic infection, which causes a granulomatous encephalitis and is characteristically associated with a mass lesion. Toxoplasmosis causes encephalitis that can be profound, but patients are usually immunocompromised and there are typically multiple lesions.

Laboratory results showed a normal white blood cell count and differential, basic metabolic profile and liver function tests, and C-reactive protein. Human immunodeficiency virus antibody testing was negative. Chest radiography and computed tomography of chest, abdomen, and pelvis were normal. A repeat MRI of the brain with contrast was reported as showing a 2.4 x 2.3 x 1.9 cm heterogeneously enhancing mass in the right frontal lobe with an enhancing dural tail and underlying hyperostosis consistent with a meningioma, and blooming within the mass consistent with prior hemorrhage. No mass effect was present.

The meningioma was resected 3 days after admission but her symptoms did not improve. Routine postoperative MRI was reported to show expected postsurgical changes but no infarct. Brain biopsy at the time of the operation was reported as meningioma and mild gliosis without encephalitis.

The reported MRI findings showing unchanged size and overall appearance of the mass, its connection to the dura and skull, and the pathology results all suggest that the mass is a meningioma. There is no evidence of disease outside of the CNS. Some cancers that provoke a paraneoplastic response can be quite small yet may incite an immune encephalitis; anti-NMDAR-mediated encephalitis can occur with malignancy (often ovarian), although it also arises in the absence of any tumor. Any inclination to definitively exclude conditions not seen on the brain biopsy must be tempered by the limited sensitivity of brain histology examination. Still, what was not seen warrants mention: vascular inflammation suggestive of CNS vasculitis, granulomas that might point to neurosarcoidosis, malignant cells of an infiltrating lymphoma or glioma, or inflammatory cells suggestive of encephalitis. Prion encephalopathy remains possible.

The patient remained unresponsive. A repeat EEG showed bilateral generalized periodic epileptiform discharges with accompanying twitching of the head, face, and left arm, which were suppressed with intravenous propofol and levetiracetam. Three weeks following meningioma resection, a new MRI was read as showing new abnormal signal in the right basal ganglia, abnormality of the cortex on the diffusion weighted images, and progressive generalized volume loss.

Among the aforementioned diagnoses, focal or diffuse periodic epileptiform discharges at 1-2 hertz are most characteristic of prion disease. Striatal and cortical transverse relaxation time (T2)-weighted and diffusion-weighted imaging (DWI) hyperintensities with corresponding restricted diffusion is characteristic of Creutzfeldt-Jakob disease (CJD), although metabolic disorders, seizures, and encephalitis can very rarely show similar MRI findings. The clinical course, the MRI and EEG findings, and nondiagnostic biopsy results, which were initially not assessed for prion disease, collectively point to prion disease. Detection of abnormal prion protein in the brain tissue by immunohistochemistry or molecular methods would confirm the diagnosis.

Review of the original right frontal cortex biopsy specimen at the National Prion Disease Pathology Surveillance Center, including immunostaining with 3F4, a monoclonal antibody to the prion protein, revealed granular deposits typical of prion disease. This finding established a diagnosis of prion disease, likely sporadic CJD. The patient was transitioned to palliative care and died shortly thereafter.

Brain autopsy showed regions with transcortical vacuolation (spongiform change), other cortical regions with varying degrees of vacuolation, abundant reactive astrocytes, paucity of neurons, and dark shrunken neurons. Vacuolation and gliosis were observed in the striatum and were most pronounced in the thalamus. There was no evidence of an inflammatory infiltrate or a neoplastic process. These findings with the positive 3F4 immunohistochemistry and positive Western blot from brain autopsy, as well as the absence of a mutation in the prion protein gene, were diagnostic for CJD.

An investigation was initiated to track the nondisposable surgical instruments used in the meningioma resection that may have been subsequently used in other patients. It was determined that 52 neurosurgical patients may have been exposed to prion-contaminated instruments. The instruments were subsequently processed specifically for prion decontamination. After 7 years, no cases of CJD have been diagnosed in the potentially exposed patients.

CJD is a rare neurodegenerative condition¹ classified as one of the transmissible spongiform encephalopathies, so called because of the characteristic spongiform pattern (vacuolation) seen on histology, as well as the presence of neuronal loss, reactive gliosis in the gray matter, and the accumulation of the abnormal isoform of the cellular prion protein.² It affects about one person in every one million people per year worldwide; in the United States there are about 300 cases per year. The most common form of human prion disease, sporadic CJD, is relentlessly progressive and invariably fatal, and in most cases, death occurs less than 5 months from onset.³ There is no cure, although temporizing treatments for symptoms can be helpful.

Sporadic CJD, which accounts for approximately 85% of all cases of prion disease in humans, typically manifests with rapidly progressive dementia and myoclonus after a prolonged incubation period in persons between 55 and 75 years of age. Genetic forms account for approximately 15% and acquired forms less than 1% of human prion diseases.¹ Prion diseases have a broad spectrum of clinical manifestations, including dementia, ataxia, parkinsonism, myoclonus, insomnia, paresthesias, and abnormal or changed behavior.⁴ Given the protean clinical manifestations of prion diseases and rarity, the diagnosis is challenging to make antemortem. One recent study showed that most patients receive about 4 misdiagnoses and are often two-thirds of the way through their disease course before the correct diagnosis of sporadic CJD is made.⁵

• Rapidly progressive dementias (RPD) are characterized by cognitive decline over weeks to months. The RPD differential diagnosis includes fulminant forms of common neurodegenerative disorders (eg, Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia spectrum), autoimmune encephalidites, CNS cancers, and prion disease.
• Sporadic CJD is the most common human prion disease. It is a rare neurodegenerative condition with onset usually between the ages of 50 and 70 years, and most commonly manifests with rapidly progressive dementia, ataxia, and myoclonus.
• Because of its protean manifestations, the diagnosis of CJD is difficult to make antemortem, and diagnosis is often delayed. Specialist evaluation of brain MRI DWI sequences and new CSF diagnostic tests may allow for earlier diagnosis, which has management and infection control implications.

Disclosure

Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr Geschwind’s institution has received R01 grant funding from NIH/NIA; and Alliance Biosecure and the Michael J Homer Family Fund as paid money to his institution, Dr Geschwind has received consulting fees or honoraria from Best Doctors, Kendall Brill & Kelly, CJD Foundation, and Tau Consortium; Dr Geschwind is a consultant for Gerson Lehrman Group, Biohaven Pharmaceuticals, and Advance Medical, outside the submitted work; has grants/grantspending with Quest, Cure PSP, and Tau Consortium, and received payment for lectures from Multiple Grand Rounds Lectures, outside the submitted work. Dr Saint is on a medical advisory board of Doximity, has received honorarium for being a member of the medical advisory board; he is also on the scientifice advisory board of Jvion. Dr Safdar’s institution has received a grant from the VA Patient Safety Center.

The “Things We Do for No Reason” (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” 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. https://www.choosingwisely.org/

Blood transfusion is not only the most common procedure performed in US hospitals but is also widely overused, according to The Joint Commission. Unnecessary transfusions can increase risks and costs, and now, multiple landmark trials support using restrictive transfusion strategies. This manuscript discusses the importance and potential impacts of giving single-unit red blood cell (RBC) transfusions in anemic patients who are not actively bleeding and are hemodynamically stable. The “thing we do for no reason” is giving 2-unit RBC transfusions when 1 unit would suffice. We call this the “Why give 2 when 1 will do?” campaign for RBC transfusion.

A 74-year-old, 70-kg male with a known history of myelodysplastic syndrome is admitted for dizziness and shortness of breath. His hemoglobin (Hb) concentration is 6.2 g/dL (baseline Hb of 8 g/dL). The patient denies any hematuria, hematemesis, and melena. Physical examination is remarkable only for tachycardia—heart rate of 110. The admitting hospitalist ponders whether to order a 2-unit red blood cell (RBC) transfusion.

