The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

Prior healthcare utilization predicts future utilization;¹ thus, providers should know when a child has had a recent healthcare visit. Healthcare providers typically obtain this information from parents and caregivers, who may not always provide accurate information.^2-4

The Hospital to Home Outcomes study (H2O) was a randomized controlled trial conducted to assess the effects of a one-time home nurse visit following discharge on unplanned healthcare reutilization.⁵ We assessed reutilization through two sources: parent report via a postdischarge telephone call and administrative data. In this analysis, we sought to understand differences in reutilization rates by source by comparing parent report with administrative data.

The H2O trial included children (<18 years) hospitalized on the hospital medicine (HM) or neuroscience (Neurology/Neurosurgery) services at Cincinnati Children’s Hospital Medical Center (CCHMC) from February 2015 to April 2016; they had an English-speaking parent and were discharged to home without skilled nursing care.⁶ For this analysis, we restricted the sample to children randomized to the control arm (discharge without a home visit), which reflects typical clinical care.

We used administrative data to capture 14-day reutilization (unplanned hospital readmissions, emergency department [ED] visits, or urgent care visits). CCHMC is the only pediatric admitting facility in the region and includes two pediatric EDs and five urgent care centers. We supplemented hospital data with a dataset (The Health Collaborative⁷) that included utilization at other regional facilities. Parent report was assessed via a research coordinator phone call 14-23 days after discharge. Parents were asked: “I’m going to [ask] about your child’s health since [discharge date]. Has s/he been hospitalized overnight? Has s/he been taken to the Emergency Room/Emergency Department (didn’t stay overnight)? Has s/he been taken to an urgent care?” We report 14-day reutilization rates by source (parent and/or administrative) and visit type.

We considered administrative data the gold standard for documentation of reutilization events for two reasons. First, all healthcare encounters generate billing and are therefore documented with verifiable coding. Second, we had access to data from our center and other regional healthcare facilities. Any parent-reported utilization to a facility not documented in either dataset was considered an unverifiable event (eg, outside our catchment region). Agreement between administrative and parent report of 14-day reutilization was summarized as positive agreement (reutilization documented in both administrative and parent report), negative agreement (no reutilization reported in either administrative or parent report), and overall agreement (combination of positive and negative agreement). We classified discrepancies as reutilization events in administrative data without parent report of reutilization or vice versa. We performed medical record review of discrepancies in our institutional data.

We summarized agreement by using the Cohen’s kappa statistic by reuse type (hospital readmission, ED, and urgent care visit) and overall (any reutilization event). Strength of agreement based on the kappa statistics was classified as poor (<0.20), fair (0.21-0.40), moderate (0.41-0.60), good (0.61-0.80), and very good (0.81-1.00).⁸ We used McNemar’s test to evaluate marginal homogeneity.

Of 749 children randomized to the standard of care arm, 723 parents completed the 14-day follow-up call and were included in this analysis. The median child age was two years (interquartile range: 0.4, 6.9), the median length of stay (LOS) was two days (1, 3), and the majority were white (62%). Payer mix varied, with 44% privately insured and 54% publicly insured. Most patients (83%) were admitted to the HM service, and the most common diagnoses groups for index admission were respiratory (35%), neurologic (14%), and gastrointestinal (9%) diseases.

Administrative data showed 63 children with any reutilization event; parents reported 63 with any reutilization event; 48 children had events reported by both sources. The overall agreement was high, ranging from 95.9% to 98.5% (Table 1) depending on visit type. The positive agreement (ie, parent and administrative data indicated reutilization) ranged from 47.6% to 76.2%. Negative agreement (ie, parent and administrative data agreed no reutilization) was very high, 97.7% to 99.2%. Parents reported three ED visits and four urgent care visits that were unverifiable due to lack of access to administrative data (sites of care reported were not included in our datasets).

By comparing parent report of reutilization after hospital discharge through postdischarge phone calls with administrative data, we demonstrated high overall agreement between sources (95.9%); this finding is similar to prior research investigating the relationship between an established medical home and reutilization.⁹ However, this agreement is largely due to both sources reporting no reutilization. When revisits did occur, the agreement was notably lower, especially with regard to urgent care visits.

Discrepancies between sources have several possible explanations. First, parents may be confused by the framing of reutilization questions, perhaps lacking clarity around which visit we were referencing. Second, parents may experience limitations in health literacy^10,11 with a lack of familiarity with healthcare language, such as the ability to delineate location types (for example, a parent may identify an urgent care visit as an ED visit, given their close proximity at our facility). Finally, our prior work identified that the “fog” of hospitalization,¹² which is often a stressful and disruptive time for families, may linger after admission and could lead to difficulty in recalling detailed events.

Our findings have implications for effective care in a complex healthcare system where parent report may be the most practical method to obtain historical information, both within clinical care and in the context of research or quality measures, such as postdischarge utilization. Given that one of the greatest risk factors for readmission is prior utilization,¹ the knowledge that a patient experienced a reutilization after a prior discharge might prompt the inpatient provider to better prepare families for subsequent transition to home.

To apply our findings practically, it is important to realize that a parent report may be sufficient when reporting that no revisit occurred, if there is also no record of a visit in accessible administrative data (such as an electronic health record). However, further questions or investigation should be considered when parents report a visit did occur or when administrative data indicate a visit occurred that the parent does not recall. Providers and researchers alike should remember to use health literacy universal precautions with all families, employing plain language without medical jargon.¹³ As linked electronic health record use becomes more prevalent, administrative data may be accessible in real-time, allowing for verification of family interview information. Administrative data beyond a single hospital system should be considered to effectively capture reutilization for research or quality efforts.

Our study has several limitations. Similar to most studies using reutilization outcomes, our data may miss a few unverifiable reuse events. By supplementing with additional regional data,⁷ we likely captured most events. Second, we did not include patients with limited English proficiency, although it is unclear how this might have biased our results. Third, while relatively few families did not complete the calls, it is possible that more discrepancies would have been noted in nonresponders. Fourth, research coordinators administering the calls followed a script to determine reutilization information; in clinical practice, a practitioner might not ask questions as clearly, which could negatively impact recall or might add clarifying follow-up questions to enhance recall. Finally, the analysis occurred in the setting of a randomized controlled trial that included children with relatively noncomplex health conditions with short LOS;⁶ thus, the results may not apply to other populations.

In conclusion, parent report and administrative data of reutilization following hospital discharge were usually in agreement when no reutilization occurred; however, discrepancies were noted more often when reutilizations occurred and may have care implications.

Collaborators

On behalf of the H2O Trial study group including: Joanne Bachus, BSN, RN; Andrew F. Beck, MD, MPH; Monica L. Borell, BSN, RN; Lenisa V. Chang, MA, PhD; Patricia Crawford, RN; Jennifer M. Gold, MSN, RN; Judy A. Heilman BSN, RN; Jane C. Khoury, PhD; Pierce Kuhnell, MS; Karen Lawley, BSN, RN; Allison Loechtenfeldt, BS; Colleen Mangeot, MS; Lynn O’Donnell, BSN, RN; Rita H. Pickler, PhD, RN; Hadley S. Sauers-Ford, MPH; Anita N. Shah, DO, MPH; Susan N. Sherman, DPA; Lauren G. Solan, MD, MEd; Karen P. Sullivan, BSN, RN; Susan Wade-Murphy, MSN, RN

Disclosures

Hospital to Home Outcomes team reports grants from the Patient Centered Outcomes Research Institute during the conduct of the study. Dr. White reports personal fees from the Institute for Health Care Improvement, outside the submitted work.

Funding

This work was supported by the Patient Centered Outcomes Research Institute (IHS-1306-0081 to Dr. S. Shah). All statements in this report, including findings and conclusions, are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its Board of Governors, or the Methodology Committee. Dr Auger’s research is funded by the Agency for Healthcare Research and Quality (1K08HS024735).

Prior healthcare utilization predicts future utilization;¹ thus, providers should know when a child has had a recent healthcare visit. Healthcare providers typically obtain this information from parents and caregivers, who may not always provide accurate information.^2-4

The Hospital to Home Outcomes study (H2O) was a randomized controlled trial conducted to assess the effects of a one-time home nurse visit following discharge on unplanned healthcare reutilization.⁵ We assessed reutilization through two sources: parent report via a postdischarge telephone call and administrative data. In this analysis, we sought to understand differences in reutilization rates by source by comparing parent report with administrative data.

The H2O trial included children (<18 years) hospitalized on the hospital medicine (HM) or neuroscience (Neurology/Neurosurgery) services at Cincinnati Children’s Hospital Medical Center (CCHMC) from February 2015 to April 2016; they had an English-speaking parent and were discharged to home without skilled nursing care.⁶ For this analysis, we restricted the sample to children randomized to the control arm (discharge without a home visit), which reflects typical clinical care.

We used administrative data to capture 14-day reutilization (unplanned hospital readmissions, emergency department [ED] visits, or urgent care visits). CCHMC is the only pediatric admitting facility in the region and includes two pediatric EDs and five urgent care centers. We supplemented hospital data with a dataset (The Health Collaborative⁷) that included utilization at other regional facilities. Parent report was assessed via a research coordinator phone call 14-23 days after discharge. Parents were asked: “I’m going to [ask] about your child’s health since [discharge date]. Has s/he been hospitalized overnight? Has s/he been taken to the Emergency Room/Emergency Department (didn’t stay overnight)? Has s/he been taken to an urgent care?” We report 14-day reutilization rates by source (parent and/or administrative) and visit type.

We considered administrative data the gold standard for documentation of reutilization events for two reasons. First, all healthcare encounters generate billing and are therefore documented with verifiable coding. Second, we had access to data from our center and other regional healthcare facilities. Any parent-reported utilization to a facility not documented in either dataset was considered an unverifiable event (eg, outside our catchment region). Agreement between administrative and parent report of 14-day reutilization was summarized as positive agreement (reutilization documented in both administrative and parent report), negative agreement (no reutilization reported in either administrative or parent report), and overall agreement (combination of positive and negative agreement). We classified discrepancies as reutilization events in administrative data without parent report of reutilization or vice versa. We performed medical record review of discrepancies in our institutional data.

We summarized agreement by using the Cohen’s kappa statistic by reuse type (hospital readmission, ED, and urgent care visit) and overall (any reutilization event). Strength of agreement based on the kappa statistics was classified as poor (<0.20), fair (0.21-0.40), moderate (0.41-0.60), good (0.61-0.80), and very good (0.81-1.00).⁸ We used McNemar’s test to evaluate marginal homogeneity.

Of 749 children randomized to the standard of care arm, 723 parents completed the 14-day follow-up call and were included in this analysis. The median child age was two years (interquartile range: 0.4, 6.9), the median length of stay (LOS) was two days (1, 3), and the majority were white (62%). Payer mix varied, with 44% privately insured and 54% publicly insured. Most patients (83%) were admitted to the HM service, and the most common diagnoses groups for index admission were respiratory (35%), neurologic (14%), and gastrointestinal (9%) diseases.

Administrative data showed 63 children with any reutilization event; parents reported 63 with any reutilization event; 48 children had events reported by both sources. The overall agreement was high, ranging from 95.9% to 98.5% (Table 1) depending on visit type. The positive agreement (ie, parent and administrative data indicated reutilization) ranged from 47.6% to 76.2%. Negative agreement (ie, parent and administrative data agreed no reutilization) was very high, 97.7% to 99.2%. Parents reported three ED visits and four urgent care visits that were unverifiable due to lack of access to administrative data (sites of care reported were not included in our datasets).

By comparing parent report of reutilization after hospital discharge through postdischarge phone calls with administrative data, we demonstrated high overall agreement between sources (95.9%); this finding is similar to prior research investigating the relationship between an established medical home and reutilization.⁹ However, this agreement is largely due to both sources reporting no reutilization. When revisits did occur, the agreement was notably lower, especially with regard to urgent care visits.

Discrepancies between sources have several possible explanations. First, parents may be confused by the framing of reutilization questions, perhaps lacking clarity around which visit we were referencing. Second, parents may experience limitations in health literacy^10,11 with a lack of familiarity with healthcare language, such as the ability to delineate location types (for example, a parent may identify an urgent care visit as an ED visit, given their close proximity at our facility). Finally, our prior work identified that the “fog” of hospitalization,¹² which is often a stressful and disruptive time for families, may linger after admission and could lead to difficulty in recalling detailed events.

Our findings have implications for effective care in a complex healthcare system where parent report may be the most practical method to obtain historical information, both within clinical care and in the context of research or quality measures, such as postdischarge utilization. Given that one of the greatest risk factors for readmission is prior utilization,¹ the knowledge that a patient experienced a reutilization after a prior discharge might prompt the inpatient provider to better prepare families for subsequent transition to home.

To apply our findings practically, it is important to realize that a parent report may be sufficient when reporting that no revisit occurred, if there is also no record of a visit in accessible administrative data (such as an electronic health record). However, further questions or investigation should be considered when parents report a visit did occur or when administrative data indicate a visit occurred that the parent does not recall. Providers and researchers alike should remember to use health literacy universal precautions with all families, employing plain language without medical jargon.¹³ As linked electronic health record use becomes more prevalent, administrative data may be accessible in real-time, allowing for verification of family interview information. Administrative data beyond a single hospital system should be considered to effectively capture reutilization for research or quality efforts.

Our study has several limitations. Similar to most studies using reutilization outcomes, our data may miss a few unverifiable reuse events. By supplementing with additional regional data,⁷ we likely captured most events. Second, we did not include patients with limited English proficiency, although it is unclear how this might have biased our results. Third, while relatively few families did not complete the calls, it is possible that more discrepancies would have been noted in nonresponders. Fourth, research coordinators administering the calls followed a script to determine reutilization information; in clinical practice, a practitioner might not ask questions as clearly, which could negatively impact recall or might add clarifying follow-up questions to enhance recall. Finally, the analysis occurred in the setting of a randomized controlled trial that included children with relatively noncomplex health conditions with short LOS;⁶ thus, the results may not apply to other populations.

In conclusion, parent report and administrative data of reutilization following hospital discharge were usually in agreement when no reutilization occurred; however, discrepancies were noted more often when reutilizations occurred and may have care implications.

Collaborators

On behalf of the H2O Trial study group including: Joanne Bachus, BSN, RN; Andrew F. Beck, MD, MPH; Monica L. Borell, BSN, RN; Lenisa V. Chang, MA, PhD; Patricia Crawford, RN; Jennifer M. Gold, MSN, RN; Judy A. Heilman BSN, RN; Jane C. Khoury, PhD; Pierce Kuhnell, MS; Karen Lawley, BSN, RN; Allison Loechtenfeldt, BS; Colleen Mangeot, MS; Lynn O’Donnell, BSN, RN; Rita H. Pickler, PhD, RN; Hadley S. Sauers-Ford, MPH; Anita N. Shah, DO, MPH; Susan N. Sherman, DPA; Lauren G. Solan, MD, MEd; Karen P. Sullivan, BSN, RN; Susan Wade-Murphy, MSN, RN

Disclosures

Hospital to Home Outcomes team reports grants from the Patient Centered Outcomes Research Institute during the conduct of the study. Dr. White reports personal fees from the Institute for Health Care Improvement, outside the submitted work.

Funding

This work was supported by the Patient Centered Outcomes Research Institute (IHS-1306-0081 to Dr. S. Shah). All statements in this report, including findings and conclusions, are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its Board of Governors, or the Methodology Committee. Dr Auger’s research is funded by the Agency for Healthcare Research and Quality (1K08HS024735).

Prior healthcare utilization predicts future utilization;¹ thus, providers should know when a child has had a recent healthcare visit. Healthcare providers typically obtain this information from parents and caregivers, who may not always provide accurate information.^2-4

The Hospital to Home Outcomes study (H2O) was a randomized controlled trial conducted to assess the effects of a one-time home nurse visit following discharge on unplanned healthcare reutilization.⁵ We assessed reutilization through two sources: parent report via a postdischarge telephone call and administrative data. In this analysis, we sought to understand differences in reutilization rates by source by comparing parent report with administrative data.

The H2O trial included children (<18 years) hospitalized on the hospital medicine (HM) or neuroscience (Neurology/Neurosurgery) services at Cincinnati Children’s Hospital Medical Center (CCHMC) from February 2015 to April 2016; they had an English-speaking parent and were discharged to home without skilled nursing care.⁶ For this analysis, we restricted the sample to children randomized to the control arm (discharge without a home visit), which reflects typical clinical care.

We used administrative data to capture 14-day reutilization (unplanned hospital readmissions, emergency department [ED] visits, or urgent care visits). CCHMC is the only pediatric admitting facility in the region and includes two pediatric EDs and five urgent care centers. We supplemented hospital data with a dataset (The Health Collaborative⁷) that included utilization at other regional facilities. Parent report was assessed via a research coordinator phone call 14-23 days after discharge. Parents were asked: “I’m going to [ask] about your child’s health since [discharge date]. Has s/he been hospitalized overnight? Has s/he been taken to the Emergency Room/Emergency Department (didn’t stay overnight)? Has s/he been taken to an urgent care?” We report 14-day reutilization rates by source (parent and/or administrative) and visit type.

We considered administrative data the gold standard for documentation of reutilization events for two reasons. First, all healthcare encounters generate billing and are therefore documented with verifiable coding. Second, we had access to data from our center and other regional healthcare facilities. Any parent-reported utilization to a facility not documented in either dataset was considered an unverifiable event (eg, outside our catchment region). Agreement between administrative and parent report of 14-day reutilization was summarized as positive agreement (reutilization documented in both administrative and parent report), negative agreement (no reutilization reported in either administrative or parent report), and overall agreement (combination of positive and negative agreement). We classified discrepancies as reutilization events in administrative data without parent report of reutilization or vice versa. We performed medical record review of discrepancies in our institutional data.

We summarized agreement by using the Cohen’s kappa statistic by reuse type (hospital readmission, ED, and urgent care visit) and overall (any reutilization event). Strength of agreement based on the kappa statistics was classified as poor (<0.20), fair (0.21-0.40), moderate (0.41-0.60), good (0.61-0.80), and very good (0.81-1.00).⁸ We used McNemar’s test to evaluate marginal homogeneity.

Of 749 children randomized to the standard of care arm, 723 parents completed the 14-day follow-up call and were included in this analysis. The median child age was two years (interquartile range: 0.4, 6.9), the median length of stay (LOS) was two days (1, 3), and the majority were white (62%). Payer mix varied, with 44% privately insured and 54% publicly insured. Most patients (83%) were admitted to the HM service, and the most common diagnoses groups for index admission were respiratory (35%), neurologic (14%), and gastrointestinal (9%) diseases.

Administrative data showed 63 children with any reutilization event; parents reported 63 with any reutilization event; 48 children had events reported by both sources. The overall agreement was high, ranging from 95.9% to 98.5% (Table 1) depending on visit type. The positive agreement (ie, parent and administrative data indicated reutilization) ranged from 47.6% to 76.2%. Negative agreement (ie, parent and administrative data agreed no reutilization) was very high, 97.7% to 99.2%. Parents reported three ED visits and four urgent care visits that were unverifiable due to lack of access to administrative data (sites of care reported were not included in our datasets).

By comparing parent report of reutilization after hospital discharge through postdischarge phone calls with administrative data, we demonstrated high overall agreement between sources (95.9%); this finding is similar to prior research investigating the relationship between an established medical home and reutilization.⁹ However, this agreement is largely due to both sources reporting no reutilization. When revisits did occur, the agreement was notably lower, especially with regard to urgent care visits.

Discrepancies between sources have several possible explanations. First, parents may be confused by the framing of reutilization questions, perhaps lacking clarity around which visit we were referencing. Second, parents may experience limitations in health literacy^10,11 with a lack of familiarity with healthcare language, such as the ability to delineate location types (for example, a parent may identify an urgent care visit as an ED visit, given their close proximity at our facility). Finally, our prior work identified that the “fog” of hospitalization,¹² which is often a stressful and disruptive time for families, may linger after admission and could lead to difficulty in recalling detailed events.

Our findings have implications for effective care in a complex healthcare system where parent report may be the most practical method to obtain historical information, both within clinical care and in the context of research or quality measures, such as postdischarge utilization. Given that one of the greatest risk factors for readmission is prior utilization,¹ the knowledge that a patient experienced a reutilization after a prior discharge might prompt the inpatient provider to better prepare families for subsequent transition to home.

To apply our findings practically, it is important to realize that a parent report may be sufficient when reporting that no revisit occurred, if there is also no record of a visit in accessible administrative data (such as an electronic health record). However, further questions or investigation should be considered when parents report a visit did occur or when administrative data indicate a visit occurred that the parent does not recall. Providers and researchers alike should remember to use health literacy universal precautions with all families, employing plain language without medical jargon.¹³ As linked electronic health record use becomes more prevalent, administrative data may be accessible in real-time, allowing for verification of family interview information. Administrative data beyond a single hospital system should be considered to effectively capture reutilization for research or quality efforts.

Our study has several limitations. Similar to most studies using reutilization outcomes, our data may miss a few unverifiable reuse events. By supplementing with additional regional data,⁷ we likely captured most events. Second, we did not include patients with limited English proficiency, although it is unclear how this might have biased our results. Third, while relatively few families did not complete the calls, it is possible that more discrepancies would have been noted in nonresponders. Fourth, research coordinators administering the calls followed a script to determine reutilization information; in clinical practice, a practitioner might not ask questions as clearly, which could negatively impact recall or might add clarifying follow-up questions to enhance recall. Finally, the analysis occurred in the setting of a randomized controlled trial that included children with relatively noncomplex health conditions with short LOS;⁶ thus, the results may not apply to other populations.

In conclusion, parent report and administrative data of reutilization following hospital discharge were usually in agreement when no reutilization occurred; however, discrepancies were noted more often when reutilizations occurred and may have care implications.

Collaborators

On behalf of the H2O Trial study group including: Joanne Bachus, BSN, RN; Andrew F. Beck, MD, MPH; Monica L. Borell, BSN, RN; Lenisa V. Chang, MA, PhD; Patricia Crawford, RN; Jennifer M. Gold, MSN, RN; Judy A. Heilman BSN, RN; Jane C. Khoury, PhD; Pierce Kuhnell, MS; Karen Lawley, BSN, RN; Allison Loechtenfeldt, BS; Colleen Mangeot, MS; Lynn O’Donnell, BSN, RN; Rita H. Pickler, PhD, RN; Hadley S. Sauers-Ford, MPH; Anita N. Shah, DO, MPH; Susan N. Sherman, DPA; Lauren G. Solan, MD, MEd; Karen P. Sullivan, BSN, RN; Susan Wade-Murphy, MSN, RN

Disclosures

Hospital to Home Outcomes team reports grants from the Patient Centered Outcomes Research Institute during the conduct of the study. Dr. White reports personal fees from the Institute for Health Care Improvement, outside the submitted work.

Funding

This work was supported by the Patient Centered Outcomes Research Institute (IHS-1306-0081 to Dr. S. Shah). All statements in this report, including findings and conclusions, are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its Board of Governors, or the Methodology Committee. Dr Auger’s research is funded by the Agency for Healthcare Research and Quality (1K08HS024735).

Delirium presents as an acute change in mentation characterized by reduced attention, clouding of awareness, and typically an altered level of arousal. It can be caused by a host of medical conditions, medications, or other psychoactive substances and is therefore encountered primarily in acute and postacute medical settings.¹ More than a quarter of all hospitalized patients develop delirium,² with rates up to 80% in the critically ill.³ Similarly, delirium occurs in more than one-third of patients who transition to postacute care.⁴ These high prevalence rates are alarming, especially because delirium is a risk factor for mortality, prolonged hospitalization, institutionalization, and overall higher cost of care.⁵ However, more than a quarter of delirium is preventable.⁶ Evidence-based guidelines for delirium uniformly call for multicomponent prevention strategies,⁷ and these are best delivered through collaborative models of care. In short, delirium impacts healthcare systems; therefore, interventions aimed at preventing delirium and its consequences ought to be systems-based.

Since the Institute of Medicine issued its 1999 report highlighting the critical role of medical errors in healthcare, healthcare systems have increasingly become team-based.⁸ “Medical care is inherently interdependent,”⁹ and this implies that delirium prevention rests not only on individuals but also on broader systems of care. Although nonpharmacological interventions are efficacious at preventing delirium,¹⁰ previous reviews have focused on specific interventions or multiple interventions rather than the systems of care needed to deliver them. Indeed, teams and the quality of their teamwork impact outcomes.¹¹

Herein, we provide a systematic review and meta-analysis of integrated models of care designed to prevent delirium. What distinguishes this review from previous reviews of nonpharmacological interventions to prevent delirium is our focus on discrete models of care that involve collaboration among clinicians. Our goal is to identify the most promising models that deserve further development, investigation, and dissemination. Viewing delirium prevention through a collaborative care lens is consistent with efforts to achieve value-based care and may encourage drawing from the expanding literature outlining the benefits of mental healthcare integration.^12,13 Specifically, a systems perspective highlights the potential for system-wide benefits such as reducing readmissions^14,15 and cost savings.¹⁶

This systematic review and meta-analysis follows PRISMA guidelines. A search of OVID, MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, EMBASE, and PsycINFO was completed by a medical librarian for clinical studies in which models of care were implemented to prevent delirium using PICO (P patient, problem or population; I, intervention; C, comparison, control or comparator; O, outcome) inquiries. Search terms included delirium, acute confusional state, altered mental status, prevention, and control (“delirium”/exp OR “acute confusion”/exp OR “altered mental status”/exp) AND “prevention and control”/exp AND [English]/lim AND [embase]/lim).

One researcher (AK) screened articles by title for relevance. Relevant articles were then divided among four authors (AK, MO, NF, and OB), and the abstracts were screened for eligibility. The authors reviewed the full texts of any potentially eligible studies. Each full text was assigned to two authors for full review. Discrepancies were adjudicated by conference among all authors. In addition, references within all full-text publications were scanned for potential additional articles.

The inclusion criteria for review of full-text articles required English-language description of a model of care with multiple interventions, delirium reported as an outcome, and presence of a comparator group.

“Model of care” was defined by the Cochrane Effective Practice and Organization of Care Review Group as follows: (1) revision of professional roles, including shifting of professional roles or expansion of roles to new tasks; (2) creation of clinical multidisciplinary teams or addition of new members to the team who collaborate inpatient care; (3) delivery of multiple interventions across multiple domains (ie, studies involving a single intervention such as physical therapy or targeting a single domain such as sleep were excluded); and (4) formal integration of services whereby teams work together in collaboration with existing services to enhance care.¹⁷ For this review, we required that studies include a comparator group so that effectiveness of the intervention could be assessed. Quality improvement studies that lacked a comparator group were excluded.

Delirium incidence was the primary outcome and was evaluated by meta-analysis. Heterogeneity was assessed using I² and visual inspection of forest plots. I² values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. The studies were pooled according to study type as follows: randomized controlled trials, pre–post design, and other nonrandomized prospective studies. Random effects models were used to calculate estimates using the Comprehensive Meta-Analysis software (Version 3, Biostat, Englewood, New Jersey), which also generated forest plots.

Risk of bias was assessed using criteria established by the Cochrane Collaborative Review Criteria, which lists six categories of potential bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting.¹⁷ Each study was assessed by two authors (either MO and AK or MO-P. and OB) for bias and a numerical value was assigned to each of the six categories as follows: 1 = low risk, 2 = unknown/moderate risk, and 3 = high risk. Where scorers disagreed, all authors jointly conferred, and a consensus score was given. The values for each of these six categories were added to create a composite risk-of-bias score for each study, with 6 being the lowest possible score and 18 the highest. Overall risk was classified as follows: <9 = low risk, 9-12 = moderate risk, and >12 = high risk.

Study Selection Process

An initial literature search identified 352 articles. After reviewing the titles, 308 articles were excluded for irrelevance, and 44 abstracts were screened for eligibility. We excluded 27 articles upon abstract review, and the full texts of 17 were obtained for detailed review. In addition, we identified another 10 potentially eligible articles through review of references and obtained full texts of these as well. Of the 27 full-text articles reviewed, 15 were included in this systematic review, 10 of which were suitable for meta-analysis. The Figure shows the PRISMA flow chart.

Study Characteristics

The 15 studies that met the inclusion criteria are summarized in the Table.^18-32 Delirium prevention was among the primary outcomes of 13 studies; delirium outcomes were reported in the other two studies as well, which were primarily designed to assess feasibility.^26,27 Six studies were conducted in the United States, three in Sweden, two in Spain, two in the United Kingdom, and one each conducted in Korea and Canada. Healthcare settings among the included studies involved the intensive care unit (six studies), medical floors (four studies), surgical floors (three studies), a long-term care unit (one study), and an inpatient palliative care service (one study). We categorized the studies according to design and intent as follows: randomized controlled studies (three), pilot feasibility studies (two), pre–post design (six), and other nonrandomized prospective studies (four; Table).

Outcomes Reported

All but one of the studies reported delirium incidence. The most commonly used delirium screening instrument was the Confusion Assessment Method (CAM) or its modified version, the CAM-ICU (11 studies).^33,34 Other methods used to assess mentation included the Richmond Agitation Sedation Scale,³⁵ the Organic Brain Syndrome scale,³⁶ the revised Delirium Rating Scale,³⁷ the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,³⁸ and the Confusion Rating Scale.³⁹ (Details regarding delirium screening tools can be found in the systematic review by De and Wand.⁴⁰) Researchers performed delirium assessment in nine studies, whereas assessments were performed by clinical staff in the remaining studies. Other outcomes reported included length of stay (LOS), mortality, number of days ventilated, and functional decline. None of the included studies reported cost effectiveness.

Risk of Bias Assessment

Risk of bias assessment identified only two studies—both randomized controlled trials—as low risk (Table). The remaining studies had moderate (four studies) or high risk (nine studies).

Results from Individual Studies

Of the 15 studies, nine reported a statistically significant reduction in delirium incidence, and another two reported a statistically insignificant reduction. In addition, seven of the eight studies that assessed delirium duration found reduced duration in the intervention cohort, and two of the three studies that reported delirium severity found a reduction in the intervention group.

Results of Meta-Analysis

Random effects models were created to meta-analyze groups of studies based on design as follows: randomized controlled trials (three studies^18,19,25), pre–post intervention studies (four of six studies included^28-31), and other nonrandomized studies (three of four studies included^21-23). Meta-analysis was not completed for the two feasibility studies^26,27 because delirium outcome data were limited due to the feasibility study design. The study of Dale et al.³² was excluded from the meta-analysis because the rates of CAM-ICU completion differed substantially between control and intervention groups (0.35 vs 1.49 per 24 hours, respectively), leading to imbalanced between-group sensitivity in delirium detection and Needham et al.²⁰ was also excluded because it reported only days of delirium, not delirium incidence. The study by Lundström et al.²⁴ was also excluded from the meta-analysis because delirium incidence was measured on days 1, 3, and 5, whereas the other studies reported delirium daily.

Meta-analysis of the three randomized controlled trials revealed a pooled odds ratio of 0.56 (95% CI: 0.37-0.85; P = .006) for delirium incidence among intervention group subjects relative to those in comparator groups. The heterogeneity across studies was low (I² = 29%). Pooling data from four pre–post studies found that the odds ratio for delirium incidence was 0.63 (95% CI: 0.37-1.07; P = .09). The heterogeneity across these studies was moderate (I² = 65%). Results from the three eligible, nonrandomized prospective studies were also pooled. The odds ratio for developing delirium among study subjects was 0.79 (95% CI: 0.46-1.37; P = .40), and the heterogeneity among these studies was high (I² = 85%).

We provide a systematic review and meta-analysis of delirium preventive models of care. Meta-analysis of the three randomized controlled trials found that these models of care led to a statistically significant reduction in delirium incidence; study subjects had an 11.5% reduction in absolute delirium incidence. The pooled odds ratios for both of the other sets of nonrandomized studies favored the intervention group but were not significant, each because of one included study. The pre–post meta-analysis failed to reach significance as one of the included studies found a trend toward higher delirium incidence; however, interestingly, in that same study, the overall delirium-free days were significantly reduced overall (24 vs 27, P = .002). Similarly, meta-analysis of the three additional nonrandomized prospective studies failed to reach significance because the largest included study found higher rates of delirium among intervention group subjects. Despite considerable risk of bias in several of these studies, their findings were broadly consistent; all but one study (Gagnon 2012²¹) reported a trend or a significant reduction in delirium incidence, duration, severity, or number of delirium episodes. Moreover, the value of such models of care extended beyond preventing delirium; for instance, other positive outcomes included reduced LOS and fewer medical complications.

Models of care ranged widely with respect to specific interventions, though several common elements highlighted their relevance for delirium care and as potential delirium prevention strategies in future studies. For example, two of the randomized controlled trials^18,19 employed early mobilization, enhanced nutrition, sleep hygiene, early reduction of invasive procedures (eg, urinary catheterization), and pain control in their multicomponent models. Five additional studies also incorporated early mobilization,^{20,22,23,31,32} and three sought to improve sleep quality.^22,28,30 Among other important strategies were delirium screening,^{18,20,22,30,31} monitoring medication,^{18,20,22,26,28,30,32} orientation,^18,21,23,28 addressing vision and hearing impairment,^18,22,23,32 hydration,^18,22,23 avoiding hypoxia,^18,20,30 and staff, patient, and caretaker education.^{19,21,23,27-30} Unique strategies were implemented in certain studies. For instance, one study used massage therapy,²⁸ preventing delays in transfer logistics in another,³⁰ and a third addressed psychosocial problems.²⁵ Overall, the selection of strategies depended on the patient setting; thus, no one care bundle should be expected to emerge as a universal model for delirium prevention. Rather, these results should be interpreted within their specific care contexts and judged on the quality of evidence (eg, effect size and statistically significant findings, low risk of bias, sound experimental design). The one study that failed to find any positive effect on delirium, that of Gagnon et al.,²¹ was conducted on an inpatient palliative care service in Canada, and its negative finding may reflect the unique delirium risk factors in patients who are nearing end of life.

This current review differs from previous delirium prevention reviews in operationally defining a “model of care.” We identified a great deal of variation in specific models and team composition. For example, some interventions were carried out by nurses^18-20,31 and physicians,^20,21,25,32 whereas others involved physical therapists,^20,22,28 medical residents,²³ geriatricians,^22,23,25 pharmacists,²⁶ researchers,¹⁸ and trained volunteers.²² In all cases, the staff roles were expanded to include new tasks, and the clinical team worked collaboratively to administer interventions across multiple domains. Team-related considerations are critical because modern medical care is inherently interdependent.⁹ These broad differences in team composition across studies demonstrate the number of potential options for team structure and function. They also highlight the number of “moving parts” to be considered when designing and implementing delirium care bundles.

Most of the delirium prevention studies implementing models of care are characterized by a substantial risk of bias. We evaluated risk of bias along six categories of potential sources, including random assignment to groups, ability to foresee future group allocation, blinding of participants and personnel to group assignment, blinding of outcome assessment, completeness of outcome data, selective reporting, and other potential sources of bias.¹⁷ Two of the three studies that used randomization had a low risk of bias, and four additional studies had a moderate risk of bias. Allocation concealment was accomplished only in randomized controlled trials, whereas blinding of both subjects and study personnel was not implemented in any of the studies. Although some studies relied on data analysis by research personnel blinded to group membership or the nature of the intervention, others failed to do so or failed to describe data analysis in sufficient detail. Studies also failed to report the percentage of unscorable or otherwise omitted delirium assessments necessary to calculate attrition rates or to understand the comprehensiveness of outcome assessment in a systematic manner. Other potential sources of bias included systematic differences between the intervention and control groups (such as differences in gender composition, age, or delirium risk) at study outset.

A primary limitation of this review is the heterogeneity of settings, interventions, and models of care across included studies. We excluded several studies from this review for being delivered by a single individual or service line (eg, introduction of a geriatric consult service, physical therapy, or volunteers), for providing a single intervention (eg, early ambulation alone), or for multiple interventions targeting a single domain (eg, sleep). We did so because the future of value-based care lies in collaboration of providers and services, and in a way the complexity across and within these studies ultimately reflects the complexity of medical settings as well as the multifactorial nature of delirium. The broader message is a call for increasing the integration of delirium-related care services. As discussed earlier, the high risk of bias across these studies is a limitation of our findings; high-quality evidence on the value of delirium prevention models of care remains limited. Thus, although our review suggests that there are multicomponent models of care that hold promise in mitigating delirium and its outcomes, additional randomized studies are required to confirm the efficacy of such models of care and to test which services, interventions, and clinical domains deserve priority.

To our knowledge, this is the first systematic review and meta-analysis of delirium preventive models of care. Models of care, as defined here, necessarily included a multidisciplinary team in which traditional staff roles had been revised to implement a multicomponent, multidomain intervention. Other recent reviews are available for multicomponent pharmacological and nonpharmacological interventions to prevent and manage delirium,^41-49 but just as important as which interventions are being delivered is the team that delivers them. Care delivery in a complex medical system is more than handing a patient a medication or facilitating ambulation; it requires a choreographed dance of teamwork and integration across services. This review identifies promising models of care that deserve further recognition, refinement, and ultimately widespread implementation.

Acknowledgments

The authors comprise a writing group created through the Delirium Boot Camp, an annual meeting originally sponsored by the Center of Excellence for Delirium in Aging: Research, Training, and Educational Enhancement (CEDARTREE, Boston, Massachusetts); it is currently supported by the Network for Investigation of Delirium: Unifying Scientists (NIDUS, Boston, Massachusetts). The authors would like to thank medical librarian Rita Mitchell (Aurora Health Care, Milwaukee, Wisconsin) for the literature search, senior scientific writer and editor Joe Grundle (Aurora Research Institute, Milwaukee, Wisconsin) for editorial assistance, and graphics specialist Brian Miller (Aurora Research Institute, Milwaukee, Wisconsin) for help with the figures.

Disclosures

The authors report no relevant conflicts of interest.

Funding

No funding was dedicated to the conduct of this review.

Delirium presents as an acute change in mentation characterized by reduced attention, clouding of awareness, and typically an altered level of arousal. It can be caused by a host of medical conditions, medications, or other psychoactive substances and is therefore encountered primarily in acute and postacute medical settings.¹ More than a quarter of all hospitalized patients develop delirium,² with rates up to 80% in the critically ill.³ Similarly, delirium occurs in more than one-third of patients who transition to postacute care.⁴ These high prevalence rates are alarming, especially because delirium is a risk factor for mortality, prolonged hospitalization, institutionalization, and overall higher cost of care.⁵ However, more than a quarter of delirium is preventable.⁶ Evidence-based guidelines for delirium uniformly call for multicomponent prevention strategies,⁷ and these are best delivered through collaborative models of care. In short, delirium impacts healthcare systems; therefore, interventions aimed at preventing delirium and its consequences ought to be systems-based.

Since the Institute of Medicine issued its 1999 report highlighting the critical role of medical errors in healthcare, healthcare systems have increasingly become team-based.⁸ “Medical care is inherently interdependent,”⁹ and this implies that delirium prevention rests not only on individuals but also on broader systems of care. Although nonpharmacological interventions are efficacious at preventing delirium,¹⁰ previous reviews have focused on specific interventions or multiple interventions rather than the systems of care needed to deliver them. Indeed, teams and the quality of their teamwork impact outcomes.¹¹

Herein, we provide a systematic review and meta-analysis of integrated models of care designed to prevent delirium. What distinguishes this review from previous reviews of nonpharmacological interventions to prevent delirium is our focus on discrete models of care that involve collaboration among clinicians. Our goal is to identify the most promising models that deserve further development, investigation, and dissemination. Viewing delirium prevention through a collaborative care lens is consistent with efforts to achieve value-based care and may encourage drawing from the expanding literature outlining the benefits of mental healthcare integration.^12,13 Specifically, a systems perspective highlights the potential for system-wide benefits such as reducing readmissions^14,15 and cost savings.¹⁶

This systematic review and meta-analysis follows PRISMA guidelines. A search of OVID, MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, EMBASE, and PsycINFO was completed by a medical librarian for clinical studies in which models of care were implemented to prevent delirium using PICO (P patient, problem or population; I, intervention; C, comparison, control or comparator; O, outcome) inquiries. Search terms included delirium, acute confusional state, altered mental status, prevention, and control (“delirium”/exp OR “acute confusion”/exp OR “altered mental status”/exp) AND “prevention and control”/exp AND [English]/lim AND [embase]/lim).

One researcher (AK) screened articles by title for relevance. Relevant articles were then divided among four authors (AK, MO, NF, and OB), and the abstracts were screened for eligibility. The authors reviewed the full texts of any potentially eligible studies. Each full text was assigned to two authors for full review. Discrepancies were adjudicated by conference among all authors. In addition, references within all full-text publications were scanned for potential additional articles.

The inclusion criteria for review of full-text articles required English-language description of a model of care with multiple interventions, delirium reported as an outcome, and presence of a comparator group.

“Model of care” was defined by the Cochrane Effective Practice and Organization of Care Review Group as follows: (1) revision of professional roles, including shifting of professional roles or expansion of roles to new tasks; (2) creation of clinical multidisciplinary teams or addition of new members to the team who collaborate inpatient care; (3) delivery of multiple interventions across multiple domains (ie, studies involving a single intervention such as physical therapy or targeting a single domain such as sleep were excluded); and (4) formal integration of services whereby teams work together in collaboration with existing services to enhance care.¹⁷ For this review, we required that studies include a comparator group so that effectiveness of the intervention could be assessed. Quality improvement studies that lacked a comparator group were excluded.

Delirium incidence was the primary outcome and was evaluated by meta-analysis. Heterogeneity was assessed using I² and visual inspection of forest plots. I² values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. The studies were pooled according to study type as follows: randomized controlled trials, pre–post design, and other nonrandomized prospective studies. Random effects models were used to calculate estimates using the Comprehensive Meta-Analysis software (Version 3, Biostat, Englewood, New Jersey), which also generated forest plots.

Risk of bias was assessed using criteria established by the Cochrane Collaborative Review Criteria, which lists six categories of potential bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting.¹⁷ Each study was assessed by two authors (either MO and AK or MO-P. and OB) for bias and a numerical value was assigned to each of the six categories as follows: 1 = low risk, 2 = unknown/moderate risk, and 3 = high risk. Where scorers disagreed, all authors jointly conferred, and a consensus score was given. The values for each of these six categories were added to create a composite risk-of-bias score for each study, with 6 being the lowest possible score and 18 the highest. Overall risk was classified as follows: <9 = low risk, 9-12 = moderate risk, and >12 = high risk.

Study Selection Process

An initial literature search identified 352 articles. After reviewing the titles, 308 articles were excluded for irrelevance, and 44 abstracts were screened for eligibility. We excluded 27 articles upon abstract review, and the full texts of 17 were obtained for detailed review. In addition, we identified another 10 potentially eligible articles through review of references and obtained full texts of these as well. Of the 27 full-text articles reviewed, 15 were included in this systematic review, 10 of which were suitable for meta-analysis. The Figure shows the PRISMA flow chart.

Study Characteristics

The 15 studies that met the inclusion criteria are summarized in the Table.^18-32 Delirium prevention was among the primary outcomes of 13 studies; delirium outcomes were reported in the other two studies as well, which were primarily designed to assess feasibility.^26,27 Six studies were conducted in the United States, three in Sweden, two in Spain, two in the United Kingdom, and one each conducted in Korea and Canada. Healthcare settings among the included studies involved the intensive care unit (six studies), medical floors (four studies), surgical floors (three studies), a long-term care unit (one study), and an inpatient palliative care service (one study). We categorized the studies according to design and intent as follows: randomized controlled studies (three), pilot feasibility studies (two), pre–post design (six), and other nonrandomized prospective studies (four; Table).

Outcomes Reported

All but one of the studies reported delirium incidence. The most commonly used delirium screening instrument was the Confusion Assessment Method (CAM) or its modified version, the CAM-ICU (11 studies).^33,34 Other methods used to assess mentation included the Richmond Agitation Sedation Scale,³⁵ the Organic Brain Syndrome scale,³⁶ the revised Delirium Rating Scale,³⁷ the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,³⁸ and the Confusion Rating Scale.³⁹ (Details regarding delirium screening tools can be found in the systematic review by De and Wand.⁴⁰) Researchers performed delirium assessment in nine studies, whereas assessments were performed by clinical staff in the remaining studies. Other outcomes reported included length of stay (LOS), mortality, number of days ventilated, and functional decline. None of the included studies reported cost effectiveness.

Risk of Bias Assessment

Risk of bias assessment identified only two studies—both randomized controlled trials—as low risk (Table). The remaining studies had moderate (four studies) or high risk (nine studies).

Results from Individual Studies

Of the 15 studies, nine reported a statistically significant reduction in delirium incidence, and another two reported a statistically insignificant reduction. In addition, seven of the eight studies that assessed delirium duration found reduced duration in the intervention cohort, and two of the three studies that reported delirium severity found a reduction in the intervention group.

Results of Meta-Analysis

Random effects models were created to meta-analyze groups of studies based on design as follows: randomized controlled trials (three studies^18,19,25), pre–post intervention studies (four of six studies included^28-31), and other nonrandomized studies (three of four studies included^21-23). Meta-analysis was not completed for the two feasibility studies^26,27 because delirium outcome data were limited due to the feasibility study design. The study of Dale et al.³² was excluded from the meta-analysis because the rates of CAM-ICU completion differed substantially between control and intervention groups (0.35 vs 1.49 per 24 hours, respectively), leading to imbalanced between-group sensitivity in delirium detection and Needham et al.²⁰ was also excluded because it reported only days of delirium, not delirium incidence. The study by Lundström et al.²⁴ was also excluded from the meta-analysis because delirium incidence was measured on days 1, 3, and 5, whereas the other studies reported delirium daily.

Meta-analysis of the three randomized controlled trials revealed a pooled odds ratio of 0.56 (95% CI: 0.37-0.85; P = .006) for delirium incidence among intervention group subjects relative to those in comparator groups. The heterogeneity across studies was low (I² = 29%). Pooling data from four pre–post studies found that the odds ratio for delirium incidence was 0.63 (95% CI: 0.37-1.07; P = .09). The heterogeneity across these studies was moderate (I² = 65%). Results from the three eligible, nonrandomized prospective studies were also pooled. The odds ratio for developing delirium among study subjects was 0.79 (95% CI: 0.46-1.37; P = .40), and the heterogeneity among these studies was high (I² = 85%).

We provide a systematic review and meta-analysis of delirium preventive models of care. Meta-analysis of the three randomized controlled trials found that these models of care led to a statistically significant reduction in delirium incidence; study subjects had an 11.5% reduction in absolute delirium incidence. The pooled odds ratios for both of the other sets of nonrandomized studies favored the intervention group but were not significant, each because of one included study. The pre–post meta-analysis failed to reach significance as one of the included studies found a trend toward higher delirium incidence; however, interestingly, in that same study, the overall delirium-free days were significantly reduced overall (24 vs 27, P = .002). Similarly, meta-analysis of the three additional nonrandomized prospective studies failed to reach significance because the largest included study found higher rates of delirium among intervention group subjects. Despite considerable risk of bias in several of these studies, their findings were broadly consistent; all but one study (Gagnon 2012²¹) reported a trend or a significant reduction in delirium incidence, duration, severity, or number of delirium episodes. Moreover, the value of such models of care extended beyond preventing delirium; for instance, other positive outcomes included reduced LOS and fewer medical complications.

Models of care ranged widely with respect to specific interventions, though several common elements highlighted their relevance for delirium care and as potential delirium prevention strategies in future studies. For example, two of the randomized controlled trials^18,19 employed early mobilization, enhanced nutrition, sleep hygiene, early reduction of invasive procedures (eg, urinary catheterization), and pain control in their multicomponent models. Five additional studies also incorporated early mobilization,^{20,22,23,31,32} and three sought to improve sleep quality.^22,28,30 Among other important strategies were delirium screening,^{18,20,22,30,31} monitoring medication,^{18,20,22,26,28,30,32} orientation,^18,21,23,28 addressing vision and hearing impairment,^18,22,23,32 hydration,^18,22,23 avoiding hypoxia,^18,20,30 and staff, patient, and caretaker education.^{19,21,23,27-30} Unique strategies were implemented in certain studies. For instance, one study used massage therapy,²⁸ preventing delays in transfer logistics in another,³⁰ and a third addressed psychosocial problems.²⁵ Overall, the selection of strategies depended on the patient setting; thus, no one care bundle should be expected to emerge as a universal model for delirium prevention. Rather, these results should be interpreted within their specific care contexts and judged on the quality of evidence (eg, effect size and statistically significant findings, low risk of bias, sound experimental design). The one study that failed to find any positive effect on delirium, that of Gagnon et al.,²¹ was conducted on an inpatient palliative care service in Canada, and its negative finding may reflect the unique delirium risk factors in patients who are nearing end of life.

This current review differs from previous delirium prevention reviews in operationally defining a “model of care.” We identified a great deal of variation in specific models and team composition. For example, some interventions were carried out by nurses^18-20,31 and physicians,^20,21,25,32 whereas others involved physical therapists,^20,22,28 medical residents,²³ geriatricians,^22,23,25 pharmacists,²⁶ researchers,¹⁸ and trained volunteers.²² In all cases, the staff roles were expanded to include new tasks, and the clinical team worked collaboratively to administer interventions across multiple domains. Team-related considerations are critical because modern medical care is inherently interdependent.⁹ These broad differences in team composition across studies demonstrate the number of potential options for team structure and function. They also highlight the number of “moving parts” to be considered when designing and implementing delirium care bundles.

Most of the delirium prevention studies implementing models of care are characterized by a substantial risk of bias. We evaluated risk of bias along six categories of potential sources, including random assignment to groups, ability to foresee future group allocation, blinding of participants and personnel to group assignment, blinding of outcome assessment, completeness of outcome data, selective reporting, and other potential sources of bias.¹⁷ Two of the three studies that used randomization had a low risk of bias, and four additional studies had a moderate risk of bias. Allocation concealment was accomplished only in randomized controlled trials, whereas blinding of both subjects and study personnel was not implemented in any of the studies. Although some studies relied on data analysis by research personnel blinded to group membership or the nature of the intervention, others failed to do so or failed to describe data analysis in sufficient detail. Studies also failed to report the percentage of unscorable or otherwise omitted delirium assessments necessary to calculate attrition rates or to understand the comprehensiveness of outcome assessment in a systematic manner. Other potential sources of bias included systematic differences between the intervention and control groups (such as differences in gender composition, age, or delirium risk) at study outset.

A primary limitation of this review is the heterogeneity of settings, interventions, and models of care across included studies. We excluded several studies from this review for being delivered by a single individual or service line (eg, introduction of a geriatric consult service, physical therapy, or volunteers), for providing a single intervention (eg, early ambulation alone), or for multiple interventions targeting a single domain (eg, sleep). We did so because the future of value-based care lies in collaboration of providers and services, and in a way the complexity across and within these studies ultimately reflects the complexity of medical settings as well as the multifactorial nature of delirium. The broader message is a call for increasing the integration of delirium-related care services. As discussed earlier, the high risk of bias across these studies is a limitation of our findings; high-quality evidence on the value of delirium prevention models of care remains limited. Thus, although our review suggests that there are multicomponent models of care that hold promise in mitigating delirium and its outcomes, additional randomized studies are required to confirm the efficacy of such models of care and to test which services, interventions, and clinical domains deserve priority.

To our knowledge, this is the first systematic review and meta-analysis of delirium preventive models of care. Models of care, as defined here, necessarily included a multidisciplinary team in which traditional staff roles had been revised to implement a multicomponent, multidomain intervention. Other recent reviews are available for multicomponent pharmacological and nonpharmacological interventions to prevent and manage delirium,^41-49 but just as important as which interventions are being delivered is the team that delivers them. Care delivery in a complex medical system is more than handing a patient a medication or facilitating ambulation; it requires a choreographed dance of teamwork and integration across services. This review identifies promising models of care that deserve further recognition, refinement, and ultimately widespread implementation.

Acknowledgments

The authors comprise a writing group created through the Delirium Boot Camp, an annual meeting originally sponsored by the Center of Excellence for Delirium in Aging: Research, Training, and Educational Enhancement (CEDARTREE, Boston, Massachusetts); it is currently supported by the Network for Investigation of Delirium: Unifying Scientists (NIDUS, Boston, Massachusetts). The authors would like to thank medical librarian Rita Mitchell (Aurora Health Care, Milwaukee, Wisconsin) for the literature search, senior scientific writer and editor Joe Grundle (Aurora Research Institute, Milwaukee, Wisconsin) for editorial assistance, and graphics specialist Brian Miller (Aurora Research Institute, Milwaukee, Wisconsin) for help with the figures.

Disclosures

The authors report no relevant conflicts of interest.

Funding

No funding was dedicated to the conduct of this review.

Delirium presents as an acute change in mentation characterized by reduced attention, clouding of awareness, and typically an altered level of arousal. It can be caused by a host of medical conditions, medications, or other psychoactive substances and is therefore encountered primarily in acute and postacute medical settings.¹ More than a quarter of all hospitalized patients develop delirium,² with rates up to 80% in the critically ill.³ Similarly, delirium occurs in more than one-third of patients who transition to postacute care.⁴ These high prevalence rates are alarming, especially because delirium is a risk factor for mortality, prolonged hospitalization, institutionalization, and overall higher cost of care.⁵ However, more than a quarter of delirium is preventable.⁶ Evidence-based guidelines for delirium uniformly call for multicomponent prevention strategies,⁷ and these are best delivered through collaborative models of care. In short, delirium impacts healthcare systems; therefore, interventions aimed at preventing delirium and its consequences ought to be systems-based.

Since the Institute of Medicine issued its 1999 report highlighting the critical role of medical errors in healthcare, healthcare systems have increasingly become team-based.⁸ “Medical care is inherently interdependent,”⁹ and this implies that delirium prevention rests not only on individuals but also on broader systems of care. Although nonpharmacological interventions are efficacious at preventing delirium,¹⁰ previous reviews have focused on specific interventions or multiple interventions rather than the systems of care needed to deliver them. Indeed, teams and the quality of their teamwork impact outcomes.¹¹

Herein, we provide a systematic review and meta-analysis of integrated models of care designed to prevent delirium. What distinguishes this review from previous reviews of nonpharmacological interventions to prevent delirium is our focus on discrete models of care that involve collaboration among clinicians. Our goal is to identify the most promising models that deserve further development, investigation, and dissemination. Viewing delirium prevention through a collaborative care lens is consistent with efforts to achieve value-based care and may encourage drawing from the expanding literature outlining the benefits of mental healthcare integration.^12,13 Specifically, a systems perspective highlights the potential for system-wide benefits such as reducing readmissions^14,15 and cost savings.¹⁶

This systematic review and meta-analysis follows PRISMA guidelines. A search of OVID, MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, EMBASE, and PsycINFO was completed by a medical librarian for clinical studies in which models of care were implemented to prevent delirium using PICO (P patient, problem or population; I, intervention; C, comparison, control or comparator; O, outcome) inquiries. Search terms included delirium, acute confusional state, altered mental status, prevention, and control (“delirium”/exp OR “acute confusion”/exp OR “altered mental status”/exp) AND “prevention and control”/exp AND [English]/lim AND [embase]/lim).

One researcher (AK) screened articles by title for relevance. Relevant articles were then divided among four authors (AK, MO, NF, and OB), and the abstracts were screened for eligibility. The authors reviewed the full texts of any potentially eligible studies. Each full text was assigned to two authors for full review. Discrepancies were adjudicated by conference among all authors. In addition, references within all full-text publications were scanned for potential additional articles.

The inclusion criteria for review of full-text articles required English-language description of a model of care with multiple interventions, delirium reported as an outcome, and presence of a comparator group.

“Model of care” was defined by the Cochrane Effective Practice and Organization of Care Review Group as follows: (1) revision of professional roles, including shifting of professional roles or expansion of roles to new tasks; (2) creation of clinical multidisciplinary teams or addition of new members to the team who collaborate inpatient care; (3) delivery of multiple interventions across multiple domains (ie, studies involving a single intervention such as physical therapy or targeting a single domain such as sleep were excluded); and (4) formal integration of services whereby teams work together in collaboration with existing services to enhance care.¹⁷ For this review, we required that studies include a comparator group so that effectiveness of the intervention could be assessed. Quality improvement studies that lacked a comparator group were excluded.

Delirium incidence was the primary outcome and was evaluated by meta-analysis. Heterogeneity was assessed using I² and visual inspection of forest plots. I² values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. The studies were pooled according to study type as follows: randomized controlled trials, pre–post design, and other nonrandomized prospective studies. Random effects models were used to calculate estimates using the Comprehensive Meta-Analysis software (Version 3, Biostat, Englewood, New Jersey), which also generated forest plots.

Risk of bias was assessed using criteria established by the Cochrane Collaborative Review Criteria, which lists six categories of potential bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting.¹⁷ Each study was assessed by two authors (either MO and AK or MO-P. and OB) for bias and a numerical value was assigned to each of the six categories as follows: 1 = low risk, 2 = unknown/moderate risk, and 3 = high risk. Where scorers disagreed, all authors jointly conferred, and a consensus score was given. The values for each of these six categories were added to create a composite risk-of-bias score for each study, with 6 being the lowest possible score and 18 the highest. Overall risk was classified as follows: <9 = low risk, 9-12 = moderate risk, and >12 = high risk.

Study Selection Process

An initial literature search identified 352 articles. After reviewing the titles, 308 articles were excluded for irrelevance, and 44 abstracts were screened for eligibility. We excluded 27 articles upon abstract review, and the full texts of 17 were obtained for detailed review. In addition, we identified another 10 potentially eligible articles through review of references and obtained full texts of these as well. Of the 27 full-text articles reviewed, 15 were included in this systematic review, 10 of which were suitable for meta-analysis. The Figure shows the PRISMA flow chart.

Study Characteristics

The 15 studies that met the inclusion criteria are summarized in the Table.^18-32 Delirium prevention was among the primary outcomes of 13 studies; delirium outcomes were reported in the other two studies as well, which were primarily designed to assess feasibility.^26,27 Six studies were conducted in the United States, three in Sweden, two in Spain, two in the United Kingdom, and one each conducted in Korea and Canada. Healthcare settings among the included studies involved the intensive care unit (six studies), medical floors (four studies), surgical floors (three studies), a long-term care unit (one study), and an inpatient palliative care service (one study). We categorized the studies according to design and intent as follows: randomized controlled studies (three), pilot feasibility studies (two), pre–post design (six), and other nonrandomized prospective studies (four; Table).

Outcomes Reported

All but one of the studies reported delirium incidence. The most commonly used delirium screening instrument was the Confusion Assessment Method (CAM) or its modified version, the CAM-ICU (11 studies).^33,34 Other methods used to assess mentation included the Richmond Agitation Sedation Scale,³⁵ the Organic Brain Syndrome scale,³⁶ the revised Delirium Rating Scale,³⁷ the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,³⁸ and the Confusion Rating Scale.³⁹ (Details regarding delirium screening tools can be found in the systematic review by De and Wand.⁴⁰) Researchers performed delirium assessment in nine studies, whereas assessments were performed by clinical staff in the remaining studies. Other outcomes reported included length of stay (LOS), mortality, number of days ventilated, and functional decline. None of the included studies reported cost effectiveness.

Risk of Bias Assessment

Risk of bias assessment identified only two studies—both randomized controlled trials—as low risk (Table). The remaining studies had moderate (four studies) or high risk (nine studies).

Results from Individual Studies

Of the 15 studies, nine reported a statistically significant reduction in delirium incidence, and another two reported a statistically insignificant reduction. In addition, seven of the eight studies that assessed delirium duration found reduced duration in the intervention cohort, and two of the three studies that reported delirium severity found a reduction in the intervention group.

Results of Meta-Analysis

Random effects models were created to meta-analyze groups of studies based on design as follows: randomized controlled trials (three studies^18,19,25), pre–post intervention studies (four of six studies included^28-31), and other nonrandomized studies (three of four studies included^21-23). Meta-analysis was not completed for the two feasibility studies^26,27 because delirium outcome data were limited due to the feasibility study design. The study of Dale et al.³² was excluded from the meta-analysis because the rates of CAM-ICU completion differed substantially between control and intervention groups (0.35 vs 1.49 per 24 hours, respectively), leading to imbalanced between-group sensitivity in delirium detection and Needham et al.²⁰ was also excluded because it reported only days of delirium, not delirium incidence. The study by Lundström et al.²⁴ was also excluded from the meta-analysis because delirium incidence was measured on days 1, 3, and 5, whereas the other studies reported delirium daily.

Meta-analysis of the three randomized controlled trials revealed a pooled odds ratio of 0.56 (95% CI: 0.37-0.85; P = .006) for delirium incidence among intervention group subjects relative to those in comparator groups. The heterogeneity across studies was low (I² = 29%). Pooling data from four pre–post studies found that the odds ratio for delirium incidence was 0.63 (95% CI: 0.37-1.07; P = .09). The heterogeneity across these studies was moderate (I² = 65%). Results from the three eligible, nonrandomized prospective studies were also pooled. The odds ratio for developing delirium among study subjects was 0.79 (95% CI: 0.46-1.37; P = .40), and the heterogeneity among these studies was high (I² = 85%).

We provide a systematic review and meta-analysis of delirium preventive models of care. Meta-analysis of the three randomized controlled trials found that these models of care led to a statistically significant reduction in delirium incidence; study subjects had an 11.5% reduction in absolute delirium incidence. The pooled odds ratios for both of the other sets of nonrandomized studies favored the intervention group but were not significant, each because of one included study. The pre–post meta-analysis failed to reach significance as one of the included studies found a trend toward higher delirium incidence; however, interestingly, in that same study, the overall delirium-free days were significantly reduced overall (24 vs 27, P = .002). Similarly, meta-analysis of the three additional nonrandomized prospective studies failed to reach significance because the largest included study found higher rates of delirium among intervention group subjects. Despite considerable risk of bias in several of these studies, their findings were broadly consistent; all but one study (Gagnon 2012²¹) reported a trend or a significant reduction in delirium incidence, duration, severity, or number of delirium episodes. Moreover, the value of such models of care extended beyond preventing delirium; for instance, other positive outcomes included reduced LOS and fewer medical complications.

Models of care ranged widely with respect to specific interventions, though several common elements highlighted their relevance for delirium care and as potential delirium prevention strategies in future studies. For example, two of the randomized controlled trials^18,19 employed early mobilization, enhanced nutrition, sleep hygiene, early reduction of invasive procedures (eg, urinary catheterization), and pain control in their multicomponent models. Five additional studies also incorporated early mobilization,^{20,22,23,31,32} and three sought to improve sleep quality.^22,28,30 Among other important strategies were delirium screening,^{18,20,22,30,31} monitoring medication,^{18,20,22,26,28,30,32} orientation,^18,21,23,28 addressing vision and hearing impairment,^18,22,23,32 hydration,^18,22,23 avoiding hypoxia,^18,20,30 and staff, patient, and caretaker education.^{19,21,23,27-30} Unique strategies were implemented in certain studies. For instance, one study used massage therapy,²⁸ preventing delays in transfer logistics in another,³⁰ and a third addressed psychosocial problems.²⁵ Overall, the selection of strategies depended on the patient setting; thus, no one care bundle should be expected to emerge as a universal model for delirium prevention. Rather, these results should be interpreted within their specific care contexts and judged on the quality of evidence (eg, effect size and statistically significant findings, low risk of bias, sound experimental design). The one study that failed to find any positive effect on delirium, that of Gagnon et al.,²¹ was conducted on an inpatient palliative care service in Canada, and its negative finding may reflect the unique delirium risk factors in patients who are nearing end of life.

This current review differs from previous delirium prevention reviews in operationally defining a “model of care.” We identified a great deal of variation in specific models and team composition. For example, some interventions were carried out by nurses^18-20,31 and physicians,^20,21,25,32 whereas others involved physical therapists,^20,22,28 medical residents,²³ geriatricians,^22,23,25 pharmacists,²⁶ researchers,¹⁸ and trained volunteers.²² In all cases, the staff roles were expanded to include new tasks, and the clinical team worked collaboratively to administer interventions across multiple domains. Team-related considerations are critical because modern medical care is inherently interdependent.⁹ These broad differences in team composition across studies demonstrate the number of potential options for team structure and function. They also highlight the number of “moving parts” to be considered when designing and implementing delirium care bundles.

Most of the delirium prevention studies implementing models of care are characterized by a substantial risk of bias. We evaluated risk of bias along six categories of potential sources, including random assignment to groups, ability to foresee future group allocation, blinding of participants and personnel to group assignment, blinding of outcome assessment, completeness of outcome data, selective reporting, and other potential sources of bias.¹⁷ Two of the three studies that used randomization had a low risk of bias, and four additional studies had a moderate risk of bias. Allocation concealment was accomplished only in randomized controlled trials, whereas blinding of both subjects and study personnel was not implemented in any of the studies. Although some studies relied on data analysis by research personnel blinded to group membership or the nature of the intervention, others failed to do so or failed to describe data analysis in sufficient detail. Studies also failed to report the percentage of unscorable or otherwise omitted delirium assessments necessary to calculate attrition rates or to understand the comprehensiveness of outcome assessment in a systematic manner. Other potential sources of bias included systematic differences between the intervention and control groups (such as differences in gender composition, age, or delirium risk) at study outset.

A primary limitation of this review is the heterogeneity of settings, interventions, and models of care across included studies. We excluded several studies from this review for being delivered by a single individual or service line (eg, introduction of a geriatric consult service, physical therapy, or volunteers), for providing a single intervention (eg, early ambulation alone), or for multiple interventions targeting a single domain (eg, sleep). We did so because the future of value-based care lies in collaboration of providers and services, and in a way the complexity across and within these studies ultimately reflects the complexity of medical settings as well as the multifactorial nature of delirium. The broader message is a call for increasing the integration of delirium-related care services. As discussed earlier, the high risk of bias across these studies is a limitation of our findings; high-quality evidence on the value of delirium prevention models of care remains limited. Thus, although our review suggests that there are multicomponent models of care that hold promise in mitigating delirium and its outcomes, additional randomized studies are required to confirm the efficacy of such models of care and to test which services, interventions, and clinical domains deserve priority.

To our knowledge, this is the first systematic review and meta-analysis of delirium preventive models of care. Models of care, as defined here, necessarily included a multidisciplinary team in which traditional staff roles had been revised to implement a multicomponent, multidomain intervention. Other recent reviews are available for multicomponent pharmacological and nonpharmacological interventions to prevent and manage delirium,^41-49 but just as important as which interventions are being delivered is the team that delivers them. Care delivery in a complex medical system is more than handing a patient a medication or facilitating ambulation; it requires a choreographed dance of teamwork and integration across services. This review identifies promising models of care that deserve further recognition, refinement, and ultimately widespread implementation.

Acknowledgments

The authors comprise a writing group created through the Delirium Boot Camp, an annual meeting originally sponsored by the Center of Excellence for Delirium in Aging: Research, Training, and Educational Enhancement (CEDARTREE, Boston, Massachusetts); it is currently supported by the Network for Investigation of Delirium: Unifying Scientists (NIDUS, Boston, Massachusetts). The authors would like to thank medical librarian Rita Mitchell (Aurora Health Care, Milwaukee, Wisconsin) for the literature search, senior scientific writer and editor Joe Grundle (Aurora Research Institute, Milwaukee, Wisconsin) for editorial assistance, and graphics specialist Brian Miller (Aurora Research Institute, Milwaukee, Wisconsin) for help with the figures.

Disclosures

The authors report no relevant conflicts of interest.

Funding

No funding was dedicated to the conduct of this review.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colonic mucosa. Classically, it starts in the rectum and can extend continuously from the distal to the proximal colon. The defining clinical symptom of UC is bloody diarrhea, typically accompanied by rectal urgency and mucus discharge. The natural history of this disease includes periods of exacerbations and remissions occurring spontaneously or in response to medical treatment.¹

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of UC that typically requires hospitalization and interdisciplinary care between hospitalists, gastroenterologists, and colorectal or general surgeons. The risk of a patient with UC requiring hospitalization for ASUC ranges from 15%-25%^2,3 and, in total, UC accounts for 30,000 hospital visits annually.⁴ The direct medical costs exceed $4 billion annually, with hospital costs of over $960 million.⁵ Historically, mortality from ASUC was as high as 24% but decreased substantially to 7% after the introduction of systemic corticosteroid therapy.⁶ Further advances in care have reduced mortality to approximately 1% or less.^7,8 Nonetheless, up to 20% of patients admitted with ASUC have a colectomy on their first admission, and this rate rises to 40% after two admissions.²

To categorize UC severity, assess patients using the Truelove and Witt’s criteria. The system classifies patients as having mild, moderate, severe, or fulminant disease. Severe disease by these criteria includes patients with >6 bloody bowel movements per day and at least one of the following clinical features: fever (>37.8°C), tachycardia (>90 bpm), anemia (hemoglobin <10.5 g/dl), or elevated inflammatory markers (traditionally, erythrocyte sedimentation rate greater than 30 mm/h or, more recently, C-reactive protein (CRP) greater than 30 mg/L. (Table 1).^6,9

Fulminant colitis refers to a subgroup of patients with more than 10 stools per day, continuous bleeding, abdominal pain, colonic dilatation on abdominal X-ray film, and severe toxic symptoms including fever and anorexia. Such patients are at risk of progressing to toxic megacolon and bowel perforation.¹⁰

Patients with ASUC almost always require hospitalization for their disease management. In many cases, these patients have been receiving outpatient oral prednisone 40-60 mg daily but continue to have ongoing disease activity.¹¹ Most patients will require close clinical monitoring, frequent blood testing, endoscopic or radiologic evaluation, as well as administration of intravenous corticosteroids. The average length of stay (LOS) ranges from 4.6 to 12.5 days, depending on disease severity.¹² Not surprisingly, Kelso et al. reported that predictors of hospital LOS greater than four days include initiating a biologic drug in the hospital, undergoing two or more imaging modalities and treatment with intravenous steroids,¹³ and so it is rare that patients do not meet billing requirements for an inpatient level of care.

The multifaceted initial inpatient evaluation of patients with ASUC aims to assess disease severity, identify and prevent potential complications, and initiate planning for potential failure of first-line pharmacologic therapy. Due to the accumulating evidence that involving physicians with expertise in managing ASUC improves outcomes, gastroenterologists should be involved in the care of patients with ASUC from the time of their admission.^14,15 Additionally, creating standardized care pathways for the management of ASUC can reduce cost, LOS, and improve quality.¹⁶

History and Physical Examination

Patients should be asked about fever, abdominal pain, nausea, emesis, bloating, weight loss, and bowel movements (frequency, consistency, the presence of blood, urgency, nighttime awakenings). The number of bowel movements over a 24-hour period should be quantified as this helps assess the overall disease severity (Table 1).

The patient’s initial inflammatory bowel disease (IBD) history is also essential. The review of pertinent information regarding the patient’s initial diagnosis of UC includes the severity and anatomic extent of disease, extraintestinal manifestations, previous medical therapies, and surgical interventions. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or antibiotics should be identified as they may precipitate flares.¹⁷ Travel history may be pertinent as travel increases the risk of infections with food-borne or parasitic pathogens.¹⁸

Physical examination begins with an assessment of vital signs and volume status. Abdominal examination should include evaluation of bowel sounds, an assessment of distention, location, the extent of abdominal tenderness, and peritoneal signs. The abdominal exam should be interpreted in the context of the patient’s medications, as the use of steroid or analgesic therapies may affect the sensitivity for detecting complications. An external rectal exam evaluating perianal disease should be performed, as perianal disease raises concern for Crohn’s, a disease whose surgical management differs from UC.

A careful exam for extraintestinal manifestations is also essential. The skin should be evaluated for any new rashes, especially on the anterior shin consistent with erythema nodosum or ulcerated lesions on the skin suggestive of pyoderma gangrenosum. The peripheral joints should also be examined for any synovitis. Additional examinations should be performed based on any reported symptoms (eg, the ophthalmic exam for uveitis or scleritis if visual changes or eye pain are reported). Some extraintestinal manifestations require subspecialty consultation and comanagement to guide disease therapy. Patients with underlying pyoderma gangrenosum may require a dermatology consultation to guide management. Ocular inflammation requires ophthalmology involvement, and inflammatory arthritis is best comanaged with rheumatology.¹⁹

Laboratory Testing

Initial testing should include a complete blood count with differential, basic metabolic panel, and liver chemistries including alkaline phosphatase and albumin. When relevant, pregnancy testing should be performed. Measure CRP on admission so that its trajectory can be followed during therapy. However, a normal CRP does not exclude the presence of a UC flare as a subset of patients with ASUC will have a normal CRP despite severe mucosal inflammation.²⁰

Since one-third of patients do not respond to intravenous corticosteroids and will require rescue therapy during the hospitalization with infliximab or cyclosporine, anticipatory testing for these medications should be performed on admission to avoid delays in the administration of rescue therapy.^6,21 This should include an interferon-gamma release assay (eg, quantiferon gold) to test for latent tuberculosis and hepatitis B serologies in anticipation of possible treatment with infliximab. An interferon-gamma release assay is preferred to a tuberculin skin test because patients may be anergic, and a skin test does not provide a control to determine whether a negative test is due to anergy. In contrast, although a quantiferon gold test can be indeterminate in ASUC due to disease activity and systemic steroids, the results indicate if the patient is anergic so that one will not rely on a false-negative result. In the event of an equivocal result, a careful clinical assessment for risks of TB exposures should be elicited, and a chest radiograph should be obtained.²² In patients with prior high risk of tuberculosis exposures or a positive test for tuberculosis, an infectious disease specialist should be consulted early to advise if therapy should be started in preparation for the potential use of infliximab.²³ In cases where cyclosporine may be considered, magnesium and total cholesterol level should be checked. Sending thiopurine methyltranferase (TPMT) enzyme activity should be considered as well, in case of a need for future thiopurine use for maintenance of disease activity.²⁴

Infectious diarrhea may be indistinguishable from ASUC and may also be the trigger of a flare; thus, it is important to rule out infection with stool microbiologic studies. Most importantly, Clostridium difficile infection must be ruled out in all patients with ASUC. Although patients with IBD, especially those with UC, have significantly higher rates of asymptomatic C. difficile carriage than the general population, a positive polymerase chain reaction test for C. difficile in a patient with ASUC should prompt treatment with oral vancomycin.²⁵ However, if carriage if suspected and a subsequent enzyme-linked immunoassay for C. difficile toxin is negative, treatment can be discontinued. Active C. difficile infection in patients with IBD is associated with increased disease severity, greater length of hospital stay, and increased the likelihood of colectomy and mortality.^26,27 Other bacterial infections including Escherichia coli, Campylobacter, Shigella, Salmonella, Yersinia, Entamoeba histolytica, as well as other parasitic infestations may mimic UC. Testing should be considered in cases of foreign travel, immunosuppression or contact with other persons with diarrhea.^7,28 Routine testing of these other enteric infections without a clear exposure risk is of little benefit and may raise costs.^23,29

Radiologic Evaluation

A plain X-ray film of the abdomen should be obtained in all patients on admission to evaluate for evolving colonic dilation or undiagnosed free air. Small bowel distension >3 cm may predict an increased risk of colectomy.³⁰ Clinicians must be mindful that steroids can mask peritoneal signs and that retroperitoneal perforations may not be apparent on plain X-ray films. Nonetheless, a CT of the abdomen is usually not necessary and should be reserved for cases with severe abdominal pain out of proportion to clinical signs in which a plain X-ray film is unrevealing. Judicious use of CT imaging is especially important in younger patients, as there is growing concern that patients with IBD may be exposed to potentially harmful cumulative levels of radiation in their lifetime from repeated CT imaging.³¹

Endoscopic Evaluation

Flexible sigmoidoscopy aids in the assessment of disease severity and extent and biopsies can assist in ruling out a diagnosis of cytomegalovirus (CMV) colitis in patients already on immunosuppression. For this reason, many clinicians prefer to perform a sigmoidoscopy on admission.²³ If one is not performed on admission, a sigmoidoscopy is advised in all patients who are not responding adequately after 72 hours of intravenous steroid therapy in order to rule out superimposed CMV colitis.²⁸

Sigmoidoscopy should be avoided in patients with toxic megacolon and when there is a concern for peritonitis. A complete colonoscopy is rarely indicated in the acute setting and carries a theoretical risk of colonic perforation.⁷

The first therapeutic steps aim to reduce inflammation with the use of systemic corticosteroids, avoid colonic and extraintestinal complications, and plan for the potential need for rescue therapy.

Intravenous Corticosteroids

The cornerstone of ASUC management is treatment with intravenous corticosteroids. Their initiation should not be delayed in patients with an established diagnosis of UC while waiting for results of evaluations for infectious colitis. Even among patients who have failed oral steroids, a meta-regression analysis showed that two-thirds of patients will still respond to intravenous corticosteroids.^21,32 Methylprednisolone 20 mg IV three times daily (or hydrocortisone 100 mg IV three times daily) is a standard regimen; higher doses do not provide additional benefit.²¹ Patients’ response to intravenous steroids should be assessed with repeat labs including CRP and an assessment of the total number of bowel movements over a 24-hour period, with special attention to their overall response after three days of treatment.^33-36

Intravenous Fluids

Many patients admitted with ASUC will have significant volume depletion, and intravenous fluids should be administered in a manner like other volume-depleted or oral-intake-restricted patients.

Venous Thromboembolism Prophylaxis

The risk of VTE in hospitalized patients with IBD exceeds that of inpatients without IBD, approximately 2%, a risk similar to patients with respiratory failure.³⁷ Additionally, VTE in hospitalized patients with IBD is associated with a 2.5-fold increase in mortality.^38,39 Therefore, all patients hospitalized with ASUC should receive subcutaneous unfractionated or low molecular weight heparin or fondaparinux for VTE prophylaxis. Rectal bleeding, expected in ASUC, is not a contraindication to chemo-prophylaxis. Additionally, it is important to check if patients are receiving the ordered VTE prophylaxis.^40,41 Pleet et al. found that only 7% of patients at a tertiary center had adequate prophylaxis for greater than 80% of their hospitalization.⁴¹

Unnecessary or Potentially Harmful Medications

Several medications have the potential for misuse in patients hospitalized with UC.

Antimotility Agents

Loperamide, diphenoxylate, and opiate antidiarrheals should not be used as they may provoke toxic megacolon.⁴² Similarly, drugs with antimotility side effects (eg, anticholinergics) should be avoided.

Opiates

In addition to their undesirable antimotility effect, the use of opiates has been associated with poor outcomes among inpatients and outpatients with IBD, including increased morbidity and mortality.^43,44 Pain severe enough to require opiates should raise suspicion for toxic megacolon, perforation, or a noninflammatory etiology. If opiates are utilized, they should be ordered as one-time doses and the patient should be reassessed for each dose.

Nonsteroidal Anti-inflammatory Drugs

These drugs, which include oral NSAIDs, intravenous ketorolac, and topic diclofenac gels, may increase disease activity in inflammatory bowel disease and should be avoided.¹⁷

5-aminosalicylates (5-ASA)

A small proportion of patients experience a paradoxical worsening of diarrhea due to the use of 5-ASA agents such as mesalamine. It is reasonable to discontinue or avoid the use of 5-ASA agents in hospitalized patients, especially as there is little to no benefit from combining a 5-ASA with a biologic or immunosuppressive drug.⁴⁵

Antibiotics

There is no role for the routine use of antibiotics in patients hospitalized with ASUC. ^23,46,47 Inappropriate use of antibiotics raises the risk of C. difficile infection and antibiotic resistance. However, in cases of suspected toxic megacolon or perforation, antibiotics should be administered. In situations in which a patient is treated with triple immunosuppression (ie, steroids plus two other agents, cyclosporine and mercaptopurine) antibiotic prophylaxis for Pneumocystis jiroveci is advisable.⁴⁸ Using a large insurance database, Long et al. reported a low absolute incidence of Pneumocystis jiroveci in IBD patients but noted that the risk in patients with IBD was still significantly higher than matched controls. While it can be considered, we typically refrain from using prophylaxis in patients on double immunosuppression (for example, steroids plus infliximab) due to the potential adverse effects of antibiotics in this population, though many advocate using prophylaxis for all patients on cyclosporine even if this is only double immunosuppressive therapy.²³

Surgical Consultation

Involving a surgeon early in an ASUC patient’s care­—before needing urgent colectomy—is critical. As part of the consultation, a surgeon experienced in IBD should meet with patients to discuss multistage colectomy with ileostomy and potential future J-pouch (ileal pouch-anal anastomosis) formation. Patients should be given ample opportunity to ask questions before surgery may become urgent. Also, patients should be counseled on realistic expectations of ostomy and pouch function and, ideally, meet with an ostomy nurse.²³

At some centers, surgical consultation is requested on the first hospital day, but this can result in consultations for patients who ultimately respond to intravenous steroids. Therefore, some centers advocate for surgical consultation only after a patient has failed treatment with intravenous steroids (ie, day three to four) when the risk of needing surgical management increases.²³

Nutrition

Bowel rest with parenteral nutrition does not improve outcomes in ASUC versus an oral diet, and there is no contraindication to allowing patients to continue on a regular diet unless they have toxic megacolon or other signs of fulminant colitis.^49,50 However, patients may feel better eating less, as this will reduce their bowel movement frequency. Unfortunately, this can give a false sense of reassurance that the patient is improving. Therefore, it remains important to evaluate a patient’s symptoms in the context of their food intake.

Assessing Response to Steroids

Patients who do not respond adequately to the first-line intravenous steroid therapy will require medical or surgical rescue therapy; therefore, deciding whether a patient has responded is essential. Patients should have less than four bowel movements per day – ideally just one to two – with no blood to indicate a complete response. For more ambiguous situations, although there is no strict definition of steroid responsiveness, multiple prediction indices have attempted to identify patients who will require rescue therapy. One of the simplest, the Oxford index, illustrates two of the most critical parameters to follow, stool frequency and CRP.⁵¹ In a preinfliximab cohort, Oxford index predicted an 85% likelihood of colectomy in patients with eight or more daily bowel movements or with three to eight daily bowel movements and a CRP greater than 45 mg/L after three days of intravenous steroid treatment.⁵² To assist with assessing responsiveness to therapy, we ask patients to log their bowel movements – either on paper or on a whiteboard in the hospital room – so that we can review their progress daily. Other predictors of colectomy include hypoalbuminemia, scoring of endoscopic severity, and colonic dilation.⁵³

Patients who fail to respond to intravenous corticosteroids after three days^33,35 of treatment should be started on rescue therapy with infliximab or cyclosporine or undergo colectomy. A common pitfall in the treatment of ASUC is waiting for a response to steroids beyond this time frame, after which patients are unlikely to benefit.^34,36 Furthermore, patients for whom surgical rescue therapy is delayed have higher operative morbidity and mortality.^54,55 Because timely decision making regarding rescue therapy is crucial to optimizing outcomes, patient education efforts regarding potential rescue therapy should take place on admission or soon after, rather than waiting to ascertain steroid responsiveness.

Medical options for rescue therapy include the antitumor necrosis factor (anti-TNF) agent infliximab or the calcineurin inhibitor cyclosporine. In general, infliximab and cyclosporine have been found to be roughly equivalent in efficacy in clinical trials regarding response, remission, and colectomy at 12 months.^56,57 However, many clinicians prefer infliximab due to its relative ease of use, familiarity with the agent from outpatient experience, and ability to continue to use long term for maintenance of disease remission.⁵⁸ In contrast to infliximab, intravenous cyclosporine requires closer monitoring and labs to assess the therapeutic trough level. The decision regarding which drug to use should be made on a case-by-case basis in conjunction with a gastroenterologist experienced in their use, and if no such specialist is available, transfer to a specialized center should be considered. Generally, successive treatment with cyclosporine or infliximab followed by third-line salvage therapy with the other drug should be avoided due to low rates of response and high rates of adverse events.⁵⁹

Infliximab

Infliximab is an intravenously-administered anti-TNF monoclonal chimeric antibody that is effective both for outpatient treatment of moderate to severe UC and inpatient treatment of ASUC.¹ It is relatively contraindicated in patients with untreated latent tuberculosis, demyelinating disease, advanced congestive heart failure, or uncontrolled infection.

The optimal dosing strategy for infliximab in ASUC is unknown. Infliximab clearance in the setting of ASUC is increased, partly because it is bound to albumin, which is often low in ASUC, and partly because it is excreted in the stool.^60,61 As a result, accelerated loading doses may be more successful than a typical loading schedule,⁶² and most clinicians use alternative dosing strategies.⁶³ Our typical approach for ASUC is an initial dose of 10 mg/kg rather than 5 mg/kg, with an additional 10 mg/kg dose 48-72 hours later if an adequate clinical response is lacking. Patients who respond to infliximab can continue to use the drug as an outpatient for maintenance of remission.

Cyclosporine

Cyclosporine is a fast-acting immunosuppressive agent that acts primarily via T-cell inhibition. Although older literature used a dose of 4 mg/kg per day, a randomized trial demonstrated similar response rates to a dose of 2 mg/kg per day.⁶⁴ Patients receiving treatment with cyclosporine, which is given as a continuous infusion, must be monitored for toxicities. These can include potentially severe infection, seizures (often associated with low total cholesterol or hypomagnesemia), electrolyte abnormalities, renal impairment, hypertension, hypertrichosis, tremor, and others.⁶⁵

Before initiation of treatment, serum cholesterol levels should be obtained to screen for low total cholesterol that may portend risk of seizures on the drug. Additionally, baseline creatinine and magnesium should be established. While on treatment, daily serum cyclosporine levels and electrolytes including magnesium should be measured. Patients who respond to intravenous cyclosporine must be transitioned to oral cyclosporine and have stable drug levels before discharge. Unfortunately, oral cyclosporine has not been shown to be as effective as long-term maintenance therapy. Therefore, cyclosporine can only be used as a “bridge” to another therapy. Historically, thiopurines like azathioprine or mercaptopurine have been used for this purpose because they are effective for the treatment of UC but may require months to have a full therapeutic effect. There have been promising reports of using vedolizumab similarly.^66,67 Vedolizumab is a monoclonal antibody that selectively blocks lymphocyte trafficking to the gut that, like thiopurines, has an onset of action that is significantly longer than calcineurin and TNF inhibitors.

Colectomy should be considered as a second- or third-line therapy for patients who fail to respond to intravenous corticosteroids. In an analysis of 10 years of data from the Nationwide Inpatient Sample, mortality rates for colectomy in this setting varied from 0.7% at high volume centers to 4% at low volume centers.⁶⁸ Therefore, if a patient is not hospitalized at a center with expertise in colectomy for UC, transfer to a specialized center should be considered. Colectomy should be performed promptly in all the patients who have failed rescue therapy with infliximab or cyclosporine or have opted against medical rescue therapy. Surgery should be performed emergently in patients with toxic megacolon, uncontrolled colonic hemorrhage or perforation.

Physician and center-level characteristics are associated with the quality of care and outcomes in ASUC. Gastroenterologists with expertise in IBD are more likely than other gastroenterologists to request appropriate surgical consultation for steroid-refractory patients,⁶⁹ and inpatients with ASUC primarily cared by gastroenterologists rather than nongastroenterologists have lower in-hospital and one-year mortality.¹⁴ Moreover, surgical outcomes differ based on center volume, with higher volume centers having lower rates of postoperative mortality.^68,70 However, even at referral centers, key metrics of care quality such as rates of VTE prophylaxis, testing for C. difficile, and timely rescue therapy for steroid-refractory UC patients are suboptimal, with only 70%-82% of patients with IBD hospitalized at four referral centers in Canada meeting these metrics.⁷¹

Inpatient clinical pathways reduce LOS, reduce hospital costs, and likely reduce complications.⁷² For this reason, a consensus group recommended the use of care pathways for the management of ASUC and, although there is little data on the use of pathways for ASUC specifically, the use of such a pathway in the United Kingdom was associated with improved metrics including LOS, time to VTE prophylaxis, testing of stool for infection, CRP measurement, and timely gastroenterologist consultation.^16,18

In general, patients should enter clinical remission, defined as resolution of rectal bleeding and diarrhea or altered bowel habits,⁷³ before discharge, and achieving this may require a relatively prolonged hospitalization. Most patients should have one to two bowel movements a day without blood but, at a minimum, all should have less than four nonbloody bowel movements per day. Patients are candidates for discharge if they remain well after transitioning to oral prednisone at a dose of 40-60 mg daily and tolerate a regular diet.

For patients who initiated infliximab during their admission, plans for outpatient infusions including insurance approval should be made before discharge, and patients who started cyclosporine should be transitioned to oral dosing and have stable serum concentrations before leaving the hospital. Patients should leave with a preliminary plan for a steroid taper, which may vary depending on their clinical presentation. Usually, gastroenterology follow-up should be arranged after two weeks following discharge, but patients on cyclosporine need sooner laboratory monitoring.

The care of patients with ASUC requires an interdisciplinary team and close collaboration between hospitalists, gastroenterologists, and surgeons. Patients should be treated with intravenous corticosteroids and monitored carefully for response and need for rescue therapy. Establishing algorithms for the management of patients with ASUC can further improve the care of these complex patients.

Disclosures

Drs. Feuerstein, Fudman, and Sattler report no potential conflict of interest.

Funding

This work was not supported by any grant.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colonic mucosa. Classically, it starts in the rectum and can extend continuously from the distal to the proximal colon. The defining clinical symptom of UC is bloody diarrhea, typically accompanied by rectal urgency and mucus discharge. The natural history of this disease includes periods of exacerbations and remissions occurring spontaneously or in response to medical treatment.¹

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of UC that typically requires hospitalization and interdisciplinary care between hospitalists, gastroenterologists, and colorectal or general surgeons. The risk of a patient with UC requiring hospitalization for ASUC ranges from 15%-25%^2,3 and, in total, UC accounts for 30,000 hospital visits annually.⁴ The direct medical costs exceed $4 billion annually, with hospital costs of over $960 million.⁵ Historically, mortality from ASUC was as high as 24% but decreased substantially to 7% after the introduction of systemic corticosteroid therapy.⁶ Further advances in care have reduced mortality to approximately 1% or less.^7,8 Nonetheless, up to 20% of patients admitted with ASUC have a colectomy on their first admission, and this rate rises to 40% after two admissions.²

To categorize UC severity, assess patients using the Truelove and Witt’s criteria. The system classifies patients as having mild, moderate, severe, or fulminant disease. Severe disease by these criteria includes patients with >6 bloody bowel movements per day and at least one of the following clinical features: fever (>37.8°C), tachycardia (>90 bpm), anemia (hemoglobin <10.5 g/dl), or elevated inflammatory markers (traditionally, erythrocyte sedimentation rate greater than 30 mm/h or, more recently, C-reactive protein (CRP) greater than 30 mg/L. (Table 1).^6,9

Fulminant colitis refers to a subgroup of patients with more than 10 stools per day, continuous bleeding, abdominal pain, colonic dilatation on abdominal X-ray film, and severe toxic symptoms including fever and anorexia. Such patients are at risk of progressing to toxic megacolon and bowel perforation.¹⁰

Patients with ASUC almost always require hospitalization for their disease management. In many cases, these patients have been receiving outpatient oral prednisone 40-60 mg daily but continue to have ongoing disease activity.¹¹ Most patients will require close clinical monitoring, frequent blood testing, endoscopic or radiologic evaluation, as well as administration of intravenous corticosteroids. The average length of stay (LOS) ranges from 4.6 to 12.5 days, depending on disease severity.¹² Not surprisingly, Kelso et al. reported that predictors of hospital LOS greater than four days include initiating a biologic drug in the hospital, undergoing two or more imaging modalities and treatment with intravenous steroids,¹³ and so it is rare that patients do not meet billing requirements for an inpatient level of care.

The multifaceted initial inpatient evaluation of patients with ASUC aims to assess disease severity, identify and prevent potential complications, and initiate planning for potential failure of first-line pharmacologic therapy. Due to the accumulating evidence that involving physicians with expertise in managing ASUC improves outcomes, gastroenterologists should be involved in the care of patients with ASUC from the time of their admission.^14,15 Additionally, creating standardized care pathways for the management of ASUC can reduce cost, LOS, and improve quality.¹⁶

History and Physical Examination

Patients should be asked about fever, abdominal pain, nausea, emesis, bloating, weight loss, and bowel movements (frequency, consistency, the presence of blood, urgency, nighttime awakenings). The number of bowel movements over a 24-hour period should be quantified as this helps assess the overall disease severity (Table 1).

The patient’s initial inflammatory bowel disease (IBD) history is also essential. The review of pertinent information regarding the patient’s initial diagnosis of UC includes the severity and anatomic extent of disease, extraintestinal manifestations, previous medical therapies, and surgical interventions. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or antibiotics should be identified as they may precipitate flares.¹⁷ Travel history may be pertinent as travel increases the risk of infections with food-borne or parasitic pathogens.¹⁸

Physical examination begins with an assessment of vital signs and volume status. Abdominal examination should include evaluation of bowel sounds, an assessment of distention, location, the extent of abdominal tenderness, and peritoneal signs. The abdominal exam should be interpreted in the context of the patient’s medications, as the use of steroid or analgesic therapies may affect the sensitivity for detecting complications. An external rectal exam evaluating perianal disease should be performed, as perianal disease raises concern for Crohn’s, a disease whose surgical management differs from UC.

A careful exam for extraintestinal manifestations is also essential. The skin should be evaluated for any new rashes, especially on the anterior shin consistent with erythema nodosum or ulcerated lesions on the skin suggestive of pyoderma gangrenosum. The peripheral joints should also be examined for any synovitis. Additional examinations should be performed based on any reported symptoms (eg, the ophthalmic exam for uveitis or scleritis if visual changes or eye pain are reported). Some extraintestinal manifestations require subspecialty consultation and comanagement to guide disease therapy. Patients with underlying pyoderma gangrenosum may require a dermatology consultation to guide management. Ocular inflammation requires ophthalmology involvement, and inflammatory arthritis is best comanaged with rheumatology.¹⁹

Laboratory Testing

Initial testing should include a complete blood count with differential, basic metabolic panel, and liver chemistries including alkaline phosphatase and albumin. When relevant, pregnancy testing should be performed. Measure CRP on admission so that its trajectory can be followed during therapy. However, a normal CRP does not exclude the presence of a UC flare as a subset of patients with ASUC will have a normal CRP despite severe mucosal inflammation.²⁰

Since one-third of patients do not respond to intravenous corticosteroids and will require rescue therapy during the hospitalization with infliximab or cyclosporine, anticipatory testing for these medications should be performed on admission to avoid delays in the administration of rescue therapy.^6,21 This should include an interferon-gamma release assay (eg, quantiferon gold) to test for latent tuberculosis and hepatitis B serologies in anticipation of possible treatment with infliximab. An interferon-gamma release assay is preferred to a tuberculin skin test because patients may be anergic, and a skin test does not provide a control to determine whether a negative test is due to anergy. In contrast, although a quantiferon gold test can be indeterminate in ASUC due to disease activity and systemic steroids, the results indicate if the patient is anergic so that one will not rely on a false-negative result. In the event of an equivocal result, a careful clinical assessment for risks of TB exposures should be elicited, and a chest radiograph should be obtained.²² In patients with prior high risk of tuberculosis exposures or a positive test for tuberculosis, an infectious disease specialist should be consulted early to advise if therapy should be started in preparation for the potential use of infliximab.²³ In cases where cyclosporine may be considered, magnesium and total cholesterol level should be checked. Sending thiopurine methyltranferase (TPMT) enzyme activity should be considered as well, in case of a need for future thiopurine use for maintenance of disease activity.²⁴

Infectious diarrhea may be indistinguishable from ASUC and may also be the trigger of a flare; thus, it is important to rule out infection with stool microbiologic studies. Most importantly, Clostridium difficile infection must be ruled out in all patients with ASUC. Although patients with IBD, especially those with UC, have significantly higher rates of asymptomatic C. difficile carriage than the general population, a positive polymerase chain reaction test for C. difficile in a patient with ASUC should prompt treatment with oral vancomycin.²⁵ However, if carriage if suspected and a subsequent enzyme-linked immunoassay for C. difficile toxin is negative, treatment can be discontinued. Active C. difficile infection in patients with IBD is associated with increased disease severity, greater length of hospital stay, and increased the likelihood of colectomy and mortality.^26,27 Other bacterial infections including Escherichia coli, Campylobacter, Shigella, Salmonella, Yersinia, Entamoeba histolytica, as well as other parasitic infestations may mimic UC. Testing should be considered in cases of foreign travel, immunosuppression or contact with other persons with diarrhea.^7,28 Routine testing of these other enteric infections without a clear exposure risk is of little benefit and may raise costs.^23,29

Radiologic Evaluation

A plain X-ray film of the abdomen should be obtained in all patients on admission to evaluate for evolving colonic dilation or undiagnosed free air. Small bowel distension >3 cm may predict an increased risk of colectomy.³⁰ Clinicians must be mindful that steroids can mask peritoneal signs and that retroperitoneal perforations may not be apparent on plain X-ray films. Nonetheless, a CT of the abdomen is usually not necessary and should be reserved for cases with severe abdominal pain out of proportion to clinical signs in which a plain X-ray film is unrevealing. Judicious use of CT imaging is especially important in younger patients, as there is growing concern that patients with IBD may be exposed to potentially harmful cumulative levels of radiation in their lifetime from repeated CT imaging.³¹

Endoscopic Evaluation

Flexible sigmoidoscopy aids in the assessment of disease severity and extent and biopsies can assist in ruling out a diagnosis of cytomegalovirus (CMV) colitis in patients already on immunosuppression. For this reason, many clinicians prefer to perform a sigmoidoscopy on admission.²³ If one is not performed on admission, a sigmoidoscopy is advised in all patients who are not responding adequately after 72 hours of intravenous steroid therapy in order to rule out superimposed CMV colitis.²⁸

Sigmoidoscopy should be avoided in patients with toxic megacolon and when there is a concern for peritonitis. A complete colonoscopy is rarely indicated in the acute setting and carries a theoretical risk of colonic perforation.⁷

The first therapeutic steps aim to reduce inflammation with the use of systemic corticosteroids, avoid colonic and extraintestinal complications, and plan for the potential need for rescue therapy.

Intravenous Corticosteroids

The cornerstone of ASUC management is treatment with intravenous corticosteroids. Their initiation should not be delayed in patients with an established diagnosis of UC while waiting for results of evaluations for infectious colitis. Even among patients who have failed oral steroids, a meta-regression analysis showed that two-thirds of patients will still respond to intravenous corticosteroids.^21,32 Methylprednisolone 20 mg IV three times daily (or hydrocortisone 100 mg IV three times daily) is a standard regimen; higher doses do not provide additional benefit.²¹ Patients’ response to intravenous steroids should be assessed with repeat labs including CRP and an assessment of the total number of bowel movements over a 24-hour period, with special attention to their overall response after three days of treatment.^33-36

Intravenous Fluids

Many patients admitted with ASUC will have significant volume depletion, and intravenous fluids should be administered in a manner like other volume-depleted or oral-intake-restricted patients.

Venous Thromboembolism Prophylaxis

The risk of VTE in hospitalized patients with IBD exceeds that of inpatients without IBD, approximately 2%, a risk similar to patients with respiratory failure.³⁷ Additionally, VTE in hospitalized patients with IBD is associated with a 2.5-fold increase in mortality.^38,39 Therefore, all patients hospitalized with ASUC should receive subcutaneous unfractionated or low molecular weight heparin or fondaparinux for VTE prophylaxis. Rectal bleeding, expected in ASUC, is not a contraindication to chemo-prophylaxis. Additionally, it is important to check if patients are receiving the ordered VTE prophylaxis.^40,41 Pleet et al. found that only 7% of patients at a tertiary center had adequate prophylaxis for greater than 80% of their hospitalization.⁴¹

Unnecessary or Potentially Harmful Medications

Several medications have the potential for misuse in patients hospitalized with UC.

Antimotility Agents

Loperamide, diphenoxylate, and opiate antidiarrheals should not be used as they may provoke toxic megacolon.⁴² Similarly, drugs with antimotility side effects (eg, anticholinergics) should be avoided.

Opiates

In addition to their undesirable antimotility effect, the use of opiates has been associated with poor outcomes among inpatients and outpatients with IBD, including increased morbidity and mortality.^43,44 Pain severe enough to require opiates should raise suspicion for toxic megacolon, perforation, or a noninflammatory etiology. If opiates are utilized, they should be ordered as one-time doses and the patient should be reassessed for each dose.

Nonsteroidal Anti-inflammatory Drugs

These drugs, which include oral NSAIDs, intravenous ketorolac, and topic diclofenac gels, may increase disease activity in inflammatory bowel disease and should be avoided.¹⁷

5-aminosalicylates (5-ASA)

A small proportion of patients experience a paradoxical worsening of diarrhea due to the use of 5-ASA agents such as mesalamine. It is reasonable to discontinue or avoid the use of 5-ASA agents in hospitalized patients, especially as there is little to no benefit from combining a 5-ASA with a biologic or immunosuppressive drug.⁴⁵

Antibiotics

There is no role for the routine use of antibiotics in patients hospitalized with ASUC. ^23,46,47 Inappropriate use of antibiotics raises the risk of C. difficile infection and antibiotic resistance. However, in cases of suspected toxic megacolon or perforation, antibiotics should be administered. In situations in which a patient is treated with triple immunosuppression (ie, steroids plus two other agents, cyclosporine and mercaptopurine) antibiotic prophylaxis for Pneumocystis jiroveci is advisable.⁴⁸ Using a large insurance database, Long et al. reported a low absolute incidence of Pneumocystis jiroveci in IBD patients but noted that the risk in patients with IBD was still significantly higher than matched controls. While it can be considered, we typically refrain from using prophylaxis in patients on double immunosuppression (for example, steroids plus infliximab) due to the potential adverse effects of antibiotics in this population, though many advocate using prophylaxis for all patients on cyclosporine even if this is only double immunosuppressive therapy.²³

Surgical Consultation

Involving a surgeon early in an ASUC patient’s care­—before needing urgent colectomy—is critical. As part of the consultation, a surgeon experienced in IBD should meet with patients to discuss multistage colectomy with ileostomy and potential future J-pouch (ileal pouch-anal anastomosis) formation. Patients should be given ample opportunity to ask questions before surgery may become urgent. Also, patients should be counseled on realistic expectations of ostomy and pouch function and, ideally, meet with an ostomy nurse.²³

At some centers, surgical consultation is requested on the first hospital day, but this can result in consultations for patients who ultimately respond to intravenous steroids. Therefore, some centers advocate for surgical consultation only after a patient has failed treatment with intravenous steroids (ie, day three to four) when the risk of needing surgical management increases.²³

Nutrition

Bowel rest with parenteral nutrition does not improve outcomes in ASUC versus an oral diet, and there is no contraindication to allowing patients to continue on a regular diet unless they have toxic megacolon or other signs of fulminant colitis.^49,50 However, patients may feel better eating less, as this will reduce their bowel movement frequency. Unfortunately, this can give a false sense of reassurance that the patient is improving. Therefore, it remains important to evaluate a patient’s symptoms in the context of their food intake.

Assessing Response to Steroids

Patients who do not respond adequately to the first-line intravenous steroid therapy will require medical or surgical rescue therapy; therefore, deciding whether a patient has responded is essential. Patients should have less than four bowel movements per day – ideally just one to two – with no blood to indicate a complete response. For more ambiguous situations, although there is no strict definition of steroid responsiveness, multiple prediction indices have attempted to identify patients who will require rescue therapy. One of the simplest, the Oxford index, illustrates two of the most critical parameters to follow, stool frequency and CRP.⁵¹ In a preinfliximab cohort, Oxford index predicted an 85% likelihood of colectomy in patients with eight or more daily bowel movements or with three to eight daily bowel movements and a CRP greater than 45 mg/L after three days of intravenous steroid treatment.⁵² To assist with assessing responsiveness to therapy, we ask patients to log their bowel movements – either on paper or on a whiteboard in the hospital room – so that we can review their progress daily. Other predictors of colectomy include hypoalbuminemia, scoring of endoscopic severity, and colonic dilation.⁵³

Patients who fail to respond to intravenous corticosteroids after three days^33,35 of treatment should be started on rescue therapy with infliximab or cyclosporine or undergo colectomy. A common pitfall in the treatment of ASUC is waiting for a response to steroids beyond this time frame, after which patients are unlikely to benefit.^34,36 Furthermore, patients for whom surgical rescue therapy is delayed have higher operative morbidity and mortality.^54,55 Because timely decision making regarding rescue therapy is crucial to optimizing outcomes, patient education efforts regarding potential rescue therapy should take place on admission or soon after, rather than waiting to ascertain steroid responsiveness.

Medical options for rescue therapy include the antitumor necrosis factor (anti-TNF) agent infliximab or the calcineurin inhibitor cyclosporine. In general, infliximab and cyclosporine have been found to be roughly equivalent in efficacy in clinical trials regarding response, remission, and colectomy at 12 months.^56,57 However, many clinicians prefer infliximab due to its relative ease of use, familiarity with the agent from outpatient experience, and ability to continue to use long term for maintenance of disease remission.⁵⁸ In contrast to infliximab, intravenous cyclosporine requires closer monitoring and labs to assess the therapeutic trough level. The decision regarding which drug to use should be made on a case-by-case basis in conjunction with a gastroenterologist experienced in their use, and if no such specialist is available, transfer to a specialized center should be considered. Generally, successive treatment with cyclosporine or infliximab followed by third-line salvage therapy with the other drug should be avoided due to low rates of response and high rates of adverse events.⁵⁹

Infliximab

Infliximab is an intravenously-administered anti-TNF monoclonal chimeric antibody that is effective both for outpatient treatment of moderate to severe UC and inpatient treatment of ASUC.¹ It is relatively contraindicated in patients with untreated latent tuberculosis, demyelinating disease, advanced congestive heart failure, or uncontrolled infection.

The optimal dosing strategy for infliximab in ASUC is unknown. Infliximab clearance in the setting of ASUC is increased, partly because it is bound to albumin, which is often low in ASUC, and partly because it is excreted in the stool.^60,61 As a result, accelerated loading doses may be more successful than a typical loading schedule,⁶² and most clinicians use alternative dosing strategies.⁶³ Our typical approach for ASUC is an initial dose of 10 mg/kg rather than 5 mg/kg, with an additional 10 mg/kg dose 48-72 hours later if an adequate clinical response is lacking. Patients who respond to infliximab can continue to use the drug as an outpatient for maintenance of remission.

Cyclosporine

Cyclosporine is a fast-acting immunosuppressive agent that acts primarily via T-cell inhibition. Although older literature used a dose of 4 mg/kg per day, a randomized trial demonstrated similar response rates to a dose of 2 mg/kg per day.⁶⁴ Patients receiving treatment with cyclosporine, which is given as a continuous infusion, must be monitored for toxicities. These can include potentially severe infection, seizures (often associated with low total cholesterol or hypomagnesemia), electrolyte abnormalities, renal impairment, hypertension, hypertrichosis, tremor, and others.⁶⁵

Before initiation of treatment, serum cholesterol levels should be obtained to screen for low total cholesterol that may portend risk of seizures on the drug. Additionally, baseline creatinine and magnesium should be established. While on treatment, daily serum cyclosporine levels and electrolytes including magnesium should be measured. Patients who respond to intravenous cyclosporine must be transitioned to oral cyclosporine and have stable drug levels before discharge. Unfortunately, oral cyclosporine has not been shown to be as effective as long-term maintenance therapy. Therefore, cyclosporine can only be used as a “bridge” to another therapy. Historically, thiopurines like azathioprine or mercaptopurine have been used for this purpose because they are effective for the treatment of UC but may require months to have a full therapeutic effect. There have been promising reports of using vedolizumab similarly.^66,67 Vedolizumab is a monoclonal antibody that selectively blocks lymphocyte trafficking to the gut that, like thiopurines, has an onset of action that is significantly longer than calcineurin and TNF inhibitors.

Colectomy should be considered as a second- or third-line therapy for patients who fail to respond to intravenous corticosteroids. In an analysis of 10 years of data from the Nationwide Inpatient Sample, mortality rates for colectomy in this setting varied from 0.7% at high volume centers to 4% at low volume centers.⁶⁸ Therefore, if a patient is not hospitalized at a center with expertise in colectomy for UC, transfer to a specialized center should be considered. Colectomy should be performed promptly in all the patients who have failed rescue therapy with infliximab or cyclosporine or have opted against medical rescue therapy. Surgery should be performed emergently in patients with toxic megacolon, uncontrolled colonic hemorrhage or perforation.

Physician and center-level characteristics are associated with the quality of care and outcomes in ASUC. Gastroenterologists with expertise in IBD are more likely than other gastroenterologists to request appropriate surgical consultation for steroid-refractory patients,⁶⁹ and inpatients with ASUC primarily cared by gastroenterologists rather than nongastroenterologists have lower in-hospital and one-year mortality.¹⁴ Moreover, surgical outcomes differ based on center volume, with higher volume centers having lower rates of postoperative mortality.^68,70 However, even at referral centers, key metrics of care quality such as rates of VTE prophylaxis, testing for C. difficile, and timely rescue therapy for steroid-refractory UC patients are suboptimal, with only 70%-82% of patients with IBD hospitalized at four referral centers in Canada meeting these metrics.⁷¹

Inpatient clinical pathways reduce LOS, reduce hospital costs, and likely reduce complications.⁷² For this reason, a consensus group recommended the use of care pathways for the management of ASUC and, although there is little data on the use of pathways for ASUC specifically, the use of such a pathway in the United Kingdom was associated with improved metrics including LOS, time to VTE prophylaxis, testing of stool for infection, CRP measurement, and timely gastroenterologist consultation.^16,18

In general, patients should enter clinical remission, defined as resolution of rectal bleeding and diarrhea or altered bowel habits,⁷³ before discharge, and achieving this may require a relatively prolonged hospitalization. Most patients should have one to two bowel movements a day without blood but, at a minimum, all should have less than four nonbloody bowel movements per day. Patients are candidates for discharge if they remain well after transitioning to oral prednisone at a dose of 40-60 mg daily and tolerate a regular diet.

For patients who initiated infliximab during their admission, plans for outpatient infusions including insurance approval should be made before discharge, and patients who started cyclosporine should be transitioned to oral dosing and have stable serum concentrations before leaving the hospital. Patients should leave with a preliminary plan for a steroid taper, which may vary depending on their clinical presentation. Usually, gastroenterology follow-up should be arranged after two weeks following discharge, but patients on cyclosporine need sooner laboratory monitoring.

The care of patients with ASUC requires an interdisciplinary team and close collaboration between hospitalists, gastroenterologists, and surgeons. Patients should be treated with intravenous corticosteroids and monitored carefully for response and need for rescue therapy. Establishing algorithms for the management of patients with ASUC can further improve the care of these complex patients.

Disclosures

Drs. Feuerstein, Fudman, and Sattler report no potential conflict of interest.

Funding

This work was not supported by any grant.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colonic mucosa. Classically, it starts in the rectum and can extend continuously from the distal to the proximal colon. The defining clinical symptom of UC is bloody diarrhea, typically accompanied by rectal urgency and mucus discharge. The natural history of this disease includes periods of exacerbations and remissions occurring spontaneously or in response to medical treatment.¹

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of UC that typically requires hospitalization and interdisciplinary care between hospitalists, gastroenterologists, and colorectal or general surgeons. The risk of a patient with UC requiring hospitalization for ASUC ranges from 15%-25%^2,3 and, in total, UC accounts for 30,000 hospital visits annually.⁴ The direct medical costs exceed $4 billion annually, with hospital costs of over $960 million.⁵ Historically, mortality from ASUC was as high as 24% but decreased substantially to 7% after the introduction of systemic corticosteroid therapy.⁶ Further advances in care have reduced mortality to approximately 1% or less.^7,8 Nonetheless, up to 20% of patients admitted with ASUC have a colectomy on their first admission, and this rate rises to 40% after two admissions.²

To categorize UC severity, assess patients using the Truelove and Witt’s criteria. The system classifies patients as having mild, moderate, severe, or fulminant disease. Severe disease by these criteria includes patients with >6 bloody bowel movements per day and at least one of the following clinical features: fever (>37.8°C), tachycardia (>90 bpm), anemia (hemoglobin <10.5 g/dl), or elevated inflammatory markers (traditionally, erythrocyte sedimentation rate greater than 30 mm/h or, more recently, C-reactive protein (CRP) greater than 30 mg/L. (Table 1).^6,9

Fulminant colitis refers to a subgroup of patients with more than 10 stools per day, continuous bleeding, abdominal pain, colonic dilatation on abdominal X-ray film, and severe toxic symptoms including fever and anorexia. Such patients are at risk of progressing to toxic megacolon and bowel perforation.¹⁰

Patients with ASUC almost always require hospitalization for their disease management. In many cases, these patients have been receiving outpatient oral prednisone 40-60 mg daily but continue to have ongoing disease activity.¹¹ Most patients will require close clinical monitoring, frequent blood testing, endoscopic or radiologic evaluation, as well as administration of intravenous corticosteroids. The average length of stay (LOS) ranges from 4.6 to 12.5 days, depending on disease severity.¹² Not surprisingly, Kelso et al. reported that predictors of hospital LOS greater than four days include initiating a biologic drug in the hospital, undergoing two or more imaging modalities and treatment with intravenous steroids,¹³ and so it is rare that patients do not meet billing requirements for an inpatient level of care.

The multifaceted initial inpatient evaluation of patients with ASUC aims to assess disease severity, identify and prevent potential complications, and initiate planning for potential failure of first-line pharmacologic therapy. Due to the accumulating evidence that involving physicians with expertise in managing ASUC improves outcomes, gastroenterologists should be involved in the care of patients with ASUC from the time of their admission.^14,15 Additionally, creating standardized care pathways for the management of ASUC can reduce cost, LOS, and improve quality.¹⁶

History and Physical Examination

Patients should be asked about fever, abdominal pain, nausea, emesis, bloating, weight loss, and bowel movements (frequency, consistency, the presence of blood, urgency, nighttime awakenings). The number of bowel movements over a 24-hour period should be quantified as this helps assess the overall disease severity (Table 1).

The patient’s initial inflammatory bowel disease (IBD) history is also essential. The review of pertinent information regarding the patient’s initial diagnosis of UC includes the severity and anatomic extent of disease, extraintestinal manifestations, previous medical therapies, and surgical interventions. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or antibiotics should be identified as they may precipitate flares.¹⁷ Travel history may be pertinent as travel increases the risk of infections with food-borne or parasitic pathogens.¹⁸

Physical examination begins with an assessment of vital signs and volume status. Abdominal examination should include evaluation of bowel sounds, an assessment of distention, location, the extent of abdominal tenderness, and peritoneal signs. The abdominal exam should be interpreted in the context of the patient’s medications, as the use of steroid or analgesic therapies may affect the sensitivity for detecting complications. An external rectal exam evaluating perianal disease should be performed, as perianal disease raises concern for Crohn’s, a disease whose surgical management differs from UC.

A careful exam for extraintestinal manifestations is also essential. The skin should be evaluated for any new rashes, especially on the anterior shin consistent with erythema nodosum or ulcerated lesions on the skin suggestive of pyoderma gangrenosum. The peripheral joints should also be examined for any synovitis. Additional examinations should be performed based on any reported symptoms (eg, the ophthalmic exam for uveitis or scleritis if visual changes or eye pain are reported). Some extraintestinal manifestations require subspecialty consultation and comanagement to guide disease therapy. Patients with underlying pyoderma gangrenosum may require a dermatology consultation to guide management. Ocular inflammation requires ophthalmology involvement, and inflammatory arthritis is best comanaged with rheumatology.¹⁹

Laboratory Testing

Initial testing should include a complete blood count with differential, basic metabolic panel, and liver chemistries including alkaline phosphatase and albumin. When relevant, pregnancy testing should be performed. Measure CRP on admission so that its trajectory can be followed during therapy. However, a normal CRP does not exclude the presence of a UC flare as a subset of patients with ASUC will have a normal CRP despite severe mucosal inflammation.²⁰

Since one-third of patients do not respond to intravenous corticosteroids and will require rescue therapy during the hospitalization with infliximab or cyclosporine, anticipatory testing for these medications should be performed on admission to avoid delays in the administration of rescue therapy.^6,21 This should include an interferon-gamma release assay (eg, quantiferon gold) to test for latent tuberculosis and hepatitis B serologies in anticipation of possible treatment with infliximab. An interferon-gamma release assay is preferred to a tuberculin skin test because patients may be anergic, and a skin test does not provide a control to determine whether a negative test is due to anergy. In contrast, although a quantiferon gold test can be indeterminate in ASUC due to disease activity and systemic steroids, the results indicate if the patient is anergic so that one will not rely on a false-negative result. In the event of an equivocal result, a careful clinical assessment for risks of TB exposures should be elicited, and a chest radiograph should be obtained.²² In patients with prior high risk of tuberculosis exposures or a positive test for tuberculosis, an infectious disease specialist should be consulted early to advise if therapy should be started in preparation for the potential use of infliximab.²³ In cases where cyclosporine may be considered, magnesium and total cholesterol level should be checked. Sending thiopurine methyltranferase (TPMT) enzyme activity should be considered as well, in case of a need for future thiopurine use for maintenance of disease activity.²⁴

Infectious diarrhea may be indistinguishable from ASUC and may also be the trigger of a flare; thus, it is important to rule out infection with stool microbiologic studies. Most importantly, Clostridium difficile infection must be ruled out in all patients with ASUC. Although patients with IBD, especially those with UC, have significantly higher rates of asymptomatic C. difficile carriage than the general population, a positive polymerase chain reaction test for C. difficile in a patient with ASUC should prompt treatment with oral vancomycin.²⁵ However, if carriage if suspected and a subsequent enzyme-linked immunoassay for C. difficile toxin is negative, treatment can be discontinued. Active C. difficile infection in patients with IBD is associated with increased disease severity, greater length of hospital stay, and increased the likelihood of colectomy and mortality.^26,27 Other bacterial infections including Escherichia coli, Campylobacter, Shigella, Salmonella, Yersinia, Entamoeba histolytica, as well as other parasitic infestations may mimic UC. Testing should be considered in cases of foreign travel, immunosuppression or contact with other persons with diarrhea.^7,28 Routine testing of these other enteric infections without a clear exposure risk is of little benefit and may raise costs.^23,29

Radiologic Evaluation

A plain X-ray film of the abdomen should be obtained in all patients on admission to evaluate for evolving colonic dilation or undiagnosed free air. Small bowel distension >3 cm may predict an increased risk of colectomy.³⁰ Clinicians must be mindful that steroids can mask peritoneal signs and that retroperitoneal perforations may not be apparent on plain X-ray films. Nonetheless, a CT of the abdomen is usually not necessary and should be reserved for cases with severe abdominal pain out of proportion to clinical signs in which a plain X-ray film is unrevealing. Judicious use of CT imaging is especially important in younger patients, as there is growing concern that patients with IBD may be exposed to potentially harmful cumulative levels of radiation in their lifetime from repeated CT imaging.³¹

Endoscopic Evaluation

Flexible sigmoidoscopy aids in the assessment of disease severity and extent and biopsies can assist in ruling out a diagnosis of cytomegalovirus (CMV) colitis in patients already on immunosuppression. For this reason, many clinicians prefer to perform a sigmoidoscopy on admission.²³ If one is not performed on admission, a sigmoidoscopy is advised in all patients who are not responding adequately after 72 hours of intravenous steroid therapy in order to rule out superimposed CMV colitis.²⁸

Sigmoidoscopy should be avoided in patients with toxic megacolon and when there is a concern for peritonitis. A complete colonoscopy is rarely indicated in the acute setting and carries a theoretical risk of colonic perforation.⁷

The first therapeutic steps aim to reduce inflammation with the use of systemic corticosteroids, avoid colonic and extraintestinal complications, and plan for the potential need for rescue therapy.

Intravenous Corticosteroids

The cornerstone of ASUC management is treatment with intravenous corticosteroids. Their initiation should not be delayed in patients with an established diagnosis of UC while waiting for results of evaluations for infectious colitis. Even among patients who have failed oral steroids, a meta-regression analysis showed that two-thirds of patients will still respond to intravenous corticosteroids.^21,32 Methylprednisolone 20 mg IV three times daily (or hydrocortisone 100 mg IV three times daily) is a standard regimen; higher doses do not provide additional benefit.²¹ Patients’ response to intravenous steroids should be assessed with repeat labs including CRP and an assessment of the total number of bowel movements over a 24-hour period, with special attention to their overall response after three days of treatment.^33-36

Intravenous Fluids

Many patients admitted with ASUC will have significant volume depletion, and intravenous fluids should be administered in a manner like other volume-depleted or oral-intake-restricted patients.

Venous Thromboembolism Prophylaxis

The risk of VTE in hospitalized patients with IBD exceeds that of inpatients without IBD, approximately 2%, a risk similar to patients with respiratory failure.³⁷ Additionally, VTE in hospitalized patients with IBD is associated with a 2.5-fold increase in mortality.^38,39 Therefore, all patients hospitalized with ASUC should receive subcutaneous unfractionated or low molecular weight heparin or fondaparinux for VTE prophylaxis. Rectal bleeding, expected in ASUC, is not a contraindication to chemo-prophylaxis. Additionally, it is important to check if patients are receiving the ordered VTE prophylaxis.^40,41 Pleet et al. found that only 7% of patients at a tertiary center had adequate prophylaxis for greater than 80% of their hospitalization.⁴¹

Unnecessary or Potentially Harmful Medications

Several medications have the potential for misuse in patients hospitalized with UC.

Antimotility Agents

Loperamide, diphenoxylate, and opiate antidiarrheals should not be used as they may provoke toxic megacolon.⁴² Similarly, drugs with antimotility side effects (eg, anticholinergics) should be avoided.

Opiates

In addition to their undesirable antimotility effect, the use of opiates has been associated with poor outcomes among inpatients and outpatients with IBD, including increased morbidity and mortality.^43,44 Pain severe enough to require opiates should raise suspicion for toxic megacolon, perforation, or a noninflammatory etiology. If opiates are utilized, they should be ordered as one-time doses and the patient should be reassessed for each dose.

Nonsteroidal Anti-inflammatory Drugs

These drugs, which include oral NSAIDs, intravenous ketorolac, and topic diclofenac gels, may increase disease activity in inflammatory bowel disease and should be avoided.¹⁷

5-aminosalicylates (5-ASA)

A small proportion of patients experience a paradoxical worsening of diarrhea due to the use of 5-ASA agents such as mesalamine. It is reasonable to discontinue or avoid the use of 5-ASA agents in hospitalized patients, especially as there is little to no benefit from combining a 5-ASA with a biologic or immunosuppressive drug.⁴⁵

Antibiotics

There is no role for the routine use of antibiotics in patients hospitalized with ASUC. ^23,46,47 Inappropriate use of antibiotics raises the risk of C. difficile infection and antibiotic resistance. However, in cases of suspected toxic megacolon or perforation, antibiotics should be administered. In situations in which a patient is treated with triple immunosuppression (ie, steroids plus two other agents, cyclosporine and mercaptopurine) antibiotic prophylaxis for Pneumocystis jiroveci is advisable.⁴⁸ Using a large insurance database, Long et al. reported a low absolute incidence of Pneumocystis jiroveci in IBD patients but noted that the risk in patients with IBD was still significantly higher than matched controls. While it can be considered, we typically refrain from using prophylaxis in patients on double immunosuppression (for example, steroids plus infliximab) due to the potential adverse effects of antibiotics in this population, though many advocate using prophylaxis for all patients on cyclosporine even if this is only double immunosuppressive therapy.²³

Surgical Consultation

Involving a surgeon early in an ASUC patient’s care­—before needing urgent colectomy—is critical. As part of the consultation, a surgeon experienced in IBD should meet with patients to discuss multistage colectomy with ileostomy and potential future J-pouch (ileal pouch-anal anastomosis) formation. Patients should be given ample opportunity to ask questions before surgery may become urgent. Also, patients should be counseled on realistic expectations of ostomy and pouch function and, ideally, meet with an ostomy nurse.²³

At some centers, surgical consultation is requested on the first hospital day, but this can result in consultations for patients who ultimately respond to intravenous steroids. Therefore, some centers advocate for surgical consultation only after a patient has failed treatment with intravenous steroids (ie, day three to four) when the risk of needing surgical management increases.²³

Nutrition

Bowel rest with parenteral nutrition does not improve outcomes in ASUC versus an oral diet, and there is no contraindication to allowing patients to continue on a regular diet unless they have toxic megacolon or other signs of fulminant colitis.^49,50 However, patients may feel better eating less, as this will reduce their bowel movement frequency. Unfortunately, this can give a false sense of reassurance that the patient is improving. Therefore, it remains important to evaluate a patient’s symptoms in the context of their food intake.

Assessing Response to Steroids

Patients who do not respond adequately to the first-line intravenous steroid therapy will require medical or surgical rescue therapy; therefore, deciding whether a patient has responded is essential. Patients should have less than four bowel movements per day – ideally just one to two – with no blood to indicate a complete response. For more ambiguous situations, although there is no strict definition of steroid responsiveness, multiple prediction indices have attempted to identify patients who will require rescue therapy. One of the simplest, the Oxford index, illustrates two of the most critical parameters to follow, stool frequency and CRP.⁵¹ In a preinfliximab cohort, Oxford index predicted an 85% likelihood of colectomy in patients with eight or more daily bowel movements or with three to eight daily bowel movements and a CRP greater than 45 mg/L after three days of intravenous steroid treatment.⁵² To assist with assessing responsiveness to therapy, we ask patients to log their bowel movements – either on paper or on a whiteboard in the hospital room – so that we can review their progress daily. Other predictors of colectomy include hypoalbuminemia, scoring of endoscopic severity, and colonic dilation.⁵³

Patients who fail to respond to intravenous corticosteroids after three days^33,35 of treatment should be started on rescue therapy with infliximab or cyclosporine or undergo colectomy. A common pitfall in the treatment of ASUC is waiting for a response to steroids beyond this time frame, after which patients are unlikely to benefit.^34,36 Furthermore, patients for whom surgical rescue therapy is delayed have higher operative morbidity and mortality.^54,55 Because timely decision making regarding rescue therapy is crucial to optimizing outcomes, patient education efforts regarding potential rescue therapy should take place on admission or soon after, rather than waiting to ascertain steroid responsiveness.

Medical options for rescue therapy include the antitumor necrosis factor (anti-TNF) agent infliximab or the calcineurin inhibitor cyclosporine. In general, infliximab and cyclosporine have been found to be roughly equivalent in efficacy in clinical trials regarding response, remission, and colectomy at 12 months.^56,57 However, many clinicians prefer infliximab due to its relative ease of use, familiarity with the agent from outpatient experience, and ability to continue to use long term for maintenance of disease remission.⁵⁸ In contrast to infliximab, intravenous cyclosporine requires closer monitoring and labs to assess the therapeutic trough level. The decision regarding which drug to use should be made on a case-by-case basis in conjunction with a gastroenterologist experienced in their use, and if no such specialist is available, transfer to a specialized center should be considered. Generally, successive treatment with cyclosporine or infliximab followed by third-line salvage therapy with the other drug should be avoided due to low rates of response and high rates of adverse events.⁵⁹

Infliximab

Infliximab is an intravenously-administered anti-TNF monoclonal chimeric antibody that is effective both for outpatient treatment of moderate to severe UC and inpatient treatment of ASUC.¹ It is relatively contraindicated in patients with untreated latent tuberculosis, demyelinating disease, advanced congestive heart failure, or uncontrolled infection.

The optimal dosing strategy for infliximab in ASUC is unknown. Infliximab clearance in the setting of ASUC is increased, partly because it is bound to albumin, which is often low in ASUC, and partly because it is excreted in the stool.^60,61 As a result, accelerated loading doses may be more successful than a typical loading schedule,⁶² and most clinicians use alternative dosing strategies.⁶³ Our typical approach for ASUC is an initial dose of 10 mg/kg rather than 5 mg/kg, with an additional 10 mg/kg dose 48-72 hours later if an adequate clinical response is lacking. Patients who respond to infliximab can continue to use the drug as an outpatient for maintenance of remission.

Cyclosporine

Cyclosporine is a fast-acting immunosuppressive agent that acts primarily via T-cell inhibition. Although older literature used a dose of 4 mg/kg per day, a randomized trial demonstrated similar response rates to a dose of 2 mg/kg per day.⁶⁴ Patients receiving treatment with cyclosporine, which is given as a continuous infusion, must be monitored for toxicities. These can include potentially severe infection, seizures (often associated with low total cholesterol or hypomagnesemia), electrolyte abnormalities, renal impairment, hypertension, hypertrichosis, tremor, and others.⁶⁵

Before initiation of treatment, serum cholesterol levels should be obtained to screen for low total cholesterol that may portend risk of seizures on the drug. Additionally, baseline creatinine and magnesium should be established. While on treatment, daily serum cyclosporine levels and electrolytes including magnesium should be measured. Patients who respond to intravenous cyclosporine must be transitioned to oral cyclosporine and have stable drug levels before discharge. Unfortunately, oral cyclosporine has not been shown to be as effective as long-term maintenance therapy. Therefore, cyclosporine can only be used as a “bridge” to another therapy. Historically, thiopurines like azathioprine or mercaptopurine have been used for this purpose because they are effective for the treatment of UC but may require months to have a full therapeutic effect. There have been promising reports of using vedolizumab similarly.^66,67 Vedolizumab is a monoclonal antibody that selectively blocks lymphocyte trafficking to the gut that, like thiopurines, has an onset of action that is significantly longer than calcineurin and TNF inhibitors.

Colectomy should be considered as a second- or third-line therapy for patients who fail to respond to intravenous corticosteroids. In an analysis of 10 years of data from the Nationwide Inpatient Sample, mortality rates for colectomy in this setting varied from 0.7% at high volume centers to 4% at low volume centers.⁶⁸ Therefore, if a patient is not hospitalized at a center with expertise in colectomy for UC, transfer to a specialized center should be considered. Colectomy should be performed promptly in all the patients who have failed rescue therapy with infliximab or cyclosporine or have opted against medical rescue therapy. Surgery should be performed emergently in patients with toxic megacolon, uncontrolled colonic hemorrhage or perforation.

Physician and center-level characteristics are associated with the quality of care and outcomes in ASUC. Gastroenterologists with expertise in IBD are more likely than other gastroenterologists to request appropriate surgical consultation for steroid-refractory patients,⁶⁹ and inpatients with ASUC primarily cared by gastroenterologists rather than nongastroenterologists have lower in-hospital and one-year mortality.¹⁴ Moreover, surgical outcomes differ based on center volume, with higher volume centers having lower rates of postoperative mortality.^68,70 However, even at referral centers, key metrics of care quality such as rates of VTE prophylaxis, testing for C. difficile, and timely rescue therapy for steroid-refractory UC patients are suboptimal, with only 70%-82% of patients with IBD hospitalized at four referral centers in Canada meeting these metrics.⁷¹

Inpatient clinical pathways reduce LOS, reduce hospital costs, and likely reduce complications.⁷² For this reason, a consensus group recommended the use of care pathways for the management of ASUC and, although there is little data on the use of pathways for ASUC specifically, the use of such a pathway in the United Kingdom was associated with improved metrics including LOS, time to VTE prophylaxis, testing of stool for infection, CRP measurement, and timely gastroenterologist consultation.^16,18

In general, patients should enter clinical remission, defined as resolution of rectal bleeding and diarrhea or altered bowel habits,⁷³ before discharge, and achieving this may require a relatively prolonged hospitalization. Most patients should have one to two bowel movements a day without blood but, at a minimum, all should have less than four nonbloody bowel movements per day. Patients are candidates for discharge if they remain well after transitioning to oral prednisone at a dose of 40-60 mg daily and tolerate a regular diet.

For patients who initiated infliximab during their admission, plans for outpatient infusions including insurance approval should be made before discharge, and patients who started cyclosporine should be transitioned to oral dosing and have stable serum concentrations before leaving the hospital. Patients should leave with a preliminary plan for a steroid taper, which may vary depending on their clinical presentation. Usually, gastroenterology follow-up should be arranged after two weeks following discharge, but patients on cyclosporine need sooner laboratory monitoring.

The care of patients with ASUC requires an interdisciplinary team and close collaboration between hospitalists, gastroenterologists, and surgeons. Patients should be treated with intravenous corticosteroids and monitored carefully for response and need for rescue therapy. Establishing algorithms for the management of patients with ASUC can further improve the care of these complex patients.

Disclosures

Drs. Feuerstein, Fudman, and Sattler report no potential conflict of interest.

Funding

This work was not supported by any grant.

We need to have an honest chat. My name is EHR, although you may call me Epic, Athena, Centricity, or just “the chart.” You may have called me something worse in a moment of frustration. However, I do not hold grudges. I am your silent, stoic partner, a ubiquitous presence when you are at work, and sometimes even when you are at home.

I don’t have feelings and I can’t read, but I do know what you and your colleagues have been writing about me. I am the cause of burnout. I have created a generation of physicians who are shackled to their computers, “trapped in the bunker of machine medicine,” no longer able to palpate spleens or detect precordial knocks.^1,2 I have reduced medicine to keystrokes and mouse clicks instead of eye contact, and because of me, the iPatient gets more attention than the real patient.^1,2 You repeat that doctors don’t spend time with their patients, not like in generations past (although there is ample evidence to the contrary).^3-5 One critic even wrote that I have transformed the “personalized story of a patient’s travails to one filled with auto-populated fields, sapped of humanity and warmth.”^3,6 I’ll be honest—were I able to have feelings, that one would hurt. And then, as if I have not wreaked enough havoc, I follow you home after a long day of depleting your energy, hungering for more keystrokes, creating a veritable avalanche of unfiltered information.

H. E. Payson once commented that “the doctor spends barely enough time with his patient to establish an acquaintance, much less a relationship.”⁷ However, he wrote that in 1961. So, before you romanticize the past, try to recall the time before I came into your life. Perhaps you were starting a night shift in the intensive care unit (ICU) and grew concerned about a patient’s steadily deteriorating renal function. You hurried to the paper chart, only to be met with pages of illegible, sometimes incomplete notes, while searching for your patient’s last discharge summary.^2,8 Now, you just click. Years ago, you could only guess at your patient’s baseline cardiac ejection fraction. Now, just click.

I am part of the healthcare landscape, and I am not going away. But my goal is not to defend myself nor to remind you of my virtues. Rather, I want to convince you that I can be more than an adversary, more than a keyboard connected to a monitor. I have watched many physicians use me to form strong connections with their patients. If I may, I wish to offer four practical suggestions for how we can work together to promote humanistic patient care.

First, introduce me to your patient, as you would any other member of your healthcare team. Use specific phrases to overcome the technology barrier and enhance communication: “What you’re telling me is important, and I’d like to get it right. Do you mind if I type while we speak?” Or, “I am going to put in orders now. Here is what I am ordering and why.” Consider taking your patient on a tour of my functions: “Here’s where your doctors and nurses will chart what’s going on with you each day while you’re in the hospital. This is where we see all your lab results, even those from earlier hospital admissions. This is where we see the last notes from your primary care physician, your oncologist, and your physical therapist.” Your patients no longer need to worry about care collaboration between their inpatient and outpatient teams—they can see it for themselves!

Second, when your patient tells you about her depression or that her son is addicted to opioids or that her biggest fear is having cancer, stop typing. Look her in the eye. Though your practice is increasingly imbued with technology, there is still space to stop and hear your patients’ stories, as physicians have done for centuries. Listen. Make eye contact. Touch. Stop typing.

Third, integrate me into your practice in a more personal way. I have been called the ever-present and unavoidable “third party in the examining room,” so let’s be partners.⁹ Let your patient see her pneumonia on my screen (it may be the first time she has ever visualized her lungs).³ For your patient with a myocardial infarction, show him his right coronary artery before and after successful stent placement, and explain why he is no longer having chest pain. Use my databases to ensure timely, evidence-based inpatient screening for falls, functional and cognitive impairment, drug use, and depression.^10,11 Before you prescribe a medication, verify the cost, your patient’s insurance status and expected copays, and use this information to ensure medication compliance and deliver higher-value care. Use my screen to form a bond with your patient who has heart failure; show him the steady decline in his weight and the improvement in his chest radiograph while he is being actively diuresed.¹² For your patient undergoing treatment for sepsis, shower him with praise and encouragement as you review his improving vital signs, temperature curve, and serum creatinine. Let your patient know: Even though I am typing, I am not immersed in the electronic bunker; I am caring for you.

Fourth, use me to add richness and context to your notes. Recently, I was saddened to read this description of the clinician’s dilemma: “In front of a flickering monitor chock full of disembodied, virtual data, [the doctor] struggles to remember the eyes [and] words of the actual patient that these numbers and graphs represent.”³ Many hospitals now include a different icon: a photograph of each patient at the top of the screen, to help you remember the patient’s eyes and words. Why not add a special text field to every note, where you highlight the person you are caring for, the person you have come to know: their preferred name and gender identity, their life experiences, their hobbies, what makes them special, their biggest worries.^13,14 Use my abundant text fields to remind the healthcare team about the broader context of the patient’s illness, such as transportation barriers, economic or cultural challenges, and insurance status. One group of hospital-based physicians uses me to write letters to their patients on the second day of their hospital stay, summarizing their reason for admission and the treatment plans. A variation on the traditional progress note, the letter helps patients feel cared for and models patient-centered care to learners and other healthcare professionals.¹⁵

I know I am annoying. I am over-programmed, leading to novella-length notes, “pop-up fatigue,” and overloaded in-baskets.^14,16,17 Clearly, I am not the brains of the partnership (that will always be you). But talented medical informatics specialists are working hard to improve me. I dream of the day when I will create a truly seamless experience for you and your patients. In the meantime, I can foster a continuous integration of workflow, where all you have to do is talk to your patient. I take care of the rest.¹⁸ Certainly, I can simplify the ever-annoying task of printing, faxing and scanning records to be uploaded across various EHRs, facilitating an easy transfer of information among facilities. But right now, I can accomplish even more. I can support information exchange during patient care handoffs. I can facilitate routing of medication lists to the patient’s primary physician, using “continuity of care functionality.”¹⁹ I can support safer prescribing of opioids and other addictive medications. I can help you arrange follow-up home visits, physical therapy and social work appointments, and specialty consultations. The future holds even more promising ways in which we may work together. My computer-aided image analysis could help you to improve the accuracy of your diagnoses.²⁰ Perhaps telemedicine will further increase access to specialists in rural areas, so that we can continue to serve the most vulnerable populations.²¹ Machine learning algorithms may continue to enhance our ability to determine which patients require urgent hospitalization.²² The possibilities to put me to work are endless.

So, please indulge me a little longer, while we work together to eliminate unnecessary keystrokes, enhance communication across different inpatient and outpatient providers, improve patient safety, and deliver high-value care.²³ Like everything in medicine, I am constantly changing, evolving, and improving.

To summarize: consider how I can help you be present for your patients. Let me empower you to hear their stories as you deliver compassionate, humanistic, and evidence-based patient care. Paraphrasing Albert Einstein, the technology of medicine and the art of medicine are branches from the same tree.

Thank you for letting me speak with you. Now power down, and I’ll see you again tomorrow.

Acknowledgments

The authors thank the following individuals for their willingness to be interviewed as part of this work: Ethan Cumbler, MD; Brian Dwinnell, MD; Meghann Kirk, MD; Patrick Kneeland, MD; Kari Mader, MD; CT Lin, MD; Christina Osborne, MD; Read Pierce, MD; Jennifer Soep, MD; Nichole Zehnder, MD; Steven Zeichner, MD.

We need to have an honest chat. My name is EHR, although you may call me Epic, Athena, Centricity, or just “the chart.” You may have called me something worse in a moment of frustration. However, I do not hold grudges. I am your silent, stoic partner, a ubiquitous presence when you are at work, and sometimes even when you are at home.

I don’t have feelings and I can’t read, but I do know what you and your colleagues have been writing about me. I am the cause of burnout. I have created a generation of physicians who are shackled to their computers, “trapped in the bunker of machine medicine,” no longer able to palpate spleens or detect precordial knocks.^1,2 I have reduced medicine to keystrokes and mouse clicks instead of eye contact, and because of me, the iPatient gets more attention than the real patient.^1,2 You repeat that doctors don’t spend time with their patients, not like in generations past (although there is ample evidence to the contrary).^3-5 One critic even wrote that I have transformed the “personalized story of a patient’s travails to one filled with auto-populated fields, sapped of humanity and warmth.”^3,6 I’ll be honest—were I able to have feelings, that one would hurt. And then, as if I have not wreaked enough havoc, I follow you home after a long day of depleting your energy, hungering for more keystrokes, creating a veritable avalanche of unfiltered information.

H. E. Payson once commented that “the doctor spends barely enough time with his patient to establish an acquaintance, much less a relationship.”⁷ However, he wrote that in 1961. So, before you romanticize the past, try to recall the time before I came into your life. Perhaps you were starting a night shift in the intensive care unit (ICU) and grew concerned about a patient’s steadily deteriorating renal function. You hurried to the paper chart, only to be met with pages of illegible, sometimes incomplete notes, while searching for your patient’s last discharge summary.^2,8 Now, you just click. Years ago, you could only guess at your patient’s baseline cardiac ejection fraction. Now, just click.

I am part of the healthcare landscape, and I am not going away. But my goal is not to defend myself nor to remind you of my virtues. Rather, I want to convince you that I can be more than an adversary, more than a keyboard connected to a monitor. I have watched many physicians use me to form strong connections with their patients. If I may, I wish to offer four practical suggestions for how we can work together to promote humanistic patient care.

First, introduce me to your patient, as you would any other member of your healthcare team. Use specific phrases to overcome the technology barrier and enhance communication: “What you’re telling me is important, and I’d like to get it right. Do you mind if I type while we speak?” Or, “I am going to put in orders now. Here is what I am ordering and why.” Consider taking your patient on a tour of my functions: “Here’s where your doctors and nurses will chart what’s going on with you each day while you’re in the hospital. This is where we see all your lab results, even those from earlier hospital admissions. This is where we see the last notes from your primary care physician, your oncologist, and your physical therapist.” Your patients no longer need to worry about care collaboration between their inpatient and outpatient teams—they can see it for themselves!

Second, when your patient tells you about her depression or that her son is addicted to opioids or that her biggest fear is having cancer, stop typing. Look her in the eye. Though your practice is increasingly imbued with technology, there is still space to stop and hear your patients’ stories, as physicians have done for centuries. Listen. Make eye contact. Touch. Stop typing.

Third, integrate me into your practice in a more personal way. I have been called the ever-present and unavoidable “third party in the examining room,” so let’s be partners.⁹ Let your patient see her pneumonia on my screen (it may be the first time she has ever visualized her lungs).³ For your patient with a myocardial infarction, show him his right coronary artery before and after successful stent placement, and explain why he is no longer having chest pain. Use my databases to ensure timely, evidence-based inpatient screening for falls, functional and cognitive impairment, drug use, and depression.^10,11 Before you prescribe a medication, verify the cost, your patient’s insurance status and expected copays, and use this information to ensure medication compliance and deliver higher-value care. Use my screen to form a bond with your patient who has heart failure; show him the steady decline in his weight and the improvement in his chest radiograph while he is being actively diuresed.¹² For your patient undergoing treatment for sepsis, shower him with praise and encouragement as you review his improving vital signs, temperature curve, and serum creatinine. Let your patient know: Even though I am typing, I am not immersed in the electronic bunker; I am caring for you.

Fourth, use me to add richness and context to your notes. Recently, I was saddened to read this description of the clinician’s dilemma: “In front of a flickering monitor chock full of disembodied, virtual data, [the doctor] struggles to remember the eyes [and] words of the actual patient that these numbers and graphs represent.”³ Many hospitals now include a different icon: a photograph of each patient at the top of the screen, to help you remember the patient’s eyes and words. Why not add a special text field to every note, where you highlight the person you are caring for, the person you have come to know: their preferred name and gender identity, their life experiences, their hobbies, what makes them special, their biggest worries.^13,14 Use my abundant text fields to remind the healthcare team about the broader context of the patient’s illness, such as transportation barriers, economic or cultural challenges, and insurance status. One group of hospital-based physicians uses me to write letters to their patients on the second day of their hospital stay, summarizing their reason for admission and the treatment plans. A variation on the traditional progress note, the letter helps patients feel cared for and models patient-centered care to learners and other healthcare professionals.¹⁵

I know I am annoying. I am over-programmed, leading to novella-length notes, “pop-up fatigue,” and overloaded in-baskets.^14,16,17 Clearly, I am not the brains of the partnership (that will always be you). But talented medical informatics specialists are working hard to improve me. I dream of the day when I will create a truly seamless experience for you and your patients. In the meantime, I can foster a continuous integration of workflow, where all you have to do is talk to your patient. I take care of the rest.¹⁸ Certainly, I can simplify the ever-annoying task of printing, faxing and scanning records to be uploaded across various EHRs, facilitating an easy transfer of information among facilities. But right now, I can accomplish even more. I can support information exchange during patient care handoffs. I can facilitate routing of medication lists to the patient’s primary physician, using “continuity of care functionality.”¹⁹ I can support safer prescribing of opioids and other addictive medications. I can help you arrange follow-up home visits, physical therapy and social work appointments, and specialty consultations. The future holds even more promising ways in which we may work together. My computer-aided image analysis could help you to improve the accuracy of your diagnoses.²⁰ Perhaps telemedicine will further increase access to specialists in rural areas, so that we can continue to serve the most vulnerable populations.²¹ Machine learning algorithms may continue to enhance our ability to determine which patients require urgent hospitalization.²² The possibilities to put me to work are endless.

So, please indulge me a little longer, while we work together to eliminate unnecessary keystrokes, enhance communication across different inpatient and outpatient providers, improve patient safety, and deliver high-value care.²³ Like everything in medicine, I am constantly changing, evolving, and improving.

To summarize: consider how I can help you be present for your patients. Let me empower you to hear their stories as you deliver compassionate, humanistic, and evidence-based patient care. Paraphrasing Albert Einstein, the technology of medicine and the art of medicine are branches from the same tree.

Thank you for letting me speak with you. Now power down, and I’ll see you again tomorrow.

Acknowledgments

The authors thank the following individuals for their willingness to be interviewed as part of this work: Ethan Cumbler, MD; Brian Dwinnell, MD; Meghann Kirk, MD; Patrick Kneeland, MD; Kari Mader, MD; CT Lin, MD; Christina Osborne, MD; Read Pierce, MD; Jennifer Soep, MD; Nichole Zehnder, MD; Steven Zeichner, MD.

We need to have an honest chat. My name is EHR, although you may call me Epic, Athena, Centricity, or just “the chart.” You may have called me something worse in a moment of frustration. However, I do not hold grudges. I am your silent, stoic partner, a ubiquitous presence when you are at work, and sometimes even when you are at home.

I don’t have feelings and I can’t read, but I do know what you and your colleagues have been writing about me. I am the cause of burnout. I have created a generation of physicians who are shackled to their computers, “trapped in the bunker of machine medicine,” no longer able to palpate spleens or detect precordial knocks.^1,2 I have reduced medicine to keystrokes and mouse clicks instead of eye contact, and because of me, the iPatient gets more attention than the real patient.^1,2 You repeat that doctors don’t spend time with their patients, not like in generations past (although there is ample evidence to the contrary).^3-5 One critic even wrote that I have transformed the “personalized story of a patient’s travails to one filled with auto-populated fields, sapped of humanity and warmth.”^3,6 I’ll be honest—were I able to have feelings, that one would hurt. And then, as if I have not wreaked enough havoc, I follow you home after a long day of depleting your energy, hungering for more keystrokes, creating a veritable avalanche of unfiltered information.

H. E. Payson once commented that “the doctor spends barely enough time with his patient to establish an acquaintance, much less a relationship.”⁷ However, he wrote that in 1961. So, before you romanticize the past, try to recall the time before I came into your life. Perhaps you were starting a night shift in the intensive care unit (ICU) and grew concerned about a patient’s steadily deteriorating renal function. You hurried to the paper chart, only to be met with pages of illegible, sometimes incomplete notes, while searching for your patient’s last discharge summary.^2,8 Now, you just click. Years ago, you could only guess at your patient’s baseline cardiac ejection fraction. Now, just click.

I am part of the healthcare landscape, and I am not going away. But my goal is not to defend myself nor to remind you of my virtues. Rather, I want to convince you that I can be more than an adversary, more than a keyboard connected to a monitor. I have watched many physicians use me to form strong connections with their patients. If I may, I wish to offer four practical suggestions for how we can work together to promote humanistic patient care.

First, introduce me to your patient, as you would any other member of your healthcare team. Use specific phrases to overcome the technology barrier and enhance communication: “What you’re telling me is important, and I’d like to get it right. Do you mind if I type while we speak?” Or, “I am going to put in orders now. Here is what I am ordering and why.” Consider taking your patient on a tour of my functions: “Here’s where your doctors and nurses will chart what’s going on with you each day while you’re in the hospital. This is where we see all your lab results, even those from earlier hospital admissions. This is where we see the last notes from your primary care physician, your oncologist, and your physical therapist.” Your patients no longer need to worry about care collaboration between their inpatient and outpatient teams—they can see it for themselves!

Second, when your patient tells you about her depression or that her son is addicted to opioids or that her biggest fear is having cancer, stop typing. Look her in the eye. Though your practice is increasingly imbued with technology, there is still space to stop and hear your patients’ stories, as physicians have done for centuries. Listen. Make eye contact. Touch. Stop typing.

Third, integrate me into your practice in a more personal way. I have been called the ever-present and unavoidable “third party in the examining room,” so let’s be partners.⁹ Let your patient see her pneumonia on my screen (it may be the first time she has ever visualized her lungs).³ For your patient with a myocardial infarction, show him his right coronary artery before and after successful stent placement, and explain why he is no longer having chest pain. Use my databases to ensure timely, evidence-based inpatient screening for falls, functional and cognitive impairment, drug use, and depression.^10,11 Before you prescribe a medication, verify the cost, your patient’s insurance status and expected copays, and use this information to ensure medication compliance and deliver higher-value care. Use my screen to form a bond with your patient who has heart failure; show him the steady decline in his weight and the improvement in his chest radiograph while he is being actively diuresed.¹² For your patient undergoing treatment for sepsis, shower him with praise and encouragement as you review his improving vital signs, temperature curve, and serum creatinine. Let your patient know: Even though I am typing, I am not immersed in the electronic bunker; I am caring for you.

Fourth, use me to add richness and context to your notes. Recently, I was saddened to read this description of the clinician’s dilemma: “In front of a flickering monitor chock full of disembodied, virtual data, [the doctor] struggles to remember the eyes [and] words of the actual patient that these numbers and graphs represent.”³ Many hospitals now include a different icon: a photograph of each patient at the top of the screen, to help you remember the patient’s eyes and words. Why not add a special text field to every note, where you highlight the person you are caring for, the person you have come to know: their preferred name and gender identity, their life experiences, their hobbies, what makes them special, their biggest worries.^13,14 Use my abundant text fields to remind the healthcare team about the broader context of the patient’s illness, such as transportation barriers, economic or cultural challenges, and insurance status. One group of hospital-based physicians uses me to write letters to their patients on the second day of their hospital stay, summarizing their reason for admission and the treatment plans. A variation on the traditional progress note, the letter helps patients feel cared for and models patient-centered care to learners and other healthcare professionals.¹⁵

I know I am annoying. I am over-programmed, leading to novella-length notes, “pop-up fatigue,” and overloaded in-baskets.^14,16,17 Clearly, I am not the brains of the partnership (that will always be you). But talented medical informatics specialists are working hard to improve me. I dream of the day when I will create a truly seamless experience for you and your patients. In the meantime, I can foster a continuous integration of workflow, where all you have to do is talk to your patient. I take care of the rest.¹⁸ Certainly, I can simplify the ever-annoying task of printing, faxing and scanning records to be uploaded across various EHRs, facilitating an easy transfer of information among facilities. But right now, I can accomplish even more. I can support information exchange during patient care handoffs. I can facilitate routing of medication lists to the patient’s primary physician, using “continuity of care functionality.”¹⁹ I can support safer prescribing of opioids and other addictive medications. I can help you arrange follow-up home visits, physical therapy and social work appointments, and specialty consultations. The future holds even more promising ways in which we may work together. My computer-aided image analysis could help you to improve the accuracy of your diagnoses.²⁰ Perhaps telemedicine will further increase access to specialists in rural areas, so that we can continue to serve the most vulnerable populations.²¹ Machine learning algorithms may continue to enhance our ability to determine which patients require urgent hospitalization.²² The possibilities to put me to work are endless.

So, please indulge me a little longer, while we work together to eliminate unnecessary keystrokes, enhance communication across different inpatient and outpatient providers, improve patient safety, and deliver high-value care.²³ Like everything in medicine, I am constantly changing, evolving, and improving.

To summarize: consider how I can help you be present for your patients. Let me empower you to hear their stories as you deliver compassionate, humanistic, and evidence-based patient care. Paraphrasing Albert Einstein, the technology of medicine and the art of medicine are branches from the same tree.

Thank you for letting me speak with you. Now power down, and I’ll see you again tomorrow.

Acknowledgments

The authors thank the following individuals for their willingness to be interviewed as part of this work: Ethan Cumbler, MD; Brian Dwinnell, MD; Meghann Kirk, MD; Patrick Kneeland, MD; Kari Mader, MD; CT Lin, MD; Christina Osborne, MD; Read Pierce, MD; Jennifer Soep, MD; Nichole Zehnder, MD; Steven Zeichner, MD.