Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.

New policy hopes to be in line with full FDA approval expected in September. When the largest employer in the world makes any significant decision, everyone sits up and takes notice.

That’s what happened when Secretary of Defense Lloyd Austin III sent out a memo to all US Department of Defense (DoD) employees saying he was seeking President Biden’s approval to make COVID-19 vaccines mandatory. His decision affects not only the 3.2 million employees on the payroll, but their families, communities, and states. Florida, for instance, where approximately 40% of the population remains unvaccinated has about 55,000 active duty service members and 36,000 reservists.

Vaccination rates in the military have lagged behind other populations, especially among Black and Hispanic service members. An April study published in Medical Surveillance Monthly Report found that “non-Hispanic Blacks, as well as those who were female, younger, of lower rank, with lower education levels, and those serving in the Army were less likely to initiate COVID-19 vaccination after adjusting for other factors.”

The decision had been in the offing for some time but when cases of the Delta variant of the virus began to spike in July, President Biden asked Sec. Austin to consider how and when the COVID vaccine could be added to the list of required vaccines for service members. It’s a long list already: Depending on their location, service members can get as many as 17 vaccines. It also folllows on the heals of the decision by the US Department of Veterans Affairs to require vaccinations for frontline health care workers.

Austin promised to “not let grass grow.” He consulted with Army Gen. Mark Milley, the Joint Chiefs of Staff, service chiefs, service secretaries, and medical professionals. Based on those discussions, he decided to ask for approval to make the vaccines mandatory no later than mid-September or immediately upon FDA licensure, whichever comes first.

However, he added, “[t]o defend this Nation, we need a healthy and ready force. I strongly encourage all DoD military and civilian personnel—as well as contractor personnel—to get vaccinated now and for military Service members to not wait for the mandate.” Currently, 73% of active-duty personnel have had at least one dose of the vaccine.

Leaping upon the news—and based on the wording in the memo—some in the media were reporting that it meant all troops have to be vaccinated by mid-September. “He’ll make the request by mid-September, unless or until FDA licensure occurs before that time, at which point the Secretary has the authority he needs…to make whatever vaccine is then given that license mandatory.”  That’s not the case, said Pentagon press secretary John Kirby in a briefing. Some voices also have called on the DoD to do more to dispel vaccine hesitancy among the troops.

In the meantime, Kirby said, “[T]wo things are going to happen. One, the services are going to be tasked to come back to the Secretary with implementation plans for how they’re going to get this moving.” Noting that mid-September isn’t far away, he pointed out that the services have a “fair but limited amount of time” to arrange their implementation plans. “I have every confidence that service leadership and your commanders will implement this new vaccination program with professionalism, skill, and compassion,” Austin wrote in his memo.

The second thing, Kirby said, was that DoD would be developing policies that comply with the President’s direction that the unvaccinated will have to be subjected to “certain requirements and restrictions.” The Delta variant is hitting the unvaccinated hardest. Austin said the DoD will keep a close eye on infection rates “and the impact these rates might have on our readiness. I will not hesitate to act sooner or recommend a different course to the President if I feel the need to do so.”

Kirby said he didn’t have all the details for that yet, but the department is “working hard” on a policy directive that will clarify what those requirements and restrictions might be.

President Biden replied almost immediately to Austin’s message. “I strongly support Secretary Austin’s message to the force today…. Secretary Austin and I share an unshakeable commitment to making sure our troops have every tool they need to do their jobs as safely as possible. These vaccines will save lives. Period.”

“All FDA-authorized COVID-19 vaccines are safe and highly effective,” Austin said in the close to his memo. “They will protect you and your family. They will protect your unit, your ship, and your co-workers. …Get the shot. Stay healthy. Stay ready.”

New policy hopes to be in line with full FDA approval expected in September. When the largest employer in the world makes any significant decision, everyone sits up and takes notice.

That’s what happened when Secretary of Defense Lloyd Austin III sent out a memo to all US Department of Defense (DoD) employees saying he was seeking President Biden’s approval to make COVID-19 vaccines mandatory. His decision affects not only the 3.2 million employees on the payroll, but their families, communities, and states. Florida, for instance, where approximately 40% of the population remains unvaccinated has about 55,000 active duty service members and 36,000 reservists.

Vaccination rates in the military have lagged behind other populations, especially among Black and Hispanic service members. An April study published in Medical Surveillance Monthly Report found that “non-Hispanic Blacks, as well as those who were female, younger, of lower rank, with lower education levels, and those serving in the Army were less likely to initiate COVID-19 vaccination after adjusting for other factors.”

The decision had been in the offing for some time but when cases of the Delta variant of the virus began to spike in July, President Biden asked Sec. Austin to consider how and when the COVID vaccine could be added to the list of required vaccines for service members. It’s a long list already: Depending on their location, service members can get as many as 17 vaccines. It also folllows on the heals of the decision by the US Department of Veterans Affairs to require vaccinations for frontline health care workers.

Austin promised to “not let grass grow.” He consulted with Army Gen. Mark Milley, the Joint Chiefs of Staff, service chiefs, service secretaries, and medical professionals. Based on those discussions, he decided to ask for approval to make the vaccines mandatory no later than mid-September or immediately upon FDA licensure, whichever comes first.

However, he added, “[t]o defend this Nation, we need a healthy and ready force. I strongly encourage all DoD military and civilian personnel—as well as contractor personnel—to get vaccinated now and for military Service members to not wait for the mandate.” Currently, 73% of active-duty personnel have had at least one dose of the vaccine.

Leaping upon the news—and based on the wording in the memo—some in the media were reporting that it meant all troops have to be vaccinated by mid-September. “He’ll make the request by mid-September, unless or until FDA licensure occurs before that time, at which point the Secretary has the authority he needs…to make whatever vaccine is then given that license mandatory.”  That’s not the case, said Pentagon press secretary John Kirby in a briefing. Some voices also have called on the DoD to do more to dispel vaccine hesitancy among the troops.

In the meantime, Kirby said, “[T]wo things are going to happen. One, the services are going to be tasked to come back to the Secretary with implementation plans for how they’re going to get this moving.” Noting that mid-September isn’t far away, he pointed out that the services have a “fair but limited amount of time” to arrange their implementation plans. “I have every confidence that service leadership and your commanders will implement this new vaccination program with professionalism, skill, and compassion,” Austin wrote in his memo.

The second thing, Kirby said, was that DoD would be developing policies that comply with the President’s direction that the unvaccinated will have to be subjected to “certain requirements and restrictions.” The Delta variant is hitting the unvaccinated hardest. Austin said the DoD will keep a close eye on infection rates “and the impact these rates might have on our readiness. I will not hesitate to act sooner or recommend a different course to the President if I feel the need to do so.”

Kirby said he didn’t have all the details for that yet, but the department is “working hard” on a policy directive that will clarify what those requirements and restrictions might be.

President Biden replied almost immediately to Austin’s message. “I strongly support Secretary Austin’s message to the force today…. Secretary Austin and I share an unshakeable commitment to making sure our troops have every tool they need to do their jobs as safely as possible. These vaccines will save lives. Period.”

“All FDA-authorized COVID-19 vaccines are safe and highly effective,” Austin said in the close to his memo. “They will protect you and your family. They will protect your unit, your ship, and your co-workers. …Get the shot. Stay healthy. Stay ready.”

New policy hopes to be in line with full FDA approval expected in September. When the largest employer in the world makes any significant decision, everyone sits up and takes notice.

That’s what happened when Secretary of Defense Lloyd Austin III sent out a memo to all US Department of Defense (DoD) employees saying he was seeking President Biden’s approval to make COVID-19 vaccines mandatory. His decision affects not only the 3.2 million employees on the payroll, but their families, communities, and states. Florida, for instance, where approximately 40% of the population remains unvaccinated has about 55,000 active duty service members and 36,000 reservists.

Vaccination rates in the military have lagged behind other populations, especially among Black and Hispanic service members. An April study published in Medical Surveillance Monthly Report found that “non-Hispanic Blacks, as well as those who were female, younger, of lower rank, with lower education levels, and those serving in the Army were less likely to initiate COVID-19 vaccination after adjusting for other factors.”

The decision had been in the offing for some time but when cases of the Delta variant of the virus began to spike in July, President Biden asked Sec. Austin to consider how and when the COVID vaccine could be added to the list of required vaccines for service members. It’s a long list already: Depending on their location, service members can get as many as 17 vaccines. It also folllows on the heals of the decision by the US Department of Veterans Affairs to require vaccinations for frontline health care workers.

Austin promised to “not let grass grow.” He consulted with Army Gen. Mark Milley, the Joint Chiefs of Staff, service chiefs, service secretaries, and medical professionals. Based on those discussions, he decided to ask for approval to make the vaccines mandatory no later than mid-September or immediately upon FDA licensure, whichever comes first.

However, he added, “[t]o defend this Nation, we need a healthy and ready force. I strongly encourage all DoD military and civilian personnel—as well as contractor personnel—to get vaccinated now and for military Service members to not wait for the mandate.” Currently, 73% of active-duty personnel have had at least one dose of the vaccine.

Leaping upon the news—and based on the wording in the memo—some in the media were reporting that it meant all troops have to be vaccinated by mid-September. “He’ll make the request by mid-September, unless or until FDA licensure occurs before that time, at which point the Secretary has the authority he needs…to make whatever vaccine is then given that license mandatory.”  That’s not the case, said Pentagon press secretary John Kirby in a briefing. Some voices also have called on the DoD to do more to dispel vaccine hesitancy among the troops.

In the meantime, Kirby said, “[T]wo things are going to happen. One, the services are going to be tasked to come back to the Secretary with implementation plans for how they’re going to get this moving.” Noting that mid-September isn’t far away, he pointed out that the services have a “fair but limited amount of time” to arrange their implementation plans. “I have every confidence that service leadership and your commanders will implement this new vaccination program with professionalism, skill, and compassion,” Austin wrote in his memo.

The second thing, Kirby said, was that DoD would be developing policies that comply with the President’s direction that the unvaccinated will have to be subjected to “certain requirements and restrictions.” The Delta variant is hitting the unvaccinated hardest. Austin said the DoD will keep a close eye on infection rates “and the impact these rates might have on our readiness. I will not hesitate to act sooner or recommend a different course to the President if I feel the need to do so.”

Kirby said he didn’t have all the details for that yet, but the department is “working hard” on a policy directive that will clarify what those requirements and restrictions might be.

President Biden replied almost immediately to Austin’s message. “I strongly support Secretary Austin’s message to the force today…. Secretary Austin and I share an unshakeable commitment to making sure our troops have every tool they need to do their jobs as safely as possible. These vaccines will save lives. Period.”

“All FDA-authorized COVID-19 vaccines are safe and highly effective,” Austin said in the close to his memo. “They will protect you and your family. They will protect your unit, your ship, and your co-workers. …Get the shot. Stay healthy. Stay ready.”

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Gupta D et al. J Ethnopharmacol. 2008 Feb 12;115(3):361-80.

2. Jura-Morawiec J & Tulik. Chemoecology. 2016;26:101-5.

3. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):155-69.

4. Fan JY et al. Molecules. 2014 Jul 22;19(7):10650-69.

5. Zhang W et al. Zhongguo Zhong Yao Za Zhi. 2016 Apr;41(7):1354-7.

6. Sun J et al. J Ethnopharmacol. 2019 Nov 15;244:112138.

7. Wang H et al. Fitoterapia. 2017 Sep;121:1-5.

8. Al-Fatimi M. Plants (Basel). 2018 Oct 26;7(4):91.

9. Pona A et al. Dermatol Ther. 2019 Mar;32(2):e12786.10. Pieters L et al. Phytomedicine. 1995 Jul;2(1):17-22.

11. Jones K. J Altern Complement Med. 2003 Dec;9(6):877-96.

12. Hu Q et al. Zhongguo Zhong Yao Za Zhi. 2012 Dec;37(23):3549-53.

13. Liu H et al. Evid Based Complement Alternat Med. 2013;2013:709865.

14. Jiang XW et al. Evid Based Complement Alternat Med. 2017:8950516.

15. Jiang X et al. J Pharmacol Sci. 2018 Feb;136(2):66-72.

16. Namjoyan F et al. J Tradit Complement Med. 2015 Jan 22;6(1):37-40.

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Gupta D et al. J Ethnopharmacol. 2008 Feb 12;115(3):361-80.

2. Jura-Morawiec J & Tulik. Chemoecology. 2016;26:101-5.

3. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):155-69.

4. Fan JY et al. Molecules. 2014 Jul 22;19(7):10650-69.

5. Zhang W et al. Zhongguo Zhong Yao Za Zhi. 2016 Apr;41(7):1354-7.

6. Sun J et al. J Ethnopharmacol. 2019 Nov 15;244:112138.

7. Wang H et al. Fitoterapia. 2017 Sep;121:1-5.

8. Al-Fatimi M. Plants (Basel). 2018 Oct 26;7(4):91.

9. Pona A et al. Dermatol Ther. 2019 Mar;32(2):e12786.10. Pieters L et al. Phytomedicine. 1995 Jul;2(1):17-22.

11. Jones K. J Altern Complement Med. 2003 Dec;9(6):877-96.

12. Hu Q et al. Zhongguo Zhong Yao Za Zhi. 2012 Dec;37(23):3549-53.

13. Liu H et al. Evid Based Complement Alternat Med. 2013;2013:709865.

14. Jiang XW et al. Evid Based Complement Alternat Med. 2017:8950516.

15. Jiang X et al. J Pharmacol Sci. 2018 Feb;136(2):66-72.

16. Namjoyan F et al. J Tradit Complement Med. 2015 Jan 22;6(1):37-40.

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Gupta D et al. J Ethnopharmacol. 2008 Feb 12;115(3):361-80.

2. Jura-Morawiec J & Tulik. Chemoecology. 2016;26:101-5.

3. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):155-69.

4. Fan JY et al. Molecules. 2014 Jul 22;19(7):10650-69.

5. Zhang W et al. Zhongguo Zhong Yao Za Zhi. 2016 Apr;41(7):1354-7.

6. Sun J et al. J Ethnopharmacol. 2019 Nov 15;244:112138.

7. Wang H et al. Fitoterapia. 2017 Sep;121:1-5.

8. Al-Fatimi M. Plants (Basel). 2018 Oct 26;7(4):91.

9. Pona A et al. Dermatol Ther. 2019 Mar;32(2):e12786.10. Pieters L et al. Phytomedicine. 1995 Jul;2(1):17-22.

11. Jones K. J Altern Complement Med. 2003 Dec;9(6):877-96.

12. Hu Q et al. Zhongguo Zhong Yao Za Zhi. 2012 Dec;37(23):3549-53.

13. Liu H et al. Evid Based Complement Alternat Med. 2013;2013:709865.

14. Jiang XW et al. Evid Based Complement Alternat Med. 2017:8950516.

15. Jiang X et al. J Pharmacol Sci. 2018 Feb;136(2):66-72.

16. Namjoyan F et al. J Tradit Complement Med. 2015 Jan 22;6(1):37-40.

The COVID-19 outbreak in February 2020 at a congregate living facility near Seattle, Washington, signaled the beginning of the pandemic in the United States. In that facility, infected residents had a 54.5% hospitalization rate and 33.7% case-fatality rate.¹ Similar to the experience in Washington, all congregate living facilities have proved particularly vulnerable to the effects of COVID-19,^2-7 with residents at increased risk for disease severity and mortality.^2-7

Due to the COVID-19 emergency, NorthShore University HealthSystem (NUHS), a multihospital, integrated health system in northern Illinois, established a best practice for appropriate use of congregate living facilities after hospitalization. This focused on the safety of discharged patients and mitigation of COVID-19 by putting in place a referral process to a newly established congregate living review committee (CLRC) for review prior to discharge. Although all discharges to congregate living settings are at high risk,² new placements to skilled nursing facilities (SNFs) were the primary focus of the committee and the sole focus of this study. In this study, we sought to determine whether establishment of the CLRC was associated with a reduction in SNF utilization, whether this was safe and efficient, and whether it was associated with a reduction in COVID-19 incidence in the 30 days following discharge.

Setting and Case Review Intervention

We conducted a retrospective cohort study for patients hospitalized within NUHS from March 19, 2019 to July 16, 2020, designed as an interrupted time series. The study was approved by the NUHS Institutional Review Board (EH21-022).

The study exposure was creation of a referral and review process for all patients with expected discharge to a SNF and was implemented as part of usual discharge planning during the COVID-19 pandemic. The key intervention was to establish a multidisciplinary committee, the CLRC, to review all potential discharges to SNFs. The CLRC had dual goals of preventing COVID-19 spread in facilities by limiting placement of new residents and protecting a vulnerable population from a setting that conferred a higher risk of acquiring COVID-19. The CLRC was organized as a multidisciplinary committee with physicians, case managers, social workers, physical therapists, occupational therapists, and the director of NUHS home health agency. Physician members were evenly split as half hospitalists and half ambulatory physicians. The CLRC review was initiated by a patient’s assigned case manager or social worker by consult through a referral in the electronic medical record (EMR). Each case was summarized and then presented to the full CLRC. The CLRC met for 1 hour per day, 6 days per week, to review all planned discharges that met criteria for review. A committee physician chaired each meeting. Three other members were needed for a quorum, with one other member with a title of director or higher. Time required was the 1-hour daily meeting, as well as one full-time position for case review, preparation, and program administration. The case presentation included a clinical summary of the hospitalization as well as COVID-19 status and testing history, previous living situation, level of home support, functional level, psychosocial needs, barrier(s) to discharging home, and long-term residential plans. A structured assessment was then made by each CLRC member in accordance with their professional expertise. Unanimous consensus would be reached before finalizing any recommended adjustments to the discharge, which would be communicated to the inpatient care team via a structured note within the EMR, along with direct communication to the assigned case manager or social worker. When the CLRC suggested adjustments to the discharge, they would work with the assigned case manager or social worker to communicate an appropriate post–acute care plan with the patient or appropriate representative. If there was disagreement or the recommendations could not be followed, the case manager or social worker would place a new referral with additional information for reconsideration. Following a recommendation for SNF, verification would be completed by the CLRC prior to discharge. This process is detailed in Figure 1.

Patient Population

Inclusion criteria for the study were: (1) inpatient hospitalization and (2) eligibility for risk scoring via the organization’s clinical analytics prediction engine (CAPE).⁸ CAPE is a validated predictive model that includes risk of readmission, in-hospital mortality, and out-of-hospital mortality,⁸ with extensive adoption at NUHS. CAPE score eligibility was used as an inclusion criterion so that CAPE could be applied for derivation of a matched control. CAPE eligibility criteria include admission age of at least 18 years and that hospitalization is not psychiatric, rehabilitative, or obstetric. Patients must not be enrolled in hospice and must be discharged alive.

Exclusions were patients who tested positive for SARS-CoV-2 prior to or during index hospitalization. Excluding COVID-19 patients from the analysis eliminated a confounder not present in the preintervention group.

For patients with multiple inpatient admissions, the first admission was the only admission used for analysis. Additionally, if a patient had an admission that occurred in both the preintervention and postintervention periods, they were included only in the postintervention period. This was done to avoid any within-subject correlation and ensure unique patients in each group. Confounding from this approach was mitigated through the process of deriving a matched control.

Outcomes Measurement

The primary outcome of interest was total discharges to SNF across NUHS facilities after hospital admission. Patients were identified as discharging to a SNF if discharge destination codes 03, 64, or 83 appeared on the hospital bill. Additionally, new discharges to SNFs were assessed and identified if documentation indicated that the patient’s living arrangement prior to admission was not a SNF but discharge billing destination codes 03, 64, or 83 appeared on the hospital bill.

Secondary outcomes were measurement of readmissions, days to readmission, and median length of stay (LOS). Readmissions and LOS were balancing measures for the primary outcome, with readmissions measured to evaluate the safety of the CLRC process and LOS measured to evaluate its efficiency. A readmission was any patient who had an unplanned inpatient admission at an NUHS facility within 30 days after an index admission. LOS was measured in days from arrival on a hospital unit to time of discharge.

Additional analysis was done to estimate the effect of the intervention on the incidence of COVID-19 in the 30 days following discharge by comparing the observed to expected incidence of COVID-19 by discharge destination. The expected values were derived by estimating COVID-19 cases that would have been expected to occur with rates of preintervention SNF utilization. This was accomplished by multiplying the observed incidence of COVID-19 in the 30 days following discharge by the number of patients who were discharged to SNFs or home/other in the preintervention period. This expected value was then compared with the observed values to estimate the effect size of the intervention on COVID-19 incidence following discharge. This method of deriving an expected value from the observed incidence was utilized because the preintervention period was before COVID-19 was widespread in the community. It was therefore not possible to directly measure COVID-19 incidence in the preintervention period.

Data Source

Data were retrieved from the NUHS Enterprise Data Warehouse, NUHS’s central data repository, which contains a nightly upload of clinical and financial data from the EMR. Data were collected between March 19, 2019, and July 16, 2020.

The preintervention period was defined as March 19, 2019, to March 18, 2020. Data from that interval were compared with the postintervention period, which was from March 19, 2020, to July 16, 2020. The preintervention period, 1 year immediately prior to the intervention, was chosen to limit any effect of temporal trends while also providing a large sample size. The postintervention period began on the first day NUHS implemented the revised approach to SNF use and ended on the last day before the review process was modified.

Data Analysis

An interrupted time series was used to measure the impact of adoption of the CLRC protocol. A matched control was derived from the preintervention population. To derive this matched control, there was an assessment of covariates in the preintervention and postintervention groups using a standardized mean difference (SMD)⁹ that indicated an imbalance (SMD ≥ 0.1) in some covariates. A propensity score–matching technique¹⁰ was applied to address this imbalance and lack of randomization.

The candidate variables for propensity matching were chosen if they had an association with 30-day readmission. Readmission was chosen to find candidate variables because, of the possible outcomes, this was the only one that was not directly impacted by any CLRC decision. Each covariate was assessed using a logistic regression model while controlling for the postintervention group. If there was an association between a covariate and the outcome, it was chosen for propensity matching. Propensity scores were calculated using a logistic regression model with the treatment (1/0) variable as the dependent variable and the chosen covariates as predictors.

There were no indications of strong multicollinearity. The propensity scores generated were then used to derive a matched control using paired matching. MatchIt package in R (R Foundation for Statistical Computing) was used to create a matched dataset with a logit distance and standard caliper of 0.2 times the standard deviations of the logit of the propensity score. If a match was not found within the caliper, the nearest available match was used.

Regression adjustment¹¹ was then performed using multivariate linear/logistic regression with LOS, readmission rate, days to readmission, total SNF discharges, and new SNF discharges as the outcomes. Treatment (1/0) variable and propensity score were used as the predictors. The adjusted coefficients or odds ratios (ORs) of the intervention variable were thus derived, and their associated P values were used to assess the impact of the intervention on the respective outcomes.

The unmatched preintervention population included 14,468 patients, with 4424 patients in the postintervention population. A matched population was derived and, after matching, the population sizes for pre and post intervention were 4424 each. In the matched population, all measured preintervention characteristics had SMDs and P values that were statistically equivalent. Patient characteristics for the unmatched and matched populations are detailed in Table 1.

During the preintervention period, 1130 (25.5%) patients were discharged to a SNF, with 776 (17.5%) patients being new SNF discharges. In the postintervention period, 568 (12.8%) patients were discharged to a SNF, with 257 (5.8%) patients being new SNF discharges. Total SNF discharges postintervention saw a 49.7% relative reduction (OR, 0.42; 95% CI, 0.38-0.47), while new SNF discharges saw a 66.9% relative reduction (OR, 0.29; 95% CI, 0.25-0.34). These results for both total and new SNF discharges were statistically significant, with P values of <.001, respectively.

Readmissions in the preintervention period were 529 (12.0%) patients, compared with 559 (12.6%) patients in the postintervention period (OR, 1.06; 95% CI, 0.93-1.20; P =.406). An OR was also calculated for readmissions, adjusting for discharge disposition, to account for changes observed in SNF use in the postintervention period. This OR was 1.11 (95% CI, 0.97-1.26; P = .131). Days to readmission in the preintervention and postintervention groups were 11.0 days and 12.0 days, respectively (OR, 0.41; 95% CI, –0.61 to 1.43; P = .429).

LOS was 3.61 days in the preintervention group and 3.64 days in the postintervention group, with an interquartile range (IQR) of 2.14 to 5.69 days in the preintervention group and 2.08 to 5.95 in the postintervention group (OR, 0.09; 95% CI, –0.09 to 0.27; P =.316). These results are summarized in Table 2.

A COVID-19 outbreak in a SNF presents a grave risk to residents and patients discharged to these facilities. It is critical for healthcare systems to do the utmost to protect the health of this vulnerable population and the public in efforts to limit COVID-19 within SNFs.^12-14

In this study, we observed that at NUHS, establishing a multidisciplinary review committee, the CLRC, to assess the appropriateness of discharge to a SNF after hospitalization resulted in a nearly 50% reduction in total SNF discharges and a greater than two-thirds reduction in new SNF discharges, without any increase in LOS or readmissions. Additionally, it was observed that discharging to settings other than a SNF greatly reduced a patient’s risk of being diagnosed with COVID-19 within 30 days, a result that reached statistical significance. Based on the observed 37.2% relative reduction in COVID-19 cases, we estimate that there may have been one COVID-19 infection prevented every 5.6 days from this intervention. Based on published COVID-19 mortality rates for SNF residents,¹ the intervention may have prevented one death every 2.6 weeks. Beyond the risk of COVID-19, other benefits of reducing SNF use are patient and family well-being. Although not measured in this study, others have published about the significant psychological burdens placed on SNF residents, who were at high risk for social isolation, anxiety, and depression during the COVID-19 pandemic^2,15-19 Family members also may have had increased stress, as they were deprived of the opportunity to visit loved ones, advocate for them, and help maintain their identity, humanity, and quality of life.²⁰

Although other hospitals have established a structured approach to reduce COVID-19 in SNFs,²¹ to the best of the authors’ knowledge, the approach described in this article is a unique response to the COVID-19 pandemic. As we have demonstrated, it is highly effective and safe and likely prevented many COVID-19 cases and deaths.

Furthermore, a review committee, such as the one we have described, has value well beyond the COVID-19 pandemic. The health and affordability of care for patients, provider success in value-based care models, and the long-term sustainability of the US healthcare system require close attention to appropriate use of expensive services and to ensuring that their use creates high value. SNF use after a hospitalization is one such service that is frequently targeted and thought to contribute to a substantial portion of wasteful medical spending.^22,23 Additionally, SNFs are known to be high risk for communicable disease outbreaks other than COVID-19,^24,25 as well as a high-risk environment for many other preventable adverse events.^25,26 This review committee ultimately serves to help determine the most appropriate postacute setting for patients being discharged with a determination made through considerations for patient safety, rehabilitation potential, and mental and physical well-being. From a population health perspective, this can lead to better outcomes and lower costs.^22,23 Therefore, although the risks of COVID-19 infection in SNFs are expected to subside, the work of evaluating appropriate use of SNFs after hospitalization at our institution continues. The broader focus now extends beyond postacute level of service toward ensuring a high-value discharge that results in both appropriate resource use and safe patient care transitions.

Limitations of this study include its retrospective nature, results from a single center, and a number of potentially unmeasured confounders that the COVID-19 pandemic created. One possible confounder is that the reduction in SNF use we observed was a temporal trend related to changing preferences. In addressing this, we reviewed Medicare claims data from the US Department of Health and Human Services in April 2020 and July 2020 compared with the same period in 2019. These data demonstrated only a modest reduction in spending on SNFs in April 2020 that was smaller than the reduction seen in Part A inpatient hospital spending during that same month.²⁷ By July 2020, the spending from Medicare on SNFs exceeded the levels seen in 2019,²⁷ suggesting that the percentage of acute care admissions discharging to SNFs was no lower for Medicare patients in response to COVD-19. We also considered more stringent SNF admission standards as another potential confounder; however, this was not seen at the SNFs in the NUHS geography, where the referral process became less stringent because of COVID-19 waivers for a qualifying stay or skilled need from the Centers for Medicare and Medicaid Services. We were also not able to account for readmissions outside of NUHS, and therefore there may have been differences in the readmission rate that were unmeasured. To address this limitation, we reviewed a data extract from the Illinois Health and Hospital Association and found that the percentage of patients who returned for readmission to a NUHS facility in the year prior to the intervention and during the intervention period were 92.8% and 95.3%, respectively. From this we concluded the unmeasured readmission rate appears to be low, stable, and unlikely to have altered the results of this study. Additionally, when calculating potential COVID-19 cases avoided, the expected number was, by necessity, derived from the observed outcome, given the absence of COVID-19 in the preintervention population. This may have introduced unmeasured confounders, limiting the ability to precisely measure the effect size or draw conclusions on causation. Finally, there may be limitations to the generalizability of these results based on the payor mix of the population at NUHS, which is predominantly insured through Medicare or commercial payors.

We believe this model is replicable and the results generalizable and could serve as both a template for reducing the risks of COVID-19 in SNFs and as part of a larger infection-control strategy to mitigate disease spread in vulnerable populations. It could also be applied as a component of value-improvement programs to foster appropriate use of postacute services after an acute care hospitalization, ensuring safe transitions of care through promotion of high-value care practices.

The authors thank Wei Ning Chi for editorial assistance.

The COVID-19 outbreak in February 2020 at a congregate living facility near Seattle, Washington, signaled the beginning of the pandemic in the United States. In that facility, infected residents had a 54.5% hospitalization rate and 33.7% case-fatality rate.¹ Similar to the experience in Washington, all congregate living facilities have proved particularly vulnerable to the effects of COVID-19,^2-7 with residents at increased risk for disease severity and mortality.^2-7

Due to the COVID-19 emergency, NorthShore University HealthSystem (NUHS), a multihospital, integrated health system in northern Illinois, established a best practice for appropriate use of congregate living facilities after hospitalization. This focused on the safety of discharged patients and mitigation of COVID-19 by putting in place a referral process to a newly established congregate living review committee (CLRC) for review prior to discharge. Although all discharges to congregate living settings are at high risk,² new placements to skilled nursing facilities (SNFs) were the primary focus of the committee and the sole focus of this study. In this study, we sought to determine whether establishment of the CLRC was associated with a reduction in SNF utilization, whether this was safe and efficient, and whether it was associated with a reduction in COVID-19 incidence in the 30 days following discharge.

Setting and Case Review Intervention

We conducted a retrospective cohort study for patients hospitalized within NUHS from March 19, 2019 to July 16, 2020, designed as an interrupted time series. The study was approved by the NUHS Institutional Review Board (EH21-022).

The study exposure was creation of a referral and review process for all patients with expected discharge to a SNF and was implemented as part of usual discharge planning during the COVID-19 pandemic. The key intervention was to establish a multidisciplinary committee, the CLRC, to review all potential discharges to SNFs. The CLRC had dual goals of preventing COVID-19 spread in facilities by limiting placement of new residents and protecting a vulnerable population from a setting that conferred a higher risk of acquiring COVID-19. The CLRC was organized as a multidisciplinary committee with physicians, case managers, social workers, physical therapists, occupational therapists, and the director of NUHS home health agency. Physician members were evenly split as half hospitalists and half ambulatory physicians. The CLRC review was initiated by a patient’s assigned case manager or social worker by consult through a referral in the electronic medical record (EMR). Each case was summarized and then presented to the full CLRC. The CLRC met for 1 hour per day, 6 days per week, to review all planned discharges that met criteria for review. A committee physician chaired each meeting. Three other members were needed for a quorum, with one other member with a title of director or higher. Time required was the 1-hour daily meeting, as well as one full-time position for case review, preparation, and program administration. The case presentation included a clinical summary of the hospitalization as well as COVID-19 status and testing history, previous living situation, level of home support, functional level, psychosocial needs, barrier(s) to discharging home, and long-term residential plans. A structured assessment was then made by each CLRC member in accordance with their professional expertise. Unanimous consensus would be reached before finalizing any recommended adjustments to the discharge, which would be communicated to the inpatient care team via a structured note within the EMR, along with direct communication to the assigned case manager or social worker. When the CLRC suggested adjustments to the discharge, they would work with the assigned case manager or social worker to communicate an appropriate post–acute care plan with the patient or appropriate representative. If there was disagreement or the recommendations could not be followed, the case manager or social worker would place a new referral with additional information for reconsideration. Following a recommendation for SNF, verification would be completed by the CLRC prior to discharge. This process is detailed in Figure 1.

Patient Population

Inclusion criteria for the study were: (1) inpatient hospitalization and (2) eligibility for risk scoring via the organization’s clinical analytics prediction engine (CAPE).⁸ CAPE is a validated predictive model that includes risk of readmission, in-hospital mortality, and out-of-hospital mortality,⁸ with extensive adoption at NUHS. CAPE score eligibility was used as an inclusion criterion so that CAPE could be applied for derivation of a matched control. CAPE eligibility criteria include admission age of at least 18 years and that hospitalization is not psychiatric, rehabilitative, or obstetric. Patients must not be enrolled in hospice and must be discharged alive.

Exclusions were patients who tested positive for SARS-CoV-2 prior to or during index hospitalization. Excluding COVID-19 patients from the analysis eliminated a confounder not present in the preintervention group.

For patients with multiple inpatient admissions, the first admission was the only admission used for analysis. Additionally, if a patient had an admission that occurred in both the preintervention and postintervention periods, they were included only in the postintervention period. This was done to avoid any within-subject correlation and ensure unique patients in each group. Confounding from this approach was mitigated through the process of deriving a matched control.

Outcomes Measurement

The primary outcome of interest was total discharges to SNF across NUHS facilities after hospital admission. Patients were identified as discharging to a SNF if discharge destination codes 03, 64, or 83 appeared on the hospital bill. Additionally, new discharges to SNFs were assessed and identified if documentation indicated that the patient’s living arrangement prior to admission was not a SNF but discharge billing destination codes 03, 64, or 83 appeared on the hospital bill.

Secondary outcomes were measurement of readmissions, days to readmission, and median length of stay (LOS). Readmissions and LOS were balancing measures for the primary outcome, with readmissions measured to evaluate the safety of the CLRC process and LOS measured to evaluate its efficiency. A readmission was any patient who had an unplanned inpatient admission at an NUHS facility within 30 days after an index admission. LOS was measured in days from arrival on a hospital unit to time of discharge.

Additional analysis was done to estimate the effect of the intervention on the incidence of COVID-19 in the 30 days following discharge by comparing the observed to expected incidence of COVID-19 by discharge destination. The expected values were derived by estimating COVID-19 cases that would have been expected to occur with rates of preintervention SNF utilization. This was accomplished by multiplying the observed incidence of COVID-19 in the 30 days following discharge by the number of patients who were discharged to SNFs or home/other in the preintervention period. This expected value was then compared with the observed values to estimate the effect size of the intervention on COVID-19 incidence following discharge. This method of deriving an expected value from the observed incidence was utilized because the preintervention period was before COVID-19 was widespread in the community. It was therefore not possible to directly measure COVID-19 incidence in the preintervention period.

Data Source

Data were retrieved from the NUHS Enterprise Data Warehouse, NUHS’s central data repository, which contains a nightly upload of clinical and financial data from the EMR. Data were collected between March 19, 2019, and July 16, 2020.

The preintervention period was defined as March 19, 2019, to March 18, 2020. Data from that interval were compared with the postintervention period, which was from March 19, 2020, to July 16, 2020. The preintervention period, 1 year immediately prior to the intervention, was chosen to limit any effect of temporal trends while also providing a large sample size. The postintervention period began on the first day NUHS implemented the revised approach to SNF use and ended on the last day before the review process was modified.

Data Analysis

An interrupted time series was used to measure the impact of adoption of the CLRC protocol. A matched control was derived from the preintervention population. To derive this matched control, there was an assessment of covariates in the preintervention and postintervention groups using a standardized mean difference (SMD)⁹ that indicated an imbalance (SMD ≥ 0.1) in some covariates. A propensity score–matching technique¹⁰ was applied to address this imbalance and lack of randomization.

The candidate variables for propensity matching were chosen if they had an association with 30-day readmission. Readmission was chosen to find candidate variables because, of the possible outcomes, this was the only one that was not directly impacted by any CLRC decision. Each covariate was assessed using a logistic regression model while controlling for the postintervention group. If there was an association between a covariate and the outcome, it was chosen for propensity matching. Propensity scores were calculated using a logistic regression model with the treatment (1/0) variable as the dependent variable and the chosen covariates as predictors.

There were no indications of strong multicollinearity. The propensity scores generated were then used to derive a matched control using paired matching. MatchIt package in R (R Foundation for Statistical Computing) was used to create a matched dataset with a logit distance and standard caliper of 0.2 times the standard deviations of the logit of the propensity score. If a match was not found within the caliper, the nearest available match was used.

Regression adjustment¹¹ was then performed using multivariate linear/logistic regression with LOS, readmission rate, days to readmission, total SNF discharges, and new SNF discharges as the outcomes. Treatment (1/0) variable and propensity score were used as the predictors. The adjusted coefficients or odds ratios (ORs) of the intervention variable were thus derived, and their associated P values were used to assess the impact of the intervention on the respective outcomes.

The unmatched preintervention population included 14,468 patients, with 4424 patients in the postintervention population. A matched population was derived and, after matching, the population sizes for pre and post intervention were 4424 each. In the matched population, all measured preintervention characteristics had SMDs and P values that were statistically equivalent. Patient characteristics for the unmatched and matched populations are detailed in Table 1.

During the preintervention period, 1130 (25.5%) patients were discharged to a SNF, with 776 (17.5%) patients being new SNF discharges. In the postintervention period, 568 (12.8%) patients were discharged to a SNF, with 257 (5.8%) patients being new SNF discharges. Total SNF discharges postintervention saw a 49.7% relative reduction (OR, 0.42; 95% CI, 0.38-0.47), while new SNF discharges saw a 66.9% relative reduction (OR, 0.29; 95% CI, 0.25-0.34). These results for both total and new SNF discharges were statistically significant, with P values of <.001, respectively.

Readmissions in the preintervention period were 529 (12.0%) patients, compared with 559 (12.6%) patients in the postintervention period (OR, 1.06; 95% CI, 0.93-1.20; P =.406). An OR was also calculated for readmissions, adjusting for discharge disposition, to account for changes observed in SNF use in the postintervention period. This OR was 1.11 (95% CI, 0.97-1.26; P = .131). Days to readmission in the preintervention and postintervention groups were 11.0 days and 12.0 days, respectively (OR, 0.41; 95% CI, –0.61 to 1.43; P = .429).

LOS was 3.61 days in the preintervention group and 3.64 days in the postintervention group, with an interquartile range (IQR) of 2.14 to 5.69 days in the preintervention group and 2.08 to 5.95 in the postintervention group (OR, 0.09; 95% CI, –0.09 to 0.27; P =.316). These results are summarized in Table 2.

A COVID-19 outbreak in a SNF presents a grave risk to residents and patients discharged to these facilities. It is critical for healthcare systems to do the utmost to protect the health of this vulnerable population and the public in efforts to limit COVID-19 within SNFs.^12-14

In this study, we observed that at NUHS, establishing a multidisciplinary review committee, the CLRC, to assess the appropriateness of discharge to a SNF after hospitalization resulted in a nearly 50% reduction in total SNF discharges and a greater than two-thirds reduction in new SNF discharges, without any increase in LOS or readmissions. Additionally, it was observed that discharging to settings other than a SNF greatly reduced a patient’s risk of being diagnosed with COVID-19 within 30 days, a result that reached statistical significance. Based on the observed 37.2% relative reduction in COVID-19 cases, we estimate that there may have been one COVID-19 infection prevented every 5.6 days from this intervention. Based on published COVID-19 mortality rates for SNF residents,¹ the intervention may have prevented one death every 2.6 weeks. Beyond the risk of COVID-19, other benefits of reducing SNF use are patient and family well-being. Although not measured in this study, others have published about the significant psychological burdens placed on SNF residents, who were at high risk for social isolation, anxiety, and depression during the COVID-19 pandemic^2,15-19 Family members also may have had increased stress, as they were deprived of the opportunity to visit loved ones, advocate for them, and help maintain their identity, humanity, and quality of life.²⁰

Although other hospitals have established a structured approach to reduce COVID-19 in SNFs,²¹ to the best of the authors’ knowledge, the approach described in this article is a unique response to the COVID-19 pandemic. As we have demonstrated, it is highly effective and safe and likely prevented many COVID-19 cases and deaths.

Furthermore, a review committee, such as the one we have described, has value well beyond the COVID-19 pandemic. The health and affordability of care for patients, provider success in value-based care models, and the long-term sustainability of the US healthcare system require close attention to appropriate use of expensive services and to ensuring that their use creates high value. SNF use after a hospitalization is one such service that is frequently targeted and thought to contribute to a substantial portion of wasteful medical spending.^22,23 Additionally, SNFs are known to be high risk for communicable disease outbreaks other than COVID-19,^24,25 as well as a high-risk environment for many other preventable adverse events.^25,26 This review committee ultimately serves to help determine the most appropriate postacute setting for patients being discharged with a determination made through considerations for patient safety, rehabilitation potential, and mental and physical well-being. From a population health perspective, this can lead to better outcomes and lower costs.^22,23 Therefore, although the risks of COVID-19 infection in SNFs are expected to subside, the work of evaluating appropriate use of SNFs after hospitalization at our institution continues. The broader focus now extends beyond postacute level of service toward ensuring a high-value discharge that results in both appropriate resource use and safe patient care transitions.

Limitations of this study include its retrospective nature, results from a single center, and a number of potentially unmeasured confounders that the COVID-19 pandemic created. One possible confounder is that the reduction in SNF use we observed was a temporal trend related to changing preferences. In addressing this, we reviewed Medicare claims data from the US Department of Health and Human Services in April 2020 and July 2020 compared with the same period in 2019. These data demonstrated only a modest reduction in spending on SNFs in April 2020 that was smaller than the reduction seen in Part A inpatient hospital spending during that same month.²⁷ By July 2020, the spending from Medicare on SNFs exceeded the levels seen in 2019,²⁷ suggesting that the percentage of acute care admissions discharging to SNFs was no lower for Medicare patients in response to COVD-19. We also considered more stringent SNF admission standards as another potential confounder; however, this was not seen at the SNFs in the NUHS geography, where the referral process became less stringent because of COVID-19 waivers for a qualifying stay or skilled need from the Centers for Medicare and Medicaid Services. We were also not able to account for readmissions outside of NUHS, and therefore there may have been differences in the readmission rate that were unmeasured. To address this limitation, we reviewed a data extract from the Illinois Health and Hospital Association and found that the percentage of patients who returned for readmission to a NUHS facility in the year prior to the intervention and during the intervention period were 92.8% and 95.3%, respectively. From this we concluded the unmeasured readmission rate appears to be low, stable, and unlikely to have altered the results of this study. Additionally, when calculating potential COVID-19 cases avoided, the expected number was, by necessity, derived from the observed outcome, given the absence of COVID-19 in the preintervention population. This may have introduced unmeasured confounders, limiting the ability to precisely measure the effect size or draw conclusions on causation. Finally, there may be limitations to the generalizability of these results based on the payor mix of the population at NUHS, which is predominantly insured through Medicare or commercial payors.

We believe this model is replicable and the results generalizable and could serve as both a template for reducing the risks of COVID-19 in SNFs and as part of a larger infection-control strategy to mitigate disease spread in vulnerable populations. It could also be applied as a component of value-improvement programs to foster appropriate use of postacute services after an acute care hospitalization, ensuring safe transitions of care through promotion of high-value care practices.

The authors thank Wei Ning Chi for editorial assistance.

The COVID-19 outbreak in February 2020 at a congregate living facility near Seattle, Washington, signaled the beginning of the pandemic in the United States. In that facility, infected residents had a 54.5% hospitalization rate and 33.7% case-fatality rate.¹ Similar to the experience in Washington, all congregate living facilities have proved particularly vulnerable to the effects of COVID-19,^2-7 with residents at increased risk for disease severity and mortality.^2-7

Due to the COVID-19 emergency, NorthShore University HealthSystem (NUHS), a multihospital, integrated health system in northern Illinois, established a best practice for appropriate use of congregate living facilities after hospitalization. This focused on the safety of discharged patients and mitigation of COVID-19 by putting in place a referral process to a newly established congregate living review committee (CLRC) for review prior to discharge. Although all discharges to congregate living settings are at high risk,² new placements to skilled nursing facilities (SNFs) were the primary focus of the committee and the sole focus of this study. In this study, we sought to determine whether establishment of the CLRC was associated with a reduction in SNF utilization, whether this was safe and efficient, and whether it was associated with a reduction in COVID-19 incidence in the 30 days following discharge.

Setting and Case Review Intervention

We conducted a retrospective cohort study for patients hospitalized within NUHS from March 19, 2019 to July 16, 2020, designed as an interrupted time series. The study was approved by the NUHS Institutional Review Board (EH21-022).

The study exposure was creation of a referral and review process for all patients with expected discharge to a SNF and was implemented as part of usual discharge planning during the COVID-19 pandemic. The key intervention was to establish a multidisciplinary committee, the CLRC, to review all potential discharges to SNFs. The CLRC had dual goals of preventing COVID-19 spread in facilities by limiting placement of new residents and protecting a vulnerable population from a setting that conferred a higher risk of acquiring COVID-19. The CLRC was organized as a multidisciplinary committee with physicians, case managers, social workers, physical therapists, occupational therapists, and the director of NUHS home health agency. Physician members were evenly split as half hospitalists and half ambulatory physicians. The CLRC review was initiated by a patient’s assigned case manager or social worker by consult through a referral in the electronic medical record (EMR). Each case was summarized and then presented to the full CLRC. The CLRC met for 1 hour per day, 6 days per week, to review all planned discharges that met criteria for review. A committee physician chaired each meeting. Three other members were needed for a quorum, with one other member with a title of director or higher. Time required was the 1-hour daily meeting, as well as one full-time position for case review, preparation, and program administration. The case presentation included a clinical summary of the hospitalization as well as COVID-19 status and testing history, previous living situation, level of home support, functional level, psychosocial needs, barrier(s) to discharging home, and long-term residential plans. A structured assessment was then made by each CLRC member in accordance with their professional expertise. Unanimous consensus would be reached before finalizing any recommended adjustments to the discharge, which would be communicated to the inpatient care team via a structured note within the EMR, along with direct communication to the assigned case manager or social worker. When the CLRC suggested adjustments to the discharge, they would work with the assigned case manager or social worker to communicate an appropriate post–acute care plan with the patient or appropriate representative. If there was disagreement or the recommendations could not be followed, the case manager or social worker would place a new referral with additional information for reconsideration. Following a recommendation for SNF, verification would be completed by the CLRC prior to discharge. This process is detailed in Figure 1.

Patient Population

Inclusion criteria for the study were: (1) inpatient hospitalization and (2) eligibility for risk scoring via the organization’s clinical analytics prediction engine (CAPE).⁸ CAPE is a validated predictive model that includes risk of readmission, in-hospital mortality, and out-of-hospital mortality,⁸ with extensive adoption at NUHS. CAPE score eligibility was used as an inclusion criterion so that CAPE could be applied for derivation of a matched control. CAPE eligibility criteria include admission age of at least 18 years and that hospitalization is not psychiatric, rehabilitative, or obstetric. Patients must not be enrolled in hospice and must be discharged alive.

Exclusions were patients who tested positive for SARS-CoV-2 prior to or during index hospitalization. Excluding COVID-19 patients from the analysis eliminated a confounder not present in the preintervention group.

For patients with multiple inpatient admissions, the first admission was the only admission used for analysis. Additionally, if a patient had an admission that occurred in both the preintervention and postintervention periods, they were included only in the postintervention period. This was done to avoid any within-subject correlation and ensure unique patients in each group. Confounding from this approach was mitigated through the process of deriving a matched control.

Outcomes Measurement

The primary outcome of interest was total discharges to SNF across NUHS facilities after hospital admission. Patients were identified as discharging to a SNF if discharge destination codes 03, 64, or 83 appeared on the hospital bill. Additionally, new discharges to SNFs were assessed and identified if documentation indicated that the patient’s living arrangement prior to admission was not a SNF but discharge billing destination codes 03, 64, or 83 appeared on the hospital bill.

Secondary outcomes were measurement of readmissions, days to readmission, and median length of stay (LOS). Readmissions and LOS were balancing measures for the primary outcome, with readmissions measured to evaluate the safety of the CLRC process and LOS measured to evaluate its efficiency. A readmission was any patient who had an unplanned inpatient admission at an NUHS facility within 30 days after an index admission. LOS was measured in days from arrival on a hospital unit to time of discharge.

Additional analysis was done to estimate the effect of the intervention on the incidence of COVID-19 in the 30 days following discharge by comparing the observed to expected incidence of COVID-19 by discharge destination. The expected values were derived by estimating COVID-19 cases that would have been expected to occur with rates of preintervention SNF utilization. This was accomplished by multiplying the observed incidence of COVID-19 in the 30 days following discharge by the number of patients who were discharged to SNFs or home/other in the preintervention period. This expected value was then compared with the observed values to estimate the effect size of the intervention on COVID-19 incidence following discharge. This method of deriving an expected value from the observed incidence was utilized because the preintervention period was before COVID-19 was widespread in the community. It was therefore not possible to directly measure COVID-19 incidence in the preintervention period.

Data Source

Data were retrieved from the NUHS Enterprise Data Warehouse, NUHS’s central data repository, which contains a nightly upload of clinical and financial data from the EMR. Data were collected between March 19, 2019, and July 16, 2020.

The preintervention period was defined as March 19, 2019, to March 18, 2020. Data from that interval were compared with the postintervention period, which was from March 19, 2020, to July 16, 2020. The preintervention period, 1 year immediately prior to the intervention, was chosen to limit any effect of temporal trends while also providing a large sample size. The postintervention period began on the first day NUHS implemented the revised approach to SNF use and ended on the last day before the review process was modified.

Data Analysis

An interrupted time series was used to measure the impact of adoption of the CLRC protocol. A matched control was derived from the preintervention population. To derive this matched control, there was an assessment of covariates in the preintervention and postintervention groups using a standardized mean difference (SMD)⁹ that indicated an imbalance (SMD ≥ 0.1) in some covariates. A propensity score–matching technique¹⁰ was applied to address this imbalance and lack of randomization.

The candidate variables for propensity matching were chosen if they had an association with 30-day readmission. Readmission was chosen to find candidate variables because, of the possible outcomes, this was the only one that was not directly impacted by any CLRC decision. Each covariate was assessed using a logistic regression model while controlling for the postintervention group. If there was an association between a covariate and the outcome, it was chosen for propensity matching. Propensity scores were calculated using a logistic regression model with the treatment (1/0) variable as the dependent variable and the chosen covariates as predictors.

There were no indications of strong multicollinearity. The propensity scores generated were then used to derive a matched control using paired matching. MatchIt package in R (R Foundation for Statistical Computing) was used to create a matched dataset with a logit distance and standard caliper of 0.2 times the standard deviations of the logit of the propensity score. If a match was not found within the caliper, the nearest available match was used.

Regression adjustment¹¹ was then performed using multivariate linear/logistic regression with LOS, readmission rate, days to readmission, total SNF discharges, and new SNF discharges as the outcomes. Treatment (1/0) variable and propensity score were used as the predictors. The adjusted coefficients or odds ratios (ORs) of the intervention variable were thus derived, and their associated P values were used to assess the impact of the intervention on the respective outcomes.

The unmatched preintervention population included 14,468 patients, with 4424 patients in the postintervention population. A matched population was derived and, after matching, the population sizes for pre and post intervention were 4424 each. In the matched population, all measured preintervention characteristics had SMDs and P values that were statistically equivalent. Patient characteristics for the unmatched and matched populations are detailed in Table 1.

During the preintervention period, 1130 (25.5%) patients were discharged to a SNF, with 776 (17.5%) patients being new SNF discharges. In the postintervention period, 568 (12.8%) patients were discharged to a SNF, with 257 (5.8%) patients being new SNF discharges. Total SNF discharges postintervention saw a 49.7% relative reduction (OR, 0.42; 95% CI, 0.38-0.47), while new SNF discharges saw a 66.9% relative reduction (OR, 0.29; 95% CI, 0.25-0.34). These results for both total and new SNF discharges were statistically significant, with P values of <.001, respectively.

Readmissions in the preintervention period were 529 (12.0%) patients, compared with 559 (12.6%) patients in the postintervention period (OR, 1.06; 95% CI, 0.93-1.20; P =.406). An OR was also calculated for readmissions, adjusting for discharge disposition, to account for changes observed in SNF use in the postintervention period. This OR was 1.11 (95% CI, 0.97-1.26; P = .131). Days to readmission in the preintervention and postintervention groups were 11.0 days and 12.0 days, respectively (OR, 0.41; 95% CI, –0.61 to 1.43; P = .429).

LOS was 3.61 days in the preintervention group and 3.64 days in the postintervention group, with an interquartile range (IQR) of 2.14 to 5.69 days in the preintervention group and 2.08 to 5.95 in the postintervention group (OR, 0.09; 95% CI, –0.09 to 0.27; P =.316). These results are summarized in Table 2.

A COVID-19 outbreak in a SNF presents a grave risk to residents and patients discharged to these facilities. It is critical for healthcare systems to do the utmost to protect the health of this vulnerable population and the public in efforts to limit COVID-19 within SNFs.^12-14

In this study, we observed that at NUHS, establishing a multidisciplinary review committee, the CLRC, to assess the appropriateness of discharge to a SNF after hospitalization resulted in a nearly 50% reduction in total SNF discharges and a greater than two-thirds reduction in new SNF discharges, without any increase in LOS or readmissions. Additionally, it was observed that discharging to settings other than a SNF greatly reduced a patient’s risk of being diagnosed with COVID-19 within 30 days, a result that reached statistical significance. Based on the observed 37.2% relative reduction in COVID-19 cases, we estimate that there may have been one COVID-19 infection prevented every 5.6 days from this intervention. Based on published COVID-19 mortality rates for SNF residents,¹ the intervention may have prevented one death every 2.6 weeks. Beyond the risk of COVID-19, other benefits of reducing SNF use are patient and family well-being. Although not measured in this study, others have published about the significant psychological burdens placed on SNF residents, who were at high risk for social isolation, anxiety, and depression during the COVID-19 pandemic^2,15-19 Family members also may have had increased stress, as they were deprived of the opportunity to visit loved ones, advocate for them, and help maintain their identity, humanity, and quality of life.²⁰

Although other hospitals have established a structured approach to reduce COVID-19 in SNFs,²¹ to the best of the authors’ knowledge, the approach described in this article is a unique response to the COVID-19 pandemic. As we have demonstrated, it is highly effective and safe and likely prevented many COVID-19 cases and deaths.

Furthermore, a review committee, such as the one we have described, has value well beyond the COVID-19 pandemic. The health and affordability of care for patients, provider success in value-based care models, and the long-term sustainability of the US healthcare system require close attention to appropriate use of expensive services and to ensuring that their use creates high value. SNF use after a hospitalization is one such service that is frequently targeted and thought to contribute to a substantial portion of wasteful medical spending.^22,23 Additionally, SNFs are known to be high risk for communicable disease outbreaks other than COVID-19,^24,25 as well as a high-risk environment for many other preventable adverse events.^25,26 This review committee ultimately serves to help determine the most appropriate postacute setting for patients being discharged with a determination made through considerations for patient safety, rehabilitation potential, and mental and physical well-being. From a population health perspective, this can lead to better outcomes and lower costs.^22,23 Therefore, although the risks of COVID-19 infection in SNFs are expected to subside, the work of evaluating appropriate use of SNFs after hospitalization at our institution continues. The broader focus now extends beyond postacute level of service toward ensuring a high-value discharge that results in both appropriate resource use and safe patient care transitions.

Limitations of this study include its retrospective nature, results from a single center, and a number of potentially unmeasured confounders that the COVID-19 pandemic created. One possible confounder is that the reduction in SNF use we observed was a temporal trend related to changing preferences. In addressing this, we reviewed Medicare claims data from the US Department of Health and Human Services in April 2020 and July 2020 compared with the same period in 2019. These data demonstrated only a modest reduction in spending on SNFs in April 2020 that was smaller than the reduction seen in Part A inpatient hospital spending during that same month.²⁷ By July 2020, the spending from Medicare on SNFs exceeded the levels seen in 2019,²⁷ suggesting that the percentage of acute care admissions discharging to SNFs was no lower for Medicare patients in response to COVD-19. We also considered more stringent SNF admission standards as another potential confounder; however, this was not seen at the SNFs in the NUHS geography, where the referral process became less stringent because of COVID-19 waivers for a qualifying stay or skilled need from the Centers for Medicare and Medicaid Services. We were also not able to account for readmissions outside of NUHS, and therefore there may have been differences in the readmission rate that were unmeasured. To address this limitation, we reviewed a data extract from the Illinois Health and Hospital Association and found that the percentage of patients who returned for readmission to a NUHS facility in the year prior to the intervention and during the intervention period were 92.8% and 95.3%, respectively. From this we concluded the unmeasured readmission rate appears to be low, stable, and unlikely to have altered the results of this study. Additionally, when calculating potential COVID-19 cases avoided, the expected number was, by necessity, derived from the observed outcome, given the absence of COVID-19 in the preintervention population. This may have introduced unmeasured confounders, limiting the ability to precisely measure the effect size or draw conclusions on causation. Finally, there may be limitations to the generalizability of these results based on the payor mix of the population at NUHS, which is predominantly insured through Medicare or commercial payors.

We believe this model is replicable and the results generalizable and could serve as both a template for reducing the risks of COVID-19 in SNFs and as part of a larger infection-control strategy to mitigate disease spread in vulnerable populations. It could also be applied as a component of value-improvement programs to foster appropriate use of postacute services after an acute care hospitalization, ensuring safe transitions of care through promotion of high-value care practices.

The authors thank Wei Ning Chi for editorial assistance.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hospital readmissions are a significant problem in the United States, affecting 15% to 30% of discharges and incurring costs of more than $17 billion annually.¹ Timely posthospitalization follow-up visits are critical to ensure the effective transfer of patients to the outpatient setting; such visits reduce readmission rates as well as hospital length of stay and overall health care resource utilization.^2-4 Patients who receive inadequate follow-up care (ie, within 4 weeks of discharge) are significantly more likely to be readmitted than those who receive close follow-up care^.5

Due to the large clinical and financial consequences associated with hospital readmission, a variety of interventions have been studied, including home visits, telemonitoring, medication management, telephone calls, and postdischarge clinics.^6,7 While studies have not shown postdischarge clinics to be universally efficacious in reducing readmission rates, there is increasing evidence of reduced readmission rates in clinics that target high-risk patients (eg, patients with congestive heart failure [CHF]) rather than the total population.² A study by Hernandez et al that evaluated the relationship between early physician follow-up and 30-day readmissions showed a significantly lower readmission rate among hospitals with higher follow-up rates.⁸ Similarly, patients with CHF in a large, integrated health system who were seen within 7 days of discharge had an odds ratio (OR) of 0.81 (95% CI, 0.70-0.94) for 30-day readmissions.⁹

Transitions-of-care clinics (TOCC), designed to provide early postdischarge follow-up to high-risk patients, have been shown to reduce 30-day readmission rates,^3,4,10,11 especially in clinics that have same-physician follow-up visits rather than follow-up visits with a community primary care physician (PCP).¹² The most pronounced impact of postdischarge follow-up is seen in high-risk patients with high complexity or high severity of disease; however, complex rural patients are less likely to have access to specialty care.¹³ As a result, since rural residents must travel farther for specialty care, they are seen less frequently than their urban counterparts.^14,15

Prior to our TOCC initiative, the Iowa City VA (ICVA) ranked in the fifth quintile of the Veterans Health Administration (VHA) Strategic Analytics for Improvement and Learning model for hospital-wide readmissions (HWR), meaning that HWR at ICVA were higher than 80% of the other VHA healthcare centers. The low score in this metric was in part due to readmission rates in high-risk populations, including patients with CHF and those with high Care Assessment Need (CAN) scores. One concern was that the ICVA system serves many veterans from rural areas, some of whom must travel up to 200 miles to access inpatient and subspecialty care.

To meet these challenges, we implemented a TOCC to deliver timely postdischarge care focusing on high-risk and high-complexity patients. To address access-to-care issues of patients living in rural areas within the ICVA, we included virtual follow-up visits as a key component of our intervention.^16,17 The aim of this project was to decrease 30-day readmission rates of ICVA patients by 20% within 12 months of implementation.

Setting/Study Population

The ICVA serves 184,000 veterans stretched over 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. Patients were initially eligible for the TOCC if they had an admission diagnosis of CHF and a CAN score > 85 at the time of discharge. The CAN score, developed by the VA to assess the risk of hospital readmission in individual patients, factors in several variables, including demographics, coexisting conditions, vital signs, utilization of services, pharmacy visits, and laboratory results. Patients in the top 5% (95-99) have a readmission rate of 20% at 90 days. Since the CAN is a proprietary tool, it may not be published in full; however, this assessment tool is commonly used and frequently cited in VA research.^18-22 The CAN score is expressed as a percentile ranging from 0 (lowest risk) to 99 (highest risk). Patient eligibility was expanded during subsequent Plan-Do-Study-Act (PDSA) cycles, as outlined below. Patient eligibility was expanded during subsequent PDSA cycles (also outlined below). A review by a local institutional review board was obtained, and the study was classified as exempt due to the use of deidentified data. Standards for Quality Improvement Reporting Excellence 2.0 guidelines were used to construct the manuscript.

Magnitude Assessment

The numbers of discharges, readmissions within 30 days, emergency department (ED) visits by all discharged veterans, and veterans discharged with a CHF hospital diagnosis were recorded from February 2017 to February 2018, which were the 12 months immediately preceding the pilot implementation.

Intervention

The primary intervention was referral to the newly formed ICVA TOCC. The multidisciplinary TOCC team consisted of hospitalists, pharmacists, schedulers, and discharge planners/care managers. Patients were identified by the hospitalist team during admission; prior to hospital discharge, these patients were referred to TOCC discharge planners to schedule appropriate follow-up appointments. Virtual follow-up visits were conducted using a patient’s home technology; in cases where a patient lacked adequate technology capabilities (eg, no computer or internet access), the ICVA provided a tablet device with cellular internet capability for temporary use. Specific clinical activities included medication reconciliation by a pharmacist, follow-up of pending laboratory studies, imaging studies, pathology results, medical diagnosis education, counseling regarding dietary restrictions, and contingency planning outside of an ED visit in the event of a change in clinical status. In addition, the TOCC aimed to facilitate a smooth transition of care back to the PCP by arranging follow-up appointments, providing visit summaries, and scheduling consults with specialty care, as appropriate.

Measures

The primary objective measure was the 30-day readmission rate in the ICVA hospital. Secondary measures included the number of VHA ED visits within 30 days of discharge. The main process measures were the number of hospital discharges per month, the number of TOCC referrals, the number of TOCC appointments made, the number of virtual and in-person visits, and the percentage of appointment “no-shows.”

Implementation

The TOCC was piloted from April 2018 to October 2018. During the pilot phase, TOCC enrollment was limited to virtual appointments and to patients with an admission diagnosis of CHF and a CAN score of > 85. The TOCC had staff on-site 2 days a week; this included pharmacists to reconcile medications and hospitalists to address follow-up care needs.

The TOCC clinic was temporarily closed at the end of October 2018 to analyze pilot results. Based on stakeholder feedback, changes made as part of the second PDSA cycle included expanding eligibility criteria to any hospital admission diagnosis and to patients with a CAN score < 85 if the hospitalist team felt the patient was likely to benefit from TOCC follow-up. In addition, on-site clinic staffing was expanded from 2 to 5 days per week to improve access, and the option for an in-person visit was added based on concerns some veterans expressed regarding the use of the technology at home. Finally, a formal resident program was added, and the order set for referrals was simplified. The TOCC was restarted in February 2019, and TOCC metrics were reviewed monthly. By July 2019, we identified issues with TOCC referrals and appointment creation that required additional modifications to the intervention.

A third PDSA cycle was initiated in July 2019 and included major changes, notably the formation of a designated TOCC committee. The committee appointed a dedicated TOCC scheduler whose role was to reduce confusion regarding scheduling, to update the discharge instructions/orders template to lower incidences of “double-booking” that occurred with PCP and TOCC appointments, to modify discharge educational instruction regarding virtual visits and tablet use, to adjust the TOCC-PCP handoff, and to formalize interactions between discharge coordinators and residents to review possible referrals every morning (Appendix Figure 1).

Statistical Analysis

Run charts were constructed by plotting monthly primary outcome values and monthly process metrics (Figure, Appendix Figure 2, Appendix Figure 3). Chi-square tests were used to compare 30-day readmission rates before and after the intervention. Statistical modeling was used to determine differences in outcomes between referred patients seen and referred patients not seen by the TOCC. In these statistical models, the outcome measures were 30-day readmissions, 30-day ED visits, and 6-month mortality. Covariates included in the final analysis were age, gender, race, CAN score, rural-urban commuting area code, referral service (resident vs nonresident), and admission diagnosis. Admission diagnoses were sorted by the investigators into one of the following seven categories: cardiac, infectious, pulmonary, gastrointestinal, neurologic, renal, and other.

Mean (SD) or counts and percentages were used to describe the distribution of continuous and categorical variables, respectively. Kruskal-Wallis test, t test, or chi-square tests were used, as appropriate, across categories. Generalized linear models with a logistic link function were used to test for differences between patients who kept their appointment at the TOCC and those who did not keep their TOCC appointment (both unadjusted and adjusted for all of the covariates previously mentioned). In addition, generalized linear models were also used to compare outcomes between TOCC patients seen virtually vs those seen in-person (both unadjusted and adjusted for all the covariates previously mentioned). All statistical tests were considered significant at a two-sided P < .05. All analyses were performed using SAS software version 9.4 (SAS Institute Inc).

Magnitude Assessment

During the preimplementation period (February 2017-February 2018), there were 3014 patient discharges from ICVA and 343 readmissions, resulting in a readmission rate of 11.4%. Among patients with a hospital-admission diagnosis of cardiorespiratory disease, which included patients with CHF, there were 381 discharges and 46 readmissions, resulting in a readmission rate of 12.1%.

Primary Outcome

During the pilot phase, which was conducted from April 2018 to October 2018, 142 patients who met inclusion criteria (CHF diagnosis and a CAN score > 85) were discharged from ICVA, and 56 referrals to the TOCC were placed. The readmission rate among the cardiorespiratory cohort of veterans was 9.5%.

During the expansion of the intervention from February 2019 to February 2020, there were 2844 discharges from the ICVA and 291 readmissions, resulting in a readmission rate of 10.2%. However, there was a further decrease in the readmission rate after the third PDSA cycle was initiated in July 2019 (Appendix Figure 1). The readmission rate was 9.2% in the final 6 months of the intervention period, and 7.9% in the final 3 months. Of note, in the group of 1948 patients who did not meet the eligibility criteria to participate in our study, the readmission rate during the same time period was 8.6% (161 readmissions).

When comparing the 6 months following the third PDSA cycle to the magnitude assessment period, there was a relative readmission reduction of 19.3% (P = .04), and an absolute reduction of 2.2%. If the final 3 months of the intervention period are included, there was an absolute reduction of 3.5% and a relative reduction of 30.7% (P = .01). Notably, before the pilot phase, ICVA was in the fifth quintile for HWR among VA hospitals but improved to the second quintile by the end of the expansion phase.

Process Outcomes

Process metrics for TOCC referrals, the number of patients seen, and the number of virtual and in-person visits over time are shown in Appendix Figure 3. Rates of TOCC referrals and the number of TOCC visits were lower than anticipated during the first 5 months of the intervention. However, TOCC referrals increased significantly after we implemented the previously described changes as part of the third PDSA cycle. As a result, total, virtual, and in-person visits also significantly increased from July 2019 to February 2020. The proportion of patients choosing virtual vs in-person visits fluctuated over time, but virtual visits were generally chosen more often than in-person visits.

Statistical Modeling

Baseline Data

Cohort characteristics are shown in Table 1. The cohort, which reflected the ICVA population, was predominantly male (96%) and White (93%), with a mean age of 67 years. The population was approximately half urban and half rural in composition, and the most common reason for hospital admission was cardiac. Other than a small but statistically significant difference in CAN scores, there were no significant differences between patients who kept their TOCC appointment and those who did not. There were also no differences in baseline characteristics between patients who chose virtual follow-up and patients who chose in-person follow-up, including the proportion of urban and rural patients.

Outcomes

Patients who kept their TOCC appointments had a 30-day readmission rate of 9.6%, which was significantly lower than the 30-day readmission rate of 27% in the group that did not keep their TOCC appointment (P < .001). Similarly, the percentage of patients treated in the ED was 15% in the TOCC group compared to 31.2% in the group that canceled their appointment (P < .001) (Table 1). In the multivariable analysis, patients who were seen in the TOCC group had an OR for 30-day readmission of 0.35 (95% CI, 0.19-0.62, P < .001), and an OR for ED visits of 0.39 (95% CI, 0.23-0.65; P < .001) (Table 2). There was no statistically significant difference in 6-month mortality between the two groups. In the virtual group compared to the in-person group, there were no statistically significant differences in outcomes between the two groups in the unadjusted or adjusted analysis (Table 2).

In this quality improvement initiative, we found that a TOCC targeting high-risk patients and offering virtual follow-up visits significantly decreased the 30-day readmission rates among veterans at ICVA. Statistical comparisons of patients seen at the TOCC vs those not seen at the TOCC showed a dramatic reduction in 30-day readmissions and ED visits. Finally, virtual follow-ups were more popular than in-person visits, and patients who followed up virtually had equivalent outcomes to those with the more traditional follow-up.

In the expansion phase, eligibility was expanded to include any hospital indication but continued to focus on high-risk patients. Existing literature suggests that providing postdischarge care to all patients, including low- or medium-risk patients, may not be as impactful as enrolling high-risk patients only. For instance, a postdischarge clinic offered to all patients at a VA system in Colorado did not reduce readmission rates compared to PCP follow-up.²³ In contrast, a study of more than 10,000 high-risk urban patients demonstrated that postdischarge care resulted in a 9.3% reduction in readmission risk.²⁴ Our data are consistent with the previously published studies, as the average CAN score of patients seen in TOCC was 90, suggesting a high risk of readmission. In the final 12 months of the intervention, 15% of discharged patients were seen at the TOCC clinic, suggesting that targeted intervention within the small subset of high-risk patients was sufficient to achieve our primary aim. Of note, among patients who did not meet the inclusion criteria for TOCC referral (ie, patients not considered high risk [CAN score ≤ 85]), the rate of readmissions was 8.6%.

Most of the available research on the efficacy of postdischarge clinics was conducted in urban environments. Our ICVA population sees a large proportion of rural veterans, who account for just over 50% of the discharge population. In a study of more than 2 million Medicare patients discharged from US hospitals, the 30-day readmission rates and adjusted mortality rates were higher among patients in rural counties, and post–acute care seemed to have a greater impact in rural rather than urban settings.²⁵ Previous studies have demonstrated that virtual visits have the potential to improve readmission rates, especially in patients with CHF²⁶ and in patients at the highest risk for readmission.²⁷ In our study, the pilot phase offered only virtual visits, but we subsequently added an in-person option based on veteran feedback. Interestingly, over the next 12 months, virtual visits were more popular with both urban and rural veterans, and there were no differences in the number of rural patients in the in-person vs the virtual group. These findings suggest factors other than rurality influenced the decision to choose virtual follow-up visits over in-person visits. Future studies should seek to determine the extent to which factors such as age, race, educational level, and socioeconomic circumstances impact veterans’ follow-up decisions. Not only were outcomes among patients who chose virtual visits the same as those of patients who chose in-person visits, but both of these groups had better outcomes compared to the non-TOCC group (Table 2). This finding demonstrating the efficacy of virtual visits among rural and urban patients has taken on increased significance due to the COVID-19 pandemic, as virtual visits offer a safer option, one that minimizes physical contact.

Our quality improvement analysis included a statistical comparison of patients seen vs those not seen at the TOCC. Patients who were referred to the TOCC but chose not to keep their appointment were similar to those seen in TOCC in terms of age, CAN score, rurality, and hospital diagnosis, but readmission rates were substantially higher in this group even after adjustments for covariates (Table 2). Evaluating causality in interventions aimed to reduce hospital readmission rates is complicated.²⁸ Our findings add greater plausibility to the utility of TOCC in accounting for at least a portion of the reported decrease in ICVA 30-day readmissions.

Our study has several strengths, including an observation period longer than 2 years, a large population of discharged veterans within an integrated healthcare system, and a large proportion of patients living in rural areas. Another strength of our study is the innovative nature of the intervention, which features a multidisciplinary team and the option of virtual or in-person visits. Nevertheless, this study also has several important limitations. As a single-center study, our findings may not be generalizable to other institutions, especially those outside the VHA system. Similarly, our study population reflected that of the ICVA, which may limit generalizability to a more diverse population. While we attempted to account in our statistical modeling for baseline differences between referred patients seen by the TOCC and those referred but not seen, we cannot exclude residual confounding between the groups. Specifically, the comparison of patients who did and did not choose TOCC follow-up introduces the possibility of selection bias. Future randomized/controlled studies will need to evaluate whether TOCC is more effective than the standard of care to reduce readmissions. Finally, since the analysis period following the final PDSA cycle was compressed due to the onset of the COVID-19 pandemic in the United States, no data are available regarding the sustained impacts of changes made during this cycle.

A multidisciplinary TOCC within the ICVA, featuring both virtual and in-person visits, reduced 30-day readmission rates by 19.3%; this approach to care was especially effective in patients with CHF. Virtual visits were the follow-up mode of choice for both urban and rural veterans, and there was no difference in outcomes between these two follow-up options. Future studies will focus on additional quality metrics, including cost-effectiveness and patient satisfaction.

Hospital readmissions are a significant problem in the United States, affecting 15% to 30% of discharges and incurring costs of more than $17 billion annually.¹ Timely posthospitalization follow-up visits are critical to ensure the effective transfer of patients to the outpatient setting; such visits reduce readmission rates as well as hospital length of stay and overall health care resource utilization.^2-4 Patients who receive inadequate follow-up care (ie, within 4 weeks of discharge) are significantly more likely to be readmitted than those who receive close follow-up care^.5

Due to the large clinical and financial consequences associated with hospital readmission, a variety of interventions have been studied, including home visits, telemonitoring, medication management, telephone calls, and postdischarge clinics.^6,7 While studies have not shown postdischarge clinics to be universally efficacious in reducing readmission rates, there is increasing evidence of reduced readmission rates in clinics that target high-risk patients (eg, patients with congestive heart failure [CHF]) rather than the total population.² A study by Hernandez et al that evaluated the relationship between early physician follow-up and 30-day readmissions showed a significantly lower readmission rate among hospitals with higher follow-up rates.⁸ Similarly, patients with CHF in a large, integrated health system who were seen within 7 days of discharge had an odds ratio (OR) of 0.81 (95% CI, 0.70-0.94) for 30-day readmissions.⁹

Transitions-of-care clinics (TOCC), designed to provide early postdischarge follow-up to high-risk patients, have been shown to reduce 30-day readmission rates,^3,4,10,11 especially in clinics that have same-physician follow-up visits rather than follow-up visits with a community primary care physician (PCP).¹² The most pronounced impact of postdischarge follow-up is seen in high-risk patients with high complexity or high severity of disease; however, complex rural patients are less likely to have access to specialty care.¹³ As a result, since rural residents must travel farther for specialty care, they are seen less frequently than their urban counterparts.^14,15

Prior to our TOCC initiative, the Iowa City VA (ICVA) ranked in the fifth quintile of the Veterans Health Administration (VHA) Strategic Analytics for Improvement and Learning model for hospital-wide readmissions (HWR), meaning that HWR at ICVA were higher than 80% of the other VHA healthcare centers. The low score in this metric was in part due to readmission rates in high-risk populations, including patients with CHF and those with high Care Assessment Need (CAN) scores. One concern was that the ICVA system serves many veterans from rural areas, some of whom must travel up to 200 miles to access inpatient and subspecialty care.

To meet these challenges, we implemented a TOCC to deliver timely postdischarge care focusing on high-risk and high-complexity patients. To address access-to-care issues of patients living in rural areas within the ICVA, we included virtual follow-up visits as a key component of our intervention.^16,17 The aim of this project was to decrease 30-day readmission rates of ICVA patients by 20% within 12 months of implementation.

Setting/Study Population

The ICVA serves 184,000 veterans stretched over 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. Patients were initially eligible for the TOCC if they had an admission diagnosis of CHF and a CAN score > 85 at the time of discharge. The CAN score, developed by the VA to assess the risk of hospital readmission in individual patients, factors in several variables, including demographics, coexisting conditions, vital signs, utilization of services, pharmacy visits, and laboratory results. Patients in the top 5% (95-99) have a readmission rate of 20% at 90 days. Since the CAN is a proprietary tool, it may not be published in full; however, this assessment tool is commonly used and frequently cited in VA research.^18-22 The CAN score is expressed as a percentile ranging from 0 (lowest risk) to 99 (highest risk). Patient eligibility was expanded during subsequent Plan-Do-Study-Act (PDSA) cycles, as outlined below. Patient eligibility was expanded during subsequent PDSA cycles (also outlined below). A review by a local institutional review board was obtained, and the study was classified as exempt due to the use of deidentified data. Standards for Quality Improvement Reporting Excellence 2.0 guidelines were used to construct the manuscript.

Magnitude Assessment

The numbers of discharges, readmissions within 30 days, emergency department (ED) visits by all discharged veterans, and veterans discharged with a CHF hospital diagnosis were recorded from February 2017 to February 2018, which were the 12 months immediately preceding the pilot implementation.

Intervention

The primary intervention was referral to the newly formed ICVA TOCC. The multidisciplinary TOCC team consisted of hospitalists, pharmacists, schedulers, and discharge planners/care managers. Patients were identified by the hospitalist team during admission; prior to hospital discharge, these patients were referred to TOCC discharge planners to schedule appropriate follow-up appointments. Virtual follow-up visits were conducted using a patient’s home technology; in cases where a patient lacked adequate technology capabilities (eg, no computer or internet access), the ICVA provided a tablet device with cellular internet capability for temporary use. Specific clinical activities included medication reconciliation by a pharmacist, follow-up of pending laboratory studies, imaging studies, pathology results, medical diagnosis education, counseling regarding dietary restrictions, and contingency planning outside of an ED visit in the event of a change in clinical status. In addition, the TOCC aimed to facilitate a smooth transition of care back to the PCP by arranging follow-up appointments, providing visit summaries, and scheduling consults with specialty care, as appropriate.

Measures

The primary objective measure was the 30-day readmission rate in the ICVA hospital. Secondary measures included the number of VHA ED visits within 30 days of discharge. The main process measures were the number of hospital discharges per month, the number of TOCC referrals, the number of TOCC appointments made, the number of virtual and in-person visits, and the percentage of appointment “no-shows.”

Implementation

The TOCC was piloted from April 2018 to October 2018. During the pilot phase, TOCC enrollment was limited to virtual appointments and to patients with an admission diagnosis of CHF and a CAN score of > 85. The TOCC had staff on-site 2 days a week; this included pharmacists to reconcile medications and hospitalists to address follow-up care needs.

The TOCC clinic was temporarily closed at the end of October 2018 to analyze pilot results. Based on stakeholder feedback, changes made as part of the second PDSA cycle included expanding eligibility criteria to any hospital admission diagnosis and to patients with a CAN score < 85 if the hospitalist team felt the patient was likely to benefit from TOCC follow-up. In addition, on-site clinic staffing was expanded from 2 to 5 days per week to improve access, and the option for an in-person visit was added based on concerns some veterans expressed regarding the use of the technology at home. Finally, a formal resident program was added, and the order set for referrals was simplified. The TOCC was restarted in February 2019, and TOCC metrics were reviewed monthly. By July 2019, we identified issues with TOCC referrals and appointment creation that required additional modifications to the intervention.

A third PDSA cycle was initiated in July 2019 and included major changes, notably the formation of a designated TOCC committee. The committee appointed a dedicated TOCC scheduler whose role was to reduce confusion regarding scheduling, to update the discharge instructions/orders template to lower incidences of “double-booking” that occurred with PCP and TOCC appointments, to modify discharge educational instruction regarding virtual visits and tablet use, to adjust the TOCC-PCP handoff, and to formalize interactions between discharge coordinators and residents to review possible referrals every morning (Appendix Figure 1).

Statistical Analysis

Run charts were constructed by plotting monthly primary outcome values and monthly process metrics (Figure, Appendix Figure 2, Appendix Figure 3). Chi-square tests were used to compare 30-day readmission rates before and after the intervention. Statistical modeling was used to determine differences in outcomes between referred patients seen and referred patients not seen by the TOCC. In these statistical models, the outcome measures were 30-day readmissions, 30-day ED visits, and 6-month mortality. Covariates included in the final analysis were age, gender, race, CAN score, rural-urban commuting area code, referral service (resident vs nonresident), and admission diagnosis. Admission diagnoses were sorted by the investigators into one of the following seven categories: cardiac, infectious, pulmonary, gastrointestinal, neurologic, renal, and other.

Mean (SD) or counts and percentages were used to describe the distribution of continuous and categorical variables, respectively. Kruskal-Wallis test, t test, or chi-square tests were used, as appropriate, across categories. Generalized linear models with a logistic link function were used to test for differences between patients who kept their appointment at the TOCC and those who did not keep their TOCC appointment (both unadjusted and adjusted for all of the covariates previously mentioned). In addition, generalized linear models were also used to compare outcomes between TOCC patients seen virtually vs those seen in-person (both unadjusted and adjusted for all the covariates previously mentioned). All statistical tests were considered significant at a two-sided P < .05. All analyses were performed using SAS software version 9.4 (SAS Institute Inc).

Magnitude Assessment

During the preimplementation period (February 2017-February 2018), there were 3014 patient discharges from ICVA and 343 readmissions, resulting in a readmission rate of 11.4%. Among patients with a hospital-admission diagnosis of cardiorespiratory disease, which included patients with CHF, there were 381 discharges and 46 readmissions, resulting in a readmission rate of 12.1%.

Primary Outcome

During the pilot phase, which was conducted from April 2018 to October 2018, 142 patients who met inclusion criteria (CHF diagnosis and a CAN score > 85) were discharged from ICVA, and 56 referrals to the TOCC were placed. The readmission rate among the cardiorespiratory cohort of veterans was 9.5%.

During the expansion of the intervention from February 2019 to February 2020, there were 2844 discharges from the ICVA and 291 readmissions, resulting in a readmission rate of 10.2%. However, there was a further decrease in the readmission rate after the third PDSA cycle was initiated in July 2019 (Appendix Figure 1). The readmission rate was 9.2% in the final 6 months of the intervention period, and 7.9% in the final 3 months. Of note, in the group of 1948 patients who did not meet the eligibility criteria to participate in our study, the readmission rate during the same time period was 8.6% (161 readmissions).

When comparing the 6 months following the third PDSA cycle to the magnitude assessment period, there was a relative readmission reduction of 19.3% (P = .04), and an absolute reduction of 2.2%. If the final 3 months of the intervention period are included, there was an absolute reduction of 3.5% and a relative reduction of 30.7% (P = .01). Notably, before the pilot phase, ICVA was in the fifth quintile for HWR among VA hospitals but improved to the second quintile by the end of the expansion phase.

Process Outcomes

Process metrics for TOCC referrals, the number of patients seen, and the number of virtual and in-person visits over time are shown in Appendix Figure 3. Rates of TOCC referrals and the number of TOCC visits were lower than anticipated during the first 5 months of the intervention. However, TOCC referrals increased significantly after we implemented the previously described changes as part of the third PDSA cycle. As a result, total, virtual, and in-person visits also significantly increased from July 2019 to February 2020. The proportion of patients choosing virtual vs in-person visits fluctuated over time, but virtual visits were generally chosen more often than in-person visits.

Statistical Modeling

Baseline Data

Cohort characteristics are shown in Table 1. The cohort, which reflected the ICVA population, was predominantly male (96%) and White (93%), with a mean age of 67 years. The population was approximately half urban and half rural in composition, and the most common reason for hospital admission was cardiac. Other than a small but statistically significant difference in CAN scores, there were no significant differences between patients who kept their TOCC appointment and those who did not. There were also no differences in baseline characteristics between patients who chose virtual follow-up and patients who chose in-person follow-up, including the proportion of urban and rural patients.

Outcomes

Patients who kept their TOCC appointments had a 30-day readmission rate of 9.6%, which was significantly lower than the 30-day readmission rate of 27% in the group that did not keep their TOCC appointment (P < .001). Similarly, the percentage of patients treated in the ED was 15% in the TOCC group compared to 31.2% in the group that canceled their appointment (P < .001) (Table 1). In the multivariable analysis, patients who were seen in the TOCC group had an OR for 30-day readmission of 0.35 (95% CI, 0.19-0.62, P < .001), and an OR for ED visits of 0.39 (95% CI, 0.23-0.65; P < .001) (Table 2). There was no statistically significant difference in 6-month mortality between the two groups. In the virtual group compared to the in-person group, there were no statistically significant differences in outcomes between the two groups in the unadjusted or adjusted analysis (Table 2).

In this quality improvement initiative, we found that a TOCC targeting high-risk patients and offering virtual follow-up visits significantly decreased the 30-day readmission rates among veterans at ICVA. Statistical comparisons of patients seen at the TOCC vs those not seen at the TOCC showed a dramatic reduction in 30-day readmissions and ED visits. Finally, virtual follow-ups were more popular than in-person visits, and patients who followed up virtually had equivalent outcomes to those with the more traditional follow-up.

In the expansion phase, eligibility was expanded to include any hospital indication but continued to focus on high-risk patients. Existing literature suggests that providing postdischarge care to all patients, including low- or medium-risk patients, may not be as impactful as enrolling high-risk patients only. For instance, a postdischarge clinic offered to all patients at a VA system in Colorado did not reduce readmission rates compared to PCP follow-up.²³ In contrast, a study of more than 10,000 high-risk urban patients demonstrated that postdischarge care resulted in a 9.3% reduction in readmission risk.²⁴ Our data are consistent with the previously published studies, as the average CAN score of patients seen in TOCC was 90, suggesting a high risk of readmission. In the final 12 months of the intervention, 15% of discharged patients were seen at the TOCC clinic, suggesting that targeted intervention within the small subset of high-risk patients was sufficient to achieve our primary aim. Of note, among patients who did not meet the inclusion criteria for TOCC referral (ie, patients not considered high risk [CAN score ≤ 85]), the rate of readmissions was 8.6%.

Most of the available research on the efficacy of postdischarge clinics was conducted in urban environments. Our ICVA population sees a large proportion of rural veterans, who account for just over 50% of the discharge population. In a study of more than 2 million Medicare patients discharged from US hospitals, the 30-day readmission rates and adjusted mortality rates were higher among patients in rural counties, and post–acute care seemed to have a greater impact in rural rather than urban settings.²⁵ Previous studies have demonstrated that virtual visits have the potential to improve readmission rates, especially in patients with CHF²⁶ and in patients at the highest risk for readmission.²⁷ In our study, the pilot phase offered only virtual visits, but we subsequently added an in-person option based on veteran feedback. Interestingly, over the next 12 months, virtual visits were more popular with both urban and rural veterans, and there were no differences in the number of rural patients in the in-person vs the virtual group. These findings suggest factors other than rurality influenced the decision to choose virtual follow-up visits over in-person visits. Future studies should seek to determine the extent to which factors such as age, race, educational level, and socioeconomic circumstances impact veterans’ follow-up decisions. Not only were outcomes among patients who chose virtual visits the same as those of patients who chose in-person visits, but both of these groups had better outcomes compared to the non-TOCC group (Table 2). This finding demonstrating the efficacy of virtual visits among rural and urban patients has taken on increased significance due to the COVID-19 pandemic, as virtual visits offer a safer option, one that minimizes physical contact.

Our quality improvement analysis included a statistical comparison of patients seen vs those not seen at the TOCC. Patients who were referred to the TOCC but chose not to keep their appointment were similar to those seen in TOCC in terms of age, CAN score, rurality, and hospital diagnosis, but readmission rates were substantially higher in this group even after adjustments for covariates (Table 2). Evaluating causality in interventions aimed to reduce hospital readmission rates is complicated.²⁸ Our findings add greater plausibility to the utility of TOCC in accounting for at least a portion of the reported decrease in ICVA 30-day readmissions.

Our study has several strengths, including an observation period longer than 2 years, a large population of discharged veterans within an integrated healthcare system, and a large proportion of patients living in rural areas. Another strength of our study is the innovative nature of the intervention, which features a multidisciplinary team and the option of virtual or in-person visits. Nevertheless, this study also has several important limitations. As a single-center study, our findings may not be generalizable to other institutions, especially those outside the VHA system. Similarly, our study population reflected that of the ICVA, which may limit generalizability to a more diverse population. While we attempted to account in our statistical modeling for baseline differences between referred patients seen by the TOCC and those referred but not seen, we cannot exclude residual confounding between the groups. Specifically, the comparison of patients who did and did not choose TOCC follow-up introduces the possibility of selection bias. Future randomized/controlled studies will need to evaluate whether TOCC is more effective than the standard of care to reduce readmissions. Finally, since the analysis period following the final PDSA cycle was compressed due to the onset of the COVID-19 pandemic in the United States, no data are available regarding the sustained impacts of changes made during this cycle.

A multidisciplinary TOCC within the ICVA, featuring both virtual and in-person visits, reduced 30-day readmission rates by 19.3%; this approach to care was especially effective in patients with CHF. Virtual visits were the follow-up mode of choice for both urban and rural veterans, and there was no difference in outcomes between these two follow-up options. Future studies will focus on additional quality metrics, including cost-effectiveness and patient satisfaction.

Hospital readmissions are a significant problem in the United States, affecting 15% to 30% of discharges and incurring costs of more than $17 billion annually.¹ Timely posthospitalization follow-up visits are critical to ensure the effective transfer of patients to the outpatient setting; such visits reduce readmission rates as well as hospital length of stay and overall health care resource utilization.^2-4 Patients who receive inadequate follow-up care (ie, within 4 weeks of discharge) are significantly more likely to be readmitted than those who receive close follow-up care^.5

Due to the large clinical and financial consequences associated with hospital readmission, a variety of interventions have been studied, including home visits, telemonitoring, medication management, telephone calls, and postdischarge clinics.^6,7 While studies have not shown postdischarge clinics to be universally efficacious in reducing readmission rates, there is increasing evidence of reduced readmission rates in clinics that target high-risk patients (eg, patients with congestive heart failure [CHF]) rather than the total population.² A study by Hernandez et al that evaluated the relationship between early physician follow-up and 30-day readmissions showed a significantly lower readmission rate among hospitals with higher follow-up rates.⁸ Similarly, patients with CHF in a large, integrated health system who were seen within 7 days of discharge had an odds ratio (OR) of 0.81 (95% CI, 0.70-0.94) for 30-day readmissions.⁹

Transitions-of-care clinics (TOCC), designed to provide early postdischarge follow-up to high-risk patients, have been shown to reduce 30-day readmission rates,^3,4,10,11 especially in clinics that have same-physician follow-up visits rather than follow-up visits with a community primary care physician (PCP).¹² The most pronounced impact of postdischarge follow-up is seen in high-risk patients with high complexity or high severity of disease; however, complex rural patients are less likely to have access to specialty care.¹³ As a result, since rural residents must travel farther for specialty care, they are seen less frequently than their urban counterparts.^14,15

Prior to our TOCC initiative, the Iowa City VA (ICVA) ranked in the fifth quintile of the Veterans Health Administration (VHA) Strategic Analytics for Improvement and Learning model for hospital-wide readmissions (HWR), meaning that HWR at ICVA were higher than 80% of the other VHA healthcare centers. The low score in this metric was in part due to readmission rates in high-risk populations, including patients with CHF and those with high Care Assessment Need (CAN) scores. One concern was that the ICVA system serves many veterans from rural areas, some of whom must travel up to 200 miles to access inpatient and subspecialty care.

To meet these challenges, we implemented a TOCC to deliver timely postdischarge care focusing on high-risk and high-complexity patients. To address access-to-care issues of patients living in rural areas within the ICVA, we included virtual follow-up visits as a key component of our intervention.^16,17 The aim of this project was to decrease 30-day readmission rates of ICVA patients by 20% within 12 months of implementation.

Setting/Study Population

The ICVA serves 184,000 veterans stretched over 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. Patients were initially eligible for the TOCC if they had an admission diagnosis of CHF and a CAN score > 85 at the time of discharge. The CAN score, developed by the VA to assess the risk of hospital readmission in individual patients, factors in several variables, including demographics, coexisting conditions, vital signs, utilization of services, pharmacy visits, and laboratory results. Patients in the top 5% (95-99) have a readmission rate of 20% at 90 days. Since the CAN is a proprietary tool, it may not be published in full; however, this assessment tool is commonly used and frequently cited in VA research.^18-22 The CAN score is expressed as a percentile ranging from 0 (lowest risk) to 99 (highest risk). Patient eligibility was expanded during subsequent Plan-Do-Study-Act (PDSA) cycles, as outlined below. Patient eligibility was expanded during subsequent PDSA cycles (also outlined below). A review by a local institutional review board was obtained, and the study was classified as exempt due to the use of deidentified data. Standards for Quality Improvement Reporting Excellence 2.0 guidelines were used to construct the manuscript.

Magnitude Assessment

The numbers of discharges, readmissions within 30 days, emergency department (ED) visits by all discharged veterans, and veterans discharged with a CHF hospital diagnosis were recorded from February 2017 to February 2018, which were the 12 months immediately preceding the pilot implementation.

Intervention

The primary intervention was referral to the newly formed ICVA TOCC. The multidisciplinary TOCC team consisted of hospitalists, pharmacists, schedulers, and discharge planners/care managers. Patients were identified by the hospitalist team during admission; prior to hospital discharge, these patients were referred to TOCC discharge planners to schedule appropriate follow-up appointments. Virtual follow-up visits were conducted using a patient’s home technology; in cases where a patient lacked adequate technology capabilities (eg, no computer or internet access), the ICVA provided a tablet device with cellular internet capability for temporary use. Specific clinical activities included medication reconciliation by a pharmacist, follow-up of pending laboratory studies, imaging studies, pathology results, medical diagnosis education, counseling regarding dietary restrictions, and contingency planning outside of an ED visit in the event of a change in clinical status. In addition, the TOCC aimed to facilitate a smooth transition of care back to the PCP by arranging follow-up appointments, providing visit summaries, and scheduling consults with specialty care, as appropriate.

Measures

The primary objective measure was the 30-day readmission rate in the ICVA hospital. Secondary measures included the number of VHA ED visits within 30 days of discharge. The main process measures were the number of hospital discharges per month, the number of TOCC referrals, the number of TOCC appointments made, the number of virtual and in-person visits, and the percentage of appointment “no-shows.”

Implementation

The TOCC was piloted from April 2018 to October 2018. During the pilot phase, TOCC enrollment was limited to virtual appointments and to patients with an admission diagnosis of CHF and a CAN score of > 85. The TOCC had staff on-site 2 days a week; this included pharmacists to reconcile medications and hospitalists to address follow-up care needs.

The TOCC clinic was temporarily closed at the end of October 2018 to analyze pilot results. Based on stakeholder feedback, changes made as part of the second PDSA cycle included expanding eligibility criteria to any hospital admission diagnosis and to patients with a CAN score < 85 if the hospitalist team felt the patient was likely to benefit from TOCC follow-up. In addition, on-site clinic staffing was expanded from 2 to 5 days per week to improve access, and the option for an in-person visit was added based on concerns some veterans expressed regarding the use of the technology at home. Finally, a formal resident program was added, and the order set for referrals was simplified. The TOCC was restarted in February 2019, and TOCC metrics were reviewed monthly. By July 2019, we identified issues with TOCC referrals and appointment creation that required additional modifications to the intervention.

A third PDSA cycle was initiated in July 2019 and included major changes, notably the formation of a designated TOCC committee. The committee appointed a dedicated TOCC scheduler whose role was to reduce confusion regarding scheduling, to update the discharge instructions/orders template to lower incidences of “double-booking” that occurred with PCP and TOCC appointments, to modify discharge educational instruction regarding virtual visits and tablet use, to adjust the TOCC-PCP handoff, and to formalize interactions between discharge coordinators and residents to review possible referrals every morning (Appendix Figure 1).

Statistical Analysis

Run charts were constructed by plotting monthly