RBC transfusion is the most common procedure performed in US hospitals, with about 12 million RBC units given to patients in the United States each year.¹ Based on an opinion paper published in 1942 by Adams and Lundy² the “10/30 rule” set the standard that the ideal transfusion thresholds were an Hb of 10 g/dL or a hematocrit of 30%. Until human immunodeficiency virus (HIV) became a threat to the nation’s blood supply in the early 1980s, few questioned the 10/30 rule. There is no doubt that blood transfusions can be lifesaving in the presence of active bleeding or hemorrhagic shock; in fact, many hospitals have blood donation campaigns reminding us to “give blood—save a life.” To some, these messages may suggest that more blood is better. Prior to the 1990s, clinicians were taught that if the patient needed an RBC transfusion, 2 units was the optimal dose for adult patients. In fact, single-unit transfusions were strongly discouraged, and authorities on the risks of transfusion wrote that single-unit transfusions were acknowledged to be unnecessary.³

According to a recent Joint Commission Overuse Summit, transfusion was identified as 1 of the top 5 overused medical procedures.⁴ Blood transfusions can cause complications such as transfusion-related acute lung injury and transfusion-associated circulatory overload, the number 1 and 2 causes of transfusion-related deaths, respectively,⁵ as well as other transfusion reactions (eg, allergic and hemolytic) and alloimmunization. Transfusion-related morbidity and mortality have been shown to be dose dependent,⁶ suggesting that the lowest effective number of units should be transfused. Although, with modern-day testing, the risks of HIV and viral hepatitis are exceedingly low, emerging infectious diseases such as the Zika virus and Babesiosis represent new threats to the nation’s blood supply, with potential transfusion-related transmission and severe consequences, especially for the immunosuppressed. As quality-improvement, patient safety, and cost-saving initiatives, many hospitals have implemented strategies to reduce unnecessary transfusions and decrease overall blood utilization.

Perhaps the most common indication for ordering multiunit RBC transfusions is active bleeding, as it is clear that whatever Hb threshold is chosen, transfusion should be given in sufficient amounts to stay ahead of the bleeding.²⁰ It is important to remember that we treat patients and their symptoms, not just their laboratory values. Good medical care adapts and/or modifies treatment protocols and guidelines according to the clinical situation. Intravascular volume is also important to consider because what really matters for oxygen content and delivery is the total red cell mass (ie, the Hb concentration times the blood volume). If a patient is hypovolemic and/or actively bleeding, the Hb transfusion trigger, as well as the dose of blood, may need to be adjusted upward, creating clinical scenarios in which 2-unit RBC transfusions may be appropriate. Other clinical settings for which multiunit RBC transfusions may be indicated include patients with severe anemia, for whom both the pretransfusion Hb (the trigger) and the posttransfusion Hb (the target) should be considered. Patients with hemoglobinopathies (eg, sickle cell or thalassemia) sometimes require multiunit transfusions or even exchange transfusions to improve oxygen delivery. Other patients who may benefit from higher Hb levels achieved by multiunit transfusions include those with acute coronary syndromes; however, the ideal Hb transfusion threshold in this setting has yet to be determined.²¹

For hemodynamically stable patients and in the absence of active bleeding, single-unit RBC transfusions, followed by reassessment, should be the standard for most patients. The reassessment should include measuring the posttransfusion Hb level and checking for improvement in vital sign abnormalities and signs or symptoms of anemia or end-organ ischemia. A recent publication on our hospital-wide campaign called “Why give 2 when 1 will do?” showed a significant (35%) reduction in 2-unit transfusion orders along with an 18% overall decrease in RBC utilization and substantial cost savings (≈$600,000 per year).¹⁰ These findings demonstrate that there is a large opportunity to reduce transfusion overuse by encouraging single-unit transfusions.

• For nonbleeding, hemodynamically stable patients who require a transfusion, transfuse a single RBC unit and then reassess the Hb level before transfusing a second unit.
• The decision to transfuse RBCs should take into account the patient’s overall condition, including their symptoms, intravascular volume, and the occurrence and rate of active bleeding, not just the Hb value alone.

In stable patients, a single unit of RBCs often is adequate to raise the Hb to an acceptable level and relieve the signs and symptoms of anemia. Additional units should be prescribed only after reassessment of the patient and the Hb level. For our patient with symptomatic anemia, it is reasonable to transfuse 1 RBC unit, and then measure the Hb level, and reassess his symptoms before giving additional RBC units.

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 [email protected].

This publication is dedicated to our beloved colleague, Dr. Rajiv N. Thakkar, who recently and unexpectedly suffered a fatal cardiac event. We will miss him dearly.

Disclosure

S.M.F. has been on advisory boards for the Haemonetics Corporation (Braintree, MA), Medtronic Inc. (Minneapolis, MN), and Zimmer Biomet (Warsaw, IN). All other authors declare no competing interests.

The “Things We Do for No Reason” (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” 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. https://www.choosingwisely.org/

Blood transfusion is not only the most common procedure performed in US hospitals but is also widely overused, according to The Joint Commission. Unnecessary transfusions can increase risks and costs, and now, multiple landmark trials support using restrictive transfusion strategies. This manuscript discusses the importance and potential impacts of giving single-unit red blood cell (RBC) transfusions in anemic patients who are not actively bleeding and are hemodynamically stable. The “thing we do for no reason” is giving 2-unit RBC transfusions when 1 unit would suffice. We call this the “Why give 2 when 1 will do?” campaign for RBC transfusion.

A 74-year-old, 70-kg male with a known history of myelodysplastic syndrome is admitted for dizziness and shortness of breath. His hemoglobin (Hb) concentration is 6.2 g/dL (baseline Hb of 8 g/dL). The patient denies any hematuria, hematemesis, and melena. Physical examination is remarkable only for tachycardia—heart rate of 110. The admitting hospitalist ponders whether to order a 2-unit red blood cell (RBC) transfusion.

RBC transfusion is the most common procedure performed in US hospitals, with about 12 million RBC units given to patients in the United States each year.¹ Based on an opinion paper published in 1942 by Adams and Lundy² the “10/30 rule” set the standard that the ideal transfusion thresholds were an Hb of 10 g/dL or a hematocrit of 30%. Until human immunodeficiency virus (HIV) became a threat to the nation’s blood supply in the early 1980s, few questioned the 10/30 rule. There is no doubt that blood transfusions can be lifesaving in the presence of active bleeding or hemorrhagic shock; in fact, many hospitals have blood donation campaigns reminding us to “give blood—save a life.” To some, these messages may suggest that more blood is better. Prior to the 1990s, clinicians were taught that if the patient needed an RBC transfusion, 2 units was the optimal dose for adult patients. In fact, single-unit transfusions were strongly discouraged, and authorities on the risks of transfusion wrote that single-unit transfusions were acknowledged to be unnecessary.³

According to a recent Joint Commission Overuse Summit, transfusion was identified as 1 of the top 5 overused medical procedures.⁴ Blood transfusions can cause complications such as transfusion-related acute lung injury and transfusion-associated circulatory overload, the number 1 and 2 causes of transfusion-related deaths, respectively,⁵ as well as other transfusion reactions (eg, allergic and hemolytic) and alloimmunization. Transfusion-related morbidity and mortality have been shown to be dose dependent,⁶ suggesting that the lowest effective number of units should be transfused. Although, with modern-day testing, the risks of HIV and viral hepatitis are exceedingly low, emerging infectious diseases such as the Zika virus and Babesiosis represent new threats to the nation’s blood supply, with potential transfusion-related transmission and severe consequences, especially for the immunosuppressed. As quality-improvement, patient safety, and cost-saving initiatives, many hospitals have implemented strategies to reduce unnecessary transfusions and decrease overall blood utilization.

Perhaps the most common indication for ordering multiunit RBC transfusions is active bleeding, as it is clear that whatever Hb threshold is chosen, transfusion should be given in sufficient amounts to stay ahead of the bleeding.²⁰ It is important to remember that we treat patients and their symptoms, not just their laboratory values. Good medical care adapts and/or modifies treatment protocols and guidelines according to the clinical situation. Intravascular volume is also important to consider because what really matters for oxygen content and delivery is the total red cell mass (ie, the Hb concentration times the blood volume). If a patient is hypovolemic and/or actively bleeding, the Hb transfusion trigger, as well as the dose of blood, may need to be adjusted upward, creating clinical scenarios in which 2-unit RBC transfusions may be appropriate. Other clinical settings for which multiunit RBC transfusions may be indicated include patients with severe anemia, for whom both the pretransfusion Hb (the trigger) and the posttransfusion Hb (the target) should be considered. Patients with hemoglobinopathies (eg, sickle cell or thalassemia) sometimes require multiunit transfusions or even exchange transfusions to improve oxygen delivery. Other patients who may benefit from higher Hb levels achieved by multiunit transfusions include those with acute coronary syndromes; however, the ideal Hb transfusion threshold in this setting has yet to be determined.²¹

For hemodynamically stable patients and in the absence of active bleeding, single-unit RBC transfusions, followed by reassessment, should be the standard for most patients. The reassessment should include measuring the posttransfusion Hb level and checking for improvement in vital sign abnormalities and signs or symptoms of anemia or end-organ ischemia. A recent publication on our hospital-wide campaign called “Why give 2 when 1 will do?” showed a significant (35%) reduction in 2-unit transfusion orders along with an 18% overall decrease in RBC utilization and substantial cost savings (≈$600,000 per year).¹⁰ These findings demonstrate that there is a large opportunity to reduce transfusion overuse by encouraging single-unit transfusions.

• For nonbleeding, hemodynamically stable patients who require a transfusion, transfuse a single RBC unit and then reassess the Hb level before transfusing a second unit.
• The decision to transfuse RBCs should take into account the patient’s overall condition, including their symptoms, intravascular volume, and the occurrence and rate of active bleeding, not just the Hb value alone.

In stable patients, a single unit of RBCs often is adequate to raise the Hb to an acceptable level and relieve the signs and symptoms of anemia. Additional units should be prescribed only after reassessment of the patient and the Hb level. For our patient with symptomatic anemia, it is reasonable to transfuse 1 RBC unit, and then measure the Hb level, and reassess his symptoms before giving additional RBC units.

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 [email protected].

This publication is dedicated to our beloved colleague, Dr. Rajiv N. Thakkar, who recently and unexpectedly suffered a fatal cardiac event. We will miss him dearly.

Disclosure

S.M.F. has been on advisory boards for the Haemonetics Corporation (Braintree, MA), Medtronic Inc. (Minneapolis, MN), and Zimmer Biomet (Warsaw, IN). All other authors declare no competing interests.

The “Things We Do for No Reason” (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” 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. https://www.choosingwisely.org/

Blood transfusion is not only the most common procedure performed in US hospitals but is also widely overused, according to The Joint Commission. Unnecessary transfusions can increase risks and costs, and now, multiple landmark trials support using restrictive transfusion strategies. This manuscript discusses the importance and potential impacts of giving single-unit red blood cell (RBC) transfusions in anemic patients who are not actively bleeding and are hemodynamically stable. The “thing we do for no reason” is giving 2-unit RBC transfusions when 1 unit would suffice. We call this the “Why give 2 when 1 will do?” campaign for RBC transfusion.

A 74-year-old, 70-kg male with a known history of myelodysplastic syndrome is admitted for dizziness and shortness of breath. His hemoglobin (Hb) concentration is 6.2 g/dL (baseline Hb of 8 g/dL). The patient denies any hematuria, hematemesis, and melena. Physical examination is remarkable only for tachycardia—heart rate of 110. The admitting hospitalist ponders whether to order a 2-unit red blood cell (RBC) transfusion.

RBC transfusion is the most common procedure performed in US hospitals, with about 12 million RBC units given to patients in the United States each year.¹ Based on an opinion paper published in 1942 by Adams and Lundy² the “10/30 rule” set the standard that the ideal transfusion thresholds were an Hb of 10 g/dL or a hematocrit of 30%. Until human immunodeficiency virus (HIV) became a threat to the nation’s blood supply in the early 1980s, few questioned the 10/30 rule. There is no doubt that blood transfusions can be lifesaving in the presence of active bleeding or hemorrhagic shock; in fact, many hospitals have blood donation campaigns reminding us to “give blood—save a life.” To some, these messages may suggest that more blood is better. Prior to the 1990s, clinicians were taught that if the patient needed an RBC transfusion, 2 units was the optimal dose for adult patients. In fact, single-unit transfusions were strongly discouraged, and authorities on the risks of transfusion wrote that single-unit transfusions were acknowledged to be unnecessary.³

According to a recent Joint Commission Overuse Summit, transfusion was identified as 1 of the top 5 overused medical procedures.⁴ Blood transfusions can cause complications such as transfusion-related acute lung injury and transfusion-associated circulatory overload, the number 1 and 2 causes of transfusion-related deaths, respectively,⁵ as well as other transfusion reactions (eg, allergic and hemolytic) and alloimmunization. Transfusion-related morbidity and mortality have been shown to be dose dependent,⁶ suggesting that the lowest effective number of units should be transfused. Although, with modern-day testing, the risks of HIV and viral hepatitis are exceedingly low, emerging infectious diseases such as the Zika virus and Babesiosis represent new threats to the nation’s blood supply, with potential transfusion-related transmission and severe consequences, especially for the immunosuppressed. As quality-improvement, patient safety, and cost-saving initiatives, many hospitals have implemented strategies to reduce unnecessary transfusions and decrease overall blood utilization.

Perhaps the most common indication for ordering multiunit RBC transfusions is active bleeding, as it is clear that whatever Hb threshold is chosen, transfusion should be given in sufficient amounts to stay ahead of the bleeding.²⁰ It is important to remember that we treat patients and their symptoms, not just their laboratory values. Good medical care adapts and/or modifies treatment protocols and guidelines according to the clinical situation. Intravascular volume is also important to consider because what really matters for oxygen content and delivery is the total red cell mass (ie, the Hb concentration times the blood volume). If a patient is hypovolemic and/or actively bleeding, the Hb transfusion trigger, as well as the dose of blood, may need to be adjusted upward, creating clinical scenarios in which 2-unit RBC transfusions may be appropriate. Other clinical settings for which multiunit RBC transfusions may be indicated include patients with severe anemia, for whom both the pretransfusion Hb (the trigger) and the posttransfusion Hb (the target) should be considered. Patients with hemoglobinopathies (eg, sickle cell or thalassemia) sometimes require multiunit transfusions or even exchange transfusions to improve oxygen delivery. Other patients who may benefit from higher Hb levels achieved by multiunit transfusions include those with acute coronary syndromes; however, the ideal Hb transfusion threshold in this setting has yet to be determined.²¹

For hemodynamically stable patients and in the absence of active bleeding, single-unit RBC transfusions, followed by reassessment, should be the standard for most patients. The reassessment should include measuring the posttransfusion Hb level and checking for improvement in vital sign abnormalities and signs or symptoms of anemia or end-organ ischemia. A recent publication on our hospital-wide campaign called “Why give 2 when 1 will do?” showed a significant (35%) reduction in 2-unit transfusion orders along with an 18% overall decrease in RBC utilization and substantial cost savings (≈$600,000 per year).¹⁰ These findings demonstrate that there is a large opportunity to reduce transfusion overuse by encouraging single-unit transfusions.

• For nonbleeding, hemodynamically stable patients who require a transfusion, transfuse a single RBC unit and then reassess the Hb level before transfusing a second unit.
• The decision to transfuse RBCs should take into account the patient’s overall condition, including their symptoms, intravascular volume, and the occurrence and rate of active bleeding, not just the Hb value alone.

In stable patients, a single unit of RBCs often is adequate to raise the Hb to an acceptable level and relieve the signs and symptoms of anemia. Additional units should be prescribed only after reassessment of the patient and the Hb level. For our patient with symptomatic anemia, it is reasonable to transfuse 1 RBC unit, and then measure the Hb level, and reassess his symptoms before giving additional RBC units.

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 [email protected].

This publication is dedicated to our beloved colleague, Dr. Rajiv N. Thakkar, who recently and unexpectedly suffered a fatal cardiac event. We will miss him dearly.

Disclosure

S.M.F. has been on advisory boards for the Haemonetics Corporation (Braintree, MA), Medtronic Inc. (Minneapolis, MN), and Zimmer Biomet (Warsaw, IN). All other authors declare no competing interests.

Recent efforts to reduce waste and overuse in healthcare include reforms, such as merit-based physician reimbursement for efficient resource use¹ and the inclusion of cost-effective care as a competency for physician trainees.² Focusing on resource use in physician training and reimbursement presumes that teaching and feedback about utilization can alter physician behavior. Early studies of social comparison feedback observed considerable variation in effectiveness, depending on the behavior targeted and how feedback was provided to physicians.^3-5 The widespread adoption of electronic medical record (EMR) software enables the design of feedback interventions that provide continuous feedback in real-time via EMR-based practice dashboards. Currently, little is known about physician engagement with practice dashboards and, in particular, about trainee engagement with dashboards aimed to improve cost-effective care.

To inform future efforts in using social comparison feedback to teach cost-effective care in residency, we measured internal medicine resident engagement with an EMR-based utilization dashboard that provides feedback on their use of routine laboratory tests on an inpatient medicine service. Routine labs are often overused in the inpatient setting. In fact, one study reported that 68% of laboratory tests ordered in an academic hospital did not contribute to improving patient outcomes.⁶ To understand resident perceptions of the dashboards and identify barriers to their use, we conducted a mixed methods study tracking resident utilization of the dashboard over time and collecting qualitative data from 3 focus groups about resident attitudes toward the dashboards.

From January 2016 to June 2016, resident-specific rates of routine lab orders (eg, complete blood count, basic metabolic panel, complete metabolic panel, liver function panel, and common coagulation tests) were synthesized continuously in a web-based dashboard. Laboratory orders could be placed either individually on a day-to-day basis or ordered on a recurrent basis (eg, daily morning labs ordered on admission). The dashboard contained an interactive graph, which plotted the average number of labs per patient-day ordered by each resident over the past week, along with an overall graph for all services for comparison (Appendix Figure). Residents could click on an individual day on the graph to review the labs they ordered for each patient. The dashboard also allowed the user to look up each patient’s medical record to obtain more detailed information.

All residents received an e-mail describing the study, including the purpose of the intervention, basic description of the feedback intervention (dashboard and e-mail), potential risks and benefits, duration and scope of data collection, and contact information of the principal investigator. One hundred and ninety-eight resident-blocks on 6 general medicine services at the Hospital of the University of Pennsylvania were cluster-randomized with an equal probability to 1 of 2 arms: (1) those e-mailed a snapshot of the personalized dashboard, a link to the online dashboard, and text containing resident and service utilization averages, and (2) those who did not receive the feedback intervention. Postgraduate year (PGY) 1 residents were attributed only orders by that resident. PGY2 and PGY3 residents were attributed orders for all patients assigned to the resident’s team.

The initial e-mails were timed to arrive in the middle of each resident’s 2-week service to allow for a baseline and follow-up period. The e-mail contained an attachment of a snapshot of the personalized graphic dashboard (Appendix Figure), a link to the online dashboard, and a few sentences summarizing the resident utilization average compared to the general medicine service overall, for the same time interval. They were followed by a reminder e-mail 24 hours later containing only the link to the report card. We measured resident engagement with the utilization dashboard by using e-mail read-receipts and a web-based tracking platform that recorded when the dashboard was opened and who logged on.

Following completion of the intervention, 3-hour-long focus groups were conducted with residents. These focus groups were guided with prescripted questions to prompt discussion on the advantages and drawbacks of the study intervention and the usage of dashboards in general. These sessions were digitally recorded and transcribed. The transcripts were reviewed by 2 authors (KR and GK) and analyzed to identify common themes by using a grounded theory approach.⁷ First, the transcripts were reviewed independently by each author, who each generated a broad list of themes across 3 domains: dashboard usability, barriers to use, and suggestions for the future. Next, the codebook was refined through an iterative series of discussions and transcript review, resulting in a unified codebook. Lastly, all transcripts were reviewed by using the final codebook definitions, resulting in a list of exemplary quotes and suggestions.

The study was approved by the University of Pennsylvania Institutional Review Board and registered on clinicaltrials.gov (NCT02330289).

Eighty unique residents participated in the intervention, including 51 PGY1s (64%) and 29 PGY2- or PGY3-level (36%) residents. Of these, 19/80 (24%) physicians participated more than once. 74% of participants opened the e-mail and 21% opened the link to the dashboard. The average elapsed time from receiving the initial e-mail to logging into the dashboard was 28.5 hours (standard deviation [SD] = 25.7, median = 25.5, interquartile range [IQR] = 40.5). On average, residents deviated from the service mean by 0.54 laboratory test orders (SD = 0.49, median = 0.40, IQR = 0.60). The mean baseline rate of targeted labs was 1.30 (SD 1.77) labs per physician per patient-day.⁸

Overall, the engagement rates of internal medicine trainees with the online dashboard were low. Most residents did open the e-mails containing the link and basic information about their utilization rates, but less than a quarter of them accessed the dashboard containing real-time data. Additionally, on average, it took them more than a day to do so. However, there is some indication that residents who deviated further from the mean in either direction, which was described in the body of the e-mail, were more motivated to investigate further and click the link to access the dashboard. This suggests that providing practice feedback in this manner may be effective for a subset of residents who deviate from the “typical practice,” and as such, dashboards may represent a potential educational tool that could be aligned with practice-based learning competencies.

The focus groups provided important context about residents’ attitudes toward EMR-based dashboards. Overall, residents were enthusiastic about receiving information regarding their personal laboratory ordering, both in terms of preventing iatrogenic harm and waste of resources. This supports previous research that found that both medical students and residents overwhelmingly believe that the overuse of labs is a problem and that there may be insufficient focus on cost-conscious care during training.^9,10 However, many residents questioned several aspects of the specific intervention used in this study and suggested that significant improvements would need to be made to future dashboards to increase their utility.

To our knowledge, this is the first attempt to evaluate resident engagement and attitudes toward receiving practice-based feedback via an EMR-based online dashboard. Previous efforts to influence resident laboratory ordering behavior have primarily focused on didactic sessions, financial incentives, price transparency, and repeated e-mail messaging containing summary statistics about ordering practices and peer comparisons.^11-14 While some prior studies observed success in decreasing unnecessary use of laboratory tests, such efforts are challenging to implement routinely on a teaching service with multiple rotating providers and may be difficult to replicate. Future iterations of dashboards that incorporate focused curriculum design and active participation of teaching attendings require further study.

This study has several limitations. The sample size of physicians is relatively small and consists of residents at a single institution. This may limit the generalizability of the results. Additionally, the dashboard captured laboratory-ordering rates during a 2-week block on an inpatient medicine service and was not adjusted for factors such as patient case mix. However, the rates were adjusted for patient volume. In future iterations of utilization dashboards, residents’ concerns about small sample size and variability in clinical severity could be addressed through the adoption of risk-adjustment methodologies to balance out patient burden. This could be accomplished using currently available EMR data, such as diagnosis related groups or diagnoses codes to adjust for clinical complexity or report expected length of stay as a surrogate indicator of complexity.

Because residents are expected to be responsive to feedback, their use of the dashboards may represent an upper bound on physician responsiveness to social comparison feedback regarding utilization. However, e-mails alone may not be an effective way to provide feedback in areas that require additional engagement by the learner, especially given the volume of e-mails and alerts physicians receive. Future efforts to improve care efficiency may try to better capture baseline ordering rates, follow resident ordering over a longer period of time, encourage hospital staff to review utilization information with trainees, integrate dashboard information into regular performance reviews by the attendings, and provide more concrete feedback from attendings or senior residents for how this information can be used to adjust behavior.

Disclosure

Dr. Ryskina’s work on this study was supported by the Ruth L. Kirschstein National Research Service Award (T32-HP10026) and the NIA Career Development Award (K08AG052572). Dr. Patel reports board membership on the advisory board of and owning stock/stock options for Healthmine Services, and serving as a consultant and owning stock/stock options for Catalyst Health LLC. The authors declare no conflict of interest.

Recent efforts to reduce waste and overuse in healthcare include reforms, such as merit-based physician reimbursement for efficient resource use¹ and the inclusion of cost-effective care as a competency for physician trainees.² Focusing on resource use in physician training and reimbursement presumes that teaching and feedback about utilization can alter physician behavior. Early studies of social comparison feedback observed considerable variation in effectiveness, depending on the behavior targeted and how feedback was provided to physicians.^3-5 The widespread adoption of electronic medical record (EMR) software enables the design of feedback interventions that provide continuous feedback in real-time via EMR-based practice dashboards. Currently, little is known about physician engagement with practice dashboards and, in particular, about trainee engagement with dashboards aimed to improve cost-effective care.

To inform future efforts in using social comparison feedback to teach cost-effective care in residency, we measured internal medicine resident engagement with an EMR-based utilization dashboard that provides feedback on their use of routine laboratory tests on an inpatient medicine service. Routine labs are often overused in the inpatient setting. In fact, one study reported that 68% of laboratory tests ordered in an academic hospital did not contribute to improving patient outcomes.⁶ To understand resident perceptions of the dashboards and identify barriers to their use, we conducted a mixed methods study tracking resident utilization of the dashboard over time and collecting qualitative data from 3 focus groups about resident attitudes toward the dashboards.

From January 2016 to June 2016, resident-specific rates of routine lab orders (eg, complete blood count, basic metabolic panel, complete metabolic panel, liver function panel, and common coagulation tests) were synthesized continuously in a web-based dashboard. Laboratory orders could be placed either individually on a day-to-day basis or ordered on a recurrent basis (eg, daily morning labs ordered on admission). The dashboard contained an interactive graph, which plotted the average number of labs per patient-day ordered by each resident over the past week, along with an overall graph for all services for comparison (Appendix Figure). Residents could click on an individual day on the graph to review the labs they ordered for each patient. The dashboard also allowed the user to look up each patient’s medical record to obtain more detailed information.

All residents received an e-mail describing the study, including the purpose of the intervention, basic description of the feedback intervention (dashboard and e-mail), potential risks and benefits, duration and scope of data collection, and contact information of the principal investigator. One hundred and ninety-eight resident-blocks on 6 general medicine services at the Hospital of the University of Pennsylvania were cluster-randomized with an equal probability to 1 of 2 arms: (1) those e-mailed a snapshot of the personalized dashboard, a link to the online dashboard, and text containing resident and service utilization averages, and (2) those who did not receive the feedback intervention. Postgraduate year (PGY) 1 residents were attributed only orders by that resident. PGY2 and PGY3 residents were attributed orders for all patients assigned to the resident’s team.

The initial e-mails were timed to arrive in the middle of each resident’s 2-week service to allow for a baseline and follow-up period. The e-mail contained an attachment of a snapshot of the personalized graphic dashboard (Appendix Figure), a link to the online dashboard, and a few sentences summarizing the resident utilization average compared to the general medicine service overall, for the same time interval. They were followed by a reminder e-mail 24 hours later containing only the link to the report card. We measured resident engagement with the utilization dashboard by using e-mail read-receipts and a web-based tracking platform that recorded when the dashboard was opened and who logged on.

Following completion of the intervention, 3-hour-long focus groups were conducted with residents. These focus groups were guided with prescripted questions to prompt discussion on the advantages and drawbacks of the study intervention and the usage of dashboards in general. These sessions were digitally recorded and transcribed. The transcripts were reviewed by 2 authors (KR and GK) and analyzed to identify common themes by using a grounded theory approach.⁷ First, the transcripts were reviewed independently by each author, who each generated a broad list of themes across 3 domains: dashboard usability, barriers to use, and suggestions for the future. Next, the codebook was refined through an iterative series of discussions and transcript review, resulting in a unified codebook. Lastly, all transcripts were reviewed by using the final codebook definitions, resulting in a list of exemplary quotes and suggestions.

The study was approved by the University of Pennsylvania Institutional Review Board and registered on clinicaltrials.gov (NCT02330289).

Eighty unique residents participated in the intervention, including 51 PGY1s (64%) and 29 PGY2- or PGY3-level (36%) residents. Of these, 19/80 (24%) physicians participated more than once. 74% of participants opened the e-mail and 21% opened the link to the dashboard. The average elapsed time from receiving the initial e-mail to logging into the dashboard was 28.5 hours (standard deviation [SD] = 25.7, median = 25.5, interquartile range [IQR] = 40.5). On average, residents deviated from the service mean by 0.54 laboratory test orders (SD = 0.49, median = 0.40, IQR = 0.60). The mean baseline rate of targeted labs was 1.30 (SD 1.77) labs per physician per patient-day.⁸

Overall, the engagement rates of internal medicine trainees with the online dashboard were low. Most residents did open the e-mails containing the link and basic information about their utilization rates, but less than a quarter of them accessed the dashboard containing real-time data. Additionally, on average, it took them more than a day to do so. However, there is some indication that residents who deviated further from the mean in either direction, which was described in the body of the e-mail, were more motivated to investigate further and click the link to access the dashboard. This suggests that providing practice feedback in this manner may be effective for a subset of residents who deviate from the “typical practice,” and as such, dashboards may represent a potential educational tool that could be aligned with practice-based learning competencies.

The focus groups provided important context about residents’ attitudes toward EMR-based dashboards. Overall, residents were enthusiastic about receiving information regarding their personal laboratory ordering, both in terms of preventing iatrogenic harm and waste of resources. This supports previous research that found that both medical students and residents overwhelmingly believe that the overuse of labs is a problem and that there may be insufficient focus on cost-conscious care during training.^9,10 However, many residents questioned several aspects of the specific intervention used in this study and suggested that significant improvements would need to be made to future dashboards to increase their utility.

To our knowledge, this is the first attempt to evaluate resident engagement and attitudes toward receiving practice-based feedback via an EMR-based online dashboard. Previous efforts to influence resident laboratory ordering behavior have primarily focused on didactic sessions, financial incentives, price transparency, and repeated e-mail messaging containing summary statistics about ordering practices and peer comparisons.^11-14 While some prior studies observed success in decreasing unnecessary use of laboratory tests, such efforts are challenging to implement routinely on a teaching service with multiple rotating providers and may be difficult to replicate. Future iterations of dashboards that incorporate focused curriculum design and active participation of teaching attendings require further study.

This study has several limitations. The sample size of physicians is relatively small and consists of residents at a single institution. This may limit the generalizability of the results. Additionally, the dashboard captured laboratory-ordering rates during a 2-week block on an inpatient medicine service and was not adjusted for factors such as patient case mix. However, the rates were adjusted for patient volume. In future iterations of utilization dashboards, residents’ concerns about small sample size and variability in clinical severity could be addressed through the adoption of risk-adjustment methodologies to balance out patient burden. This could be accomplished using currently available EMR data, such as diagnosis related groups or diagnoses codes to adjust for clinical complexity or report expected length of stay as a surrogate indicator of complexity.

Because residents are expected to be responsive to feedback, their use of the dashboards may represent an upper bound on physician responsiveness to social comparison feedback regarding utilization. However, e-mails alone may not be an effective way to provide feedback in areas that require additional engagement by the learner, especially given the volume of e-mails and alerts physicians receive. Future efforts to improve care efficiency may try to better capture baseline ordering rates, follow resident ordering over a longer period of time, encourage hospital staff to review utilization information with trainees, integrate dashboard information into regular performance reviews by the attendings, and provide more concrete feedback from attendings or senior residents for how this information can be used to adjust behavior.

Disclosure

Dr. Ryskina’s work on this study was supported by the Ruth L. Kirschstein National Research Service Award (T32-HP10026) and the NIA Career Development Award (K08AG052572). Dr. Patel reports board membership on the advisory board of and owning stock/stock options for Healthmine Services, and serving as a consultant and owning stock/stock options for Catalyst Health LLC. The authors declare no conflict of interest.

Recent efforts to reduce waste and overuse in healthcare include reforms, such as merit-based physician reimbursement for efficient resource use¹ and the inclusion of cost-effective care as a competency for physician trainees.² Focusing on resource use in physician training and reimbursement presumes that teaching and feedback about utilization can alter physician behavior. Early studies of social comparison feedback observed considerable variation in effectiveness, depending on the behavior targeted and how feedback was provided to physicians.^3-5 The widespread adoption of electronic medical record (EMR) software enables the design of feedback interventions that provide continuous feedback in real-time via EMR-based practice dashboards. Currently, little is known about physician engagement with practice dashboards and, in particular, about trainee engagement with dashboards aimed to improve cost-effective care.

To inform future efforts in using social comparison feedback to teach cost-effective care in residency, we measured internal medicine resident engagement with an EMR-based utilization dashboard that provides feedback on their use of routine laboratory tests on an inpatient medicine service. Routine labs are often overused in the inpatient setting. In fact, one study reported that 68% of laboratory tests ordered in an academic hospital did not contribute to improving patient outcomes.⁶ To understand resident perceptions of the dashboards and identify barriers to their use, we conducted a mixed methods study tracking resident utilization of the dashboard over time and collecting qualitative data from 3 focus groups about resident attitudes toward the dashboards.

From January 2016 to June 2016, resident-specific rates of routine lab orders (eg, complete blood count, basic metabolic panel, complete metabolic panel, liver function panel, and common coagulation tests) were synthesized continuously in a web-based dashboard. Laboratory orders could be placed either individually on a day-to-day basis or ordered on a recurrent basis (eg, daily morning labs ordered on admission). The dashboard contained an interactive graph, which plotted the average number of labs per patient-day ordered by each resident over the past week, along with an overall graph for all services for comparison (Appendix Figure). Residents could click on an individual day on the graph to review the labs they ordered for each patient. The dashboard also allowed the user to look up each patient’s medical record to obtain more detailed information.

All residents received an e-mail describing the study, including the purpose of the intervention, basic description of the feedback intervention (dashboard and e-mail), potential risks and benefits, duration and scope of data collection, and contact information of the principal investigator. One hundred and ninety-eight resident-blocks on 6 general medicine services at the Hospital of the University of Pennsylvania were cluster-randomized with an equal probability to 1 of 2 arms: (1) those e-mailed a snapshot of the personalized dashboard, a link to the online dashboard, and text containing resident and service utilization averages, and (2) those who did not receive the feedback intervention. Postgraduate year (PGY) 1 residents were attributed only orders by that resident. PGY2 and PGY3 residents were attributed orders for all patients assigned to the resident’s team.

The initial e-mails were timed to arrive in the middle of each resident’s 2-week service to allow for a baseline and follow-up period. The e-mail contained an attachment of a snapshot of the personalized graphic dashboard (Appendix Figure), a link to the online dashboard, and a few sentences summarizing the resident utilization average compared to the general medicine service overall, for the same time interval. They were followed by a reminder e-mail 24 hours later containing only the link to the report card. We measured resident engagement with the utilization dashboard by using e-mail read-receipts and a web-based tracking platform that recorded when the dashboard was opened and who logged on.

Following completion of the intervention, 3-hour-long focus groups were conducted with residents. These focus groups were guided with prescripted questions to prompt discussion on the advantages and drawbacks of the study intervention and the usage of dashboards in general. These sessions were digitally recorded and transcribed. The transcripts were reviewed by 2 authors (KR and GK) and analyzed to identify common themes by using a grounded theory approach.⁷ First, the transcripts were reviewed independently by each author, who each generated a broad list of themes across 3 domains: dashboard usability, barriers to use, and suggestions for the future. Next, the codebook was refined through an iterative series of discussions and transcript review, resulting in a unified codebook. Lastly, all transcripts were reviewed by using the final codebook definitions, resulting in a list of exemplary quotes and suggestions.

The study was approved by the University of Pennsylvania Institutional Review Board and registered on clinicaltrials.gov (NCT02330289).

Eighty unique residents participated in the intervention, including 51 PGY1s (64%) and 29 PGY2- or PGY3-level (36%) residents. Of these, 19/80 (24%) physicians participated more than once. 74% of participants opened the e-mail and 21% opened the link to the dashboard. The average elapsed time from receiving the initial e-mail to logging into the dashboard was 28.5 hours (standard deviation [SD] = 25.7, median = 25.5, interquartile range [IQR] = 40.5). On average, residents deviated from the service mean by 0.54 laboratory test orders (SD = 0.49, median = 0.40, IQR = 0.60). The mean baseline rate of targeted labs was 1.30 (SD 1.77) labs per physician per patient-day.⁸

Overall, the engagement rates of internal medicine trainees with the online dashboard were low. Most residents did open the e-mails containing the link and basic information about their utilization rates, but less than a quarter of them accessed the dashboard containing real-time data. Additionally, on average, it took them more than a day to do so. However, there is some indication that residents who deviated further from the mean in either direction, which was described in the body of the e-mail, were more motivated to investigate further and click the link to access the dashboard. This suggests that providing practice feedback in this manner may be effective for a subset of residents who deviate from the “typical practice,” and as such, dashboards may represent a potential educational tool that could be aligned with practice-based learning competencies.

The focus groups provided important context about residents’ attitudes toward EMR-based dashboards. Overall, residents were enthusiastic about receiving information regarding their personal laboratory ordering, both in terms of preventing iatrogenic harm and waste of resources. This supports previous research that found that both medical students and residents overwhelmingly believe that the overuse of labs is a problem and that there may be insufficient focus on cost-conscious care during training.^9,10 However, many residents questioned several aspects of the specific intervention used in this study and suggested that significant improvements would need to be made to future dashboards to increase their utility.

To our knowledge, this is the first attempt to evaluate resident engagement and attitudes toward receiving practice-based feedback via an EMR-based online dashboard. Previous efforts to influence resident laboratory ordering behavior have primarily focused on didactic sessions, financial incentives, price transparency, and repeated e-mail messaging containing summary statistics about ordering practices and peer comparisons.^11-14 While some prior studies observed success in decreasing unnecessary use of laboratory tests, such efforts are challenging to implement routinely on a teaching service with multiple rotating providers and may be difficult to replicate. Future iterations of dashboards that incorporate focused curriculum design and active participation of teaching attendings require further study.

This study has several limitations. The sample size of physicians is relatively small and consists of residents at a single institution. This may limit the generalizability of the results. Additionally, the dashboard captured laboratory-ordering rates during a 2-week block on an inpatient medicine service and was not adjusted for factors such as patient case mix. However, the rates were adjusted for patient volume. In future iterations of utilization dashboards, residents’ concerns about small sample size and variability in clinical severity could be addressed through the adoption of risk-adjustment methodologies to balance out patient burden. This could be accomplished using currently available EMR data, such as diagnosis related groups or diagnoses codes to adjust for clinical complexity or report expected length of stay as a surrogate indicator of complexity.

Because residents are expected to be responsive to feedback, their use of the dashboards may represent an upper bound on physician responsiveness to social comparison feedback regarding utilization. However, e-mails alone may not be an effective way to provide feedback in areas that require additional engagement by the learner, especially given the volume of e-mails and alerts physicians receive. Future efforts to improve care efficiency may try to better capture baseline ordering rates, follow resident ordering over a longer period of time, encourage hospital staff to review utilization information with trainees, integrate dashboard information into regular performance reviews by the attendings, and provide more concrete feedback from attendings or senior residents for how this information can be used to adjust behavior.

Disclosure

Dr. Ryskina’s work on this study was supported by the Ruth L. Kirschstein National Research Service Award (T32-HP10026) and the NIA Career Development Award (K08AG052572). Dr. Patel reports board membership on the advisory board of and owning stock/stock options for Healthmine Services, and serving as a consultant and owning stock/stock options for Catalyst Health LLC. The authors declare no conflict of interest.

Critical care physicians frequently find themselves providing care that they find to be futile or inappropriate for hospitalized critically ill patients. A survey of physicians found that 87% felt that “futile” treatment was provided in their intensive care unit (ICU) in the past year.¹ In a single-day cross-sectional study, 27% of ICU clinicians reported providing inappropriate care to at least 1 patient, most of which was excessive.² In a 3-month study, 11% of all ICU patients were perceived by their physician as receiving futile treatment at some point during their ICU hospitalization.³ Given that more than 1 in 5 decedents die after an ICU stay during a terminal admission, there is increasing scrutiny of the ICU as a setting where potentially inappropriate resource-intensive treatment is provided.^4-6 Blood is an especially valuable resource, not only because it exists in finite supply (and is sometimes in shortage) but also because it is donated in ways that arguably create special stewardship expectations and responsibilities for those trusted to make decisions about its use. The amount of blood products used for patients who are perceived to be receiving inappropriate critical care has not been quantified.

Blood transfusion is the most frequently performed inpatient procedure, occurring in more than 10% of hospital admissions that involve a procedure.⁷ When used appropriately, the transfusion of blood products can be lifesaving; however, studies show that some transfused blood might not be needed and efforts are afoot to improve the match between transfusion and transfusion need.^8,9 These efforts largely focus on generating guidelines based on physiologic benefit and aim mainly at promoting a restrictive transfusion protocol by avoiding blood product use for patients who will likely do well even without transfusion.^8,10-12 The guiding principle behind efforts to improve the stewardship of scarce blood products is that they should only be used if they will make a difference in patient outcomes. Unlike prior studies, the goal of this study is to quantify the amount of blood products administered to patients who would do poorly with or without receipt of blood products, that is, patients perceived by their physicians as receiving futile critical care.

Based on a focus group discussion with physicians who cared for critically ill patients, a questionnaire was developed to identify patients perceived as receiving futile critical care. Details of the definition of futile treatment and the core data collection are described in detail elsewhere.³

For each ICU patient under the physician’s care, the attending physician completed a daily questionnaire asking whether the patient was receiving futile treatment, probably futile treatment, or nonfutile treatment. These surveys were administered every day from December 15, 2011, through March 15, 2012, to each critical care specialist providing care in 5 ICUs (medical ICU, neurocritical care ICU, cardiac care unit, cardiothoracic ICU, and a mixed medical-surgical ICU) in 1 academic health system. All clinicians provided informed consent.

Patients were categorized into the following 3 groups: patients for whom treatment was never perceived as futile; patients with at least 1 assessment that treatment was probably futile, but no futile treatment assessments; and patients who had at least 1 assessment of futile treatment. Hospital and 6-month mortality was abstracted for all patients.

The Division of Transfusion Medicine provided a database of all adult patients during the 3-month study period who received a transfusion of packed red blood cells (PRBCs), apheresis platelets, plasma, or cryoprecipitate (5 unit prepooled units). This database was merged with the daily assessments of the appropriateness of critical care. To determine the proportion of blood products that was utilized for patients receiving inappropriate treatment, we tallied the blood products infused to these patients after the day the patient was assessed as receiving probably inappropriate or inappropriate treatment. The denominator was the total amount of blood products used by all assessed patients during the 3-month study period.

This study was approved by the University of California Los Angeles Institutional Review Board.

During the 3-month study period, 36 critical care clinicians in 5 ICUs provided care to 1193 adult patients. After excluding boarders in the ICUs and missed and invalid assessments, 6916 assessments were made on 1136 patients. Of these 1136 patients, 98 (8.6%) patients received probably futile treatment and 123 (11%) patients received futile treatment according to the physicians caring for them.

For patients who were never rated as receiving futile treatment, the in-hospital mortality was 4.6% and the 6-month mortality was 7.3%. On the contrary, 68% of the patients who were perceived to receive futile ICU treatment died before hospital discharge and 85% died within 6 months; survivors remained in severely compromised health states.³

Blood and blood products are donated resources. These biological products are altruistically given with the expectation that they will be used to benefit others.¹³ It is the clinicians’ responsibility to use these precious gifts to achieve the goals of medicine, which include curing, preserving function, and preventing clinical deterioration that has meaning to the patient. Our study shows that a small, but not insignificant, proportion of these donated resources are provided to hospitalized patients who are perceived as receiving futile critical care. That means that these transfusions are used as part of the critical care interventions that prolong the dying process and achieve outcomes, such as existence in coma, which few, if any, patients would desire. However, it should be noted that some of the health states preserved, such as neurological devastation or multi-organ failure with an inability to survive outside an ICU, were likely desired by patients’ families and might even have been desired by patients themselves. Whether blood donors would wish to donate blood to preserve life in such compromised health states is testable. This proportion of blood provided to ICU patients perceived as receiving futile treatment (7.6%) is similar to or greater than that lost due to wastage, which ranges from 0.1% to 6.7%.¹⁴ While the loss of this small proportion of blood products due to expiration or procedural issues is probably unavoidable, but should be minimized as much as possible, the provision of blood products to patients receiving futile critical care is under the control of the healthcare team. This raises the question of how altruistic blood donors would feel about donating if they were aware that 1 of every 13 units transfused in the ICU would be given to a patient that the physician feels will not benefit. In turn, it raises the question of whether the physician should refrain from using these blood products for patients who will not benefit in accordance with principles of evidence-based medicine, in order to ensure their availability for patients that will benefit.

This study has several limitations. Family/patient perspectives were not included in the assessment of futile treatment. It should also be recognized that the percentage of blood products provided to patients receiving inappropriate critical care is likely an underestimate as only blood product use during the 3-month study period was included, as many of these patients were admitted to the ICU prior the study period, and/or remained in the ICU or hospital after this window.

Similar to other treatments provided to patients who are perceived to receive futile critical care, blood products represent a healthcare resource that has the potential to be used without achieving the goals of medicine. But unlike many other medical treatments, the ability to maintain an adequate blood supply for transfusion relies on altruistic blood donors, individuals who are simply motivated by a desire to achieve a healthcare good.¹³ Explicit guidelines on the use of blood products should be developed to ensure that the use of this precious resource achieves meaningful goals. These goals need to be transparently defined such that a physician’s decision to not transfuse is expected as part of evidence-based medicine. Empiric research, educational interventions, and clearly delineated conflict-resolution processes may improve clinicians’ ability to handle these difficult cases.¹⁵

Disclosure

T. Neville was supported by the UCLA CTSI KL2 UL1TR000124, the NIH-NIA 1K23AG047900 - 01A1, and the NIH Loan Repayment Program grant. This project was supported by a donation from Mary Kay Farley to RAND Health. The funder played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The authors have no conflicts of interest to disclose.

Critical care physicians frequently find themselves providing care that they find to be futile or inappropriate for hospitalized critically ill patients. A survey of physicians found that 87% felt that “futile” treatment was provided in their intensive care unit (ICU) in the past year.¹ In a single-day cross-sectional study, 27% of ICU clinicians reported providing inappropriate care to at least 1 patient, most of which was excessive.² In a 3-month study, 11% of all ICU patients were perceived by their physician as receiving futile treatment at some point during their ICU hospitalization.³ Given that more than 1 in 5 decedents die after an ICU stay during a terminal admission, there is increasing scrutiny of the ICU as a setting where potentially inappropriate resource-intensive treatment is provided.^4-6 Blood is an especially valuable resource, not only because it exists in finite supply (and is sometimes in shortage) but also because it is donated in ways that arguably create special stewardship expectations and responsibilities for those trusted to make decisions about its use. The amount of blood products used for patients who are perceived to be receiving inappropriate critical care has not been quantified.

Blood transfusion is the most frequently performed inpatient procedure, occurring in more than 10% of hospital admissions that involve a procedure.⁷ When used appropriately, the transfusion of blood products can be lifesaving; however, studies show that some transfused blood might not be needed and efforts are afoot to improve the match between transfusion and transfusion need.^8,9 These efforts largely focus on generating guidelines based on physiologic benefit and aim mainly at promoting a restrictive transfusion protocol by avoiding blood product use for patients who will likely do well even without transfusion.^8,10-12 The guiding principle behind efforts to improve the stewardship of scarce blood products is that they should only be used if they will make a difference in patient outcomes. Unlike prior studies, the goal of this study is to quantify the amount of blood products administered to patients who would do poorly with or without receipt of blood products, that is, patients perceived by their physicians as receiving futile critical care.

Based on a focus group discussion with physicians who cared for critically ill patients, a questionnaire was developed to identify patients perceived as receiving futile critical care. Details of the definition of futile treatment and the core data collection are described in detail elsewhere.³

For each ICU patient under the physician’s care, the attending physician completed a daily questionnaire asking whether the patient was receiving futile treatment, probably futile treatment, or nonfutile treatment. These surveys were administered every day from December 15, 2011, through March 15, 2012, to each critical care specialist providing care in 5 ICUs (medical ICU, neurocritical care ICU, cardiac care unit, cardiothoracic ICU, and a mixed medical-surgical ICU) in 1 academic health system. All clinicians provided informed consent.

Patients were categorized into the following 3 groups: patients for whom treatment was never perceived as futile; patients with at least 1 assessment that treatment was probably futile, but no futile treatment assessments; and patients who had at least 1 assessment of futile treatment. Hospital and 6-month mortality was abstracted for all patients.

The Division of Transfusion Medicine provided a database of all adult patients during the 3-month study period who received a transfusion of packed red blood cells (PRBCs), apheresis platelets, plasma, or cryoprecipitate (5 unit prepooled units). This database was merged with the daily assessments of the appropriateness of critical care. To determine the proportion of blood products that was utilized for patients receiving inappropriate treatment, we tallied the blood products infused to these patients after the day the patient was assessed as receiving probably inappropriate or inappropriate treatment. The denominator was the total amount of blood products used by all assessed patients during the 3-month study period.

This study was approved by the University of California Los Angeles Institutional Review Board.

During the 3-month study period, 36 critical care clinicians in 5 ICUs provided care to 1193 adult patients. After excluding boarders in the ICUs and missed and invalid assessments, 6916 assessments were made on 1136 patients. Of these 1136 patients, 98 (8.6%) patients received probably futile treatment and 123 (11%) patients received futile treatment according to the physicians caring for them.

For patients who were never rated as receiving futile treatment, the in-hospital mortality was 4.6% and the 6-month mortality was 7.3%. On the contrary, 68% of the patients who were perceived to receive futile ICU treatment died before hospital discharge and 85% died within 6 months; survivors remained in severely compromised health states.³

Blood and blood products are donated resources. These biological products are altruistically given with the expectation that they will be used to benefit others.¹³ It is the clinicians’ responsibility to use these precious gifts to achieve the goals of medicine, which include curing, preserving function, and preventing clinical deterioration that has meaning to the patient. Our study shows that a small, but not insignificant, proportion of these donated resources are provided to hospitalized patients who are perceived as receiving futile critical care. That means that these transfusions are used as part of the critical care interventions that prolong the dying process and achieve outcomes, such as existence in coma, which few, if any, patients would desire. However, it should be noted that some of the health states preserved, such as neurological devastation or multi-organ failure with an inability to survive outside an ICU, were likely desired by patients’ families and might even have been desired by patients themselves. Whether blood donors would wish to donate blood to preserve life in such compromised health states is testable. This proportion of blood provided to ICU patients perceived as receiving futile treatment (7.6%) is similar to or greater than that lost due to wastage, which ranges from 0.1% to 6.7%.¹⁴ While the loss of this small proportion of blood products due to expiration or procedural issues is probably unavoidable, but should be minimized as much as possible, the provision of blood products to patients receiving futile critical care is under the control of the healthcare team. This raises the question of how altruistic blood donors would feel about donating if they were aware that 1 of every 13 units transfused in the ICU would be given to a patient that the physician feels will not benefit. In turn, it raises the question of whether the physician should refrain from using these blood products for patients who will not benefit in accordance with principles of evidence-based medicine, in order to ensure their availability for patients that will benefit.

This study has several limitations. Family/patient perspectives were not included in the assessment of futile treatment. It should also be recognized that the percentage of blood products provided to patients receiving inappropriate critical care is likely an underestimate as only blood product use during the 3-month study period was included, as many of these patients were admitted to the ICU prior the study period, and/or remained in the ICU or hospital after this window.

Similar to other treatments provided to patients who are perceived to receive futile critical care, blood products represent a healthcare resource that has the potential to be used without achieving the goals of medicine. But unlike many other medical treatments, the ability to maintain an adequate blood supply for transfusion relies on altruistic blood donors, individuals who are simply motivated by a desire to achieve a healthcare good.¹³ Explicit guidelines on the use of blood products should be developed to ensure that the use of this precious resource achieves meaningful goals. These goals need to be transparently defined such that a physician’s decision to not transfuse is expected as part of evidence-based medicine. Empiric research, educational interventions, and clearly delineated conflict-resolution processes may improve clinicians’ ability to handle these difficult cases.¹⁵

Disclosure

T. Neville was supported by the UCLA CTSI KL2 UL1TR000124, the NIH-NIA 1K23AG047900 - 01A1, and the NIH Loan Repayment Program grant. This project was supported by a donation from Mary Kay Farley to RAND Health. The funder played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The authors have no conflicts of interest to disclose.

Critical care physicians frequently find themselves providing care that they find to be futile or inappropriate for hospitalized critically ill patients. A survey of physicians found that 87% felt that “futile” treatment was provided in their intensive care unit (ICU) in the past year.¹ In a single-day cross-sectional study, 27% of ICU clinicians reported providing inappropriate care to at least 1 patient, most of which was excessive.² In a 3-month study, 11% of all ICU patients were perceived by their physician as receiving futile treatment at some point during their ICU hospitalization.³ Given that more than 1 in 5 decedents die after an ICU stay during a terminal admission, there is increasing scrutiny of the ICU as a setting where potentially inappropriate resource-intensive treatment is provided.^4-6 Blood is an especially valuable resource, not only because it exists in finite supply (and is sometimes in shortage) but also because it is donated in ways that arguably create special stewardship expectations and responsibilities for those trusted to make decisions about its use. The amount of blood products used for patients who are perceived to be receiving inappropriate critical care has not been quantified.

Blood transfusion is the most frequently performed inpatient procedure, occurring in more than 10% of hospital admissions that involve a procedure.⁷ When used appropriately, the transfusion of blood products can be lifesaving; however, studies show that some transfused blood might not be needed and efforts are afoot to improve the match between transfusion and transfusion need.^8,9 These efforts largely focus on generating guidelines based on physiologic benefit and aim mainly at promoting a restrictive transfusion protocol by avoiding blood product use for patients who will likely do well even without transfusion.^8,10-12 The guiding principle behind efforts to improve the stewardship of scarce blood products is that they should only be used if they will make a difference in patient outcomes. Unlike prior studies, the goal of this study is to quantify the amount of blood products administered to patients who would do poorly with or without receipt of blood products, that is, patients perceived by their physicians as receiving futile critical care.

Based on a focus group discussion with physicians who cared for critically ill patients, a questionnaire was developed to identify patients perceived as receiving futile critical care. Details of the definition of futile treatment and the core data collection are described in detail elsewhere.³

For each ICU patient under the physician’s care, the attending physician completed a daily questionnaire asking whether the patient was receiving futile treatment, probably futile treatment, or nonfutile treatment. These surveys were administered every day from December 15, 2011, through March 15, 2012, to each critical care specialist providing care in 5 ICUs (medical ICU, neurocritical care ICU, cardiac care unit, cardiothoracic ICU, and a mixed medical-surgical ICU) in 1 academic health system. All clinicians provided informed consent.

Patients were categorized into the following 3 groups: patients for whom treatment was never perceived as futile; patients with at least 1 assessment that treatment was probably futile, but no futile treatment assessments; and patients who had at least 1 assessment of futile treatment. Hospital and 6-month mortality was abstracted for all patients.

The Division of Transfusion Medicine provided a database of all adult patients during the 3-month study period who received a transfusion of packed red blood cells (PRBCs), apheresis platelets, plasma, or cryoprecipitate (5 unit prepooled units). This database was merged with the daily assessments of the appropriateness of critical care. To determine the proportion of blood products that was utilized for patients receiving inappropriate treatment, we tallied the blood products infused to these patients after the day the patient was assessed as receiving probably inappropriate or inappropriate treatment. The denominator was the total amount of blood products used by all assessed patients during the 3-month study period.

This study was approved by the University of California Los Angeles Institutional Review Board.

During the 3-month study period, 36 critical care clinicians in 5 ICUs provided care to 1193 adult patients. After excluding boarders in the ICUs and missed and invalid assessments, 6916 assessments were made on 1136 patients. Of these 1136 patients, 98 (8.6%) patients received probably futile treatment and 123 (11%) patients received futile treatment according to the physicians caring for them.

For patients who were never rated as receiving futile treatment, the in-hospital mortality was 4.6% and the 6-month mortality was 7.3%. On the contrary, 68% of the patients who were perceived to receive futile ICU treatment died before hospital discharge and 85% died within 6 months; survivors remained in severely compromised health states.³

Blood and blood products are donated resources. These biological products are altruistically given with the expectation that they will be used to benefit others.¹³ It is the clinicians’ responsibility to use these precious gifts to achieve the goals of medicine, which include curing, preserving function, and preventing clinical deterioration that has meaning to the patient. Our study shows that a small, but not insignificant, proportion of these donated resources are provided to hospitalized patients who are perceived as receiving futile critical care. That means that these transfusions are used as part of the critical care interventions that prolong the dying process and achieve outcomes, such as existence in coma, which few, if any, patients would desire. However, it should be noted that some of the health states preserved, such as neurological devastation or multi-organ failure with an inability to survive outside an ICU, were likely desired by patients’ families and might even have been desired by patients themselves. Whether blood donors would wish to donate blood to preserve life in such compromised health states is testable. This proportion of blood provided to ICU patients perceived as receiving futile treatment (7.6%) is similar to or greater than that lost due to wastage, which ranges from 0.1% to 6.7%.¹⁴ While the loss of this small proportion of blood products due to expiration or procedural issues is probably unavoidable, but should be minimized as much as possible, the provision of blood products to patients receiving futile critical care is under the control of the healthcare team. This raises the question of how altruistic blood donors would feel about donating if they were aware that 1 of every 13 units transfused in the ICU would be given to a patient that the physician feels will not benefit. In turn, it raises the question of whether the physician should refrain from using these blood products for patients who will not benefit in accordance with principles of evidence-based medicine, in order to ensure their availability for patients that will benefit.

This study has several limitations. Family/patient perspectives were not included in the assessment of futile treatment. It should also be recognized that the percentage of blood products provided to patients receiving inappropriate critical care is likely an underestimate as only blood product use during the 3-month study period was included, as many of these patients were admitted to the ICU prior the study period, and/or remained in the ICU or hospital after this window.

Similar to other treatments provided to patients who are perceived to receive futile critical care, blood products represent a healthcare resource that has the potential to be used without achieving the goals of medicine. But unlike many other medical treatments, the ability to maintain an adequate blood supply for transfusion relies on altruistic blood donors, individuals who are simply motivated by a desire to achieve a healthcare good.¹³ Explicit guidelines on the use of blood products should be developed to ensure that the use of this precious resource achieves meaningful goals. These goals need to be transparently defined such that a physician’s decision to not transfuse is expected as part of evidence-based medicine. Empiric research, educational interventions, and clearly delineated conflict-resolution processes may improve clinicians’ ability to handle these difficult cases.¹⁵

Disclosure

T. Neville was supported by the UCLA CTSI KL2 UL1TR000124, the NIH-NIA 1K23AG047900 - 01A1, and the NIH Loan Repayment Program grant. This project was supported by a donation from Mary Kay Farley to RAND Health. The funder played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The authors have no conflicts of interest to disclose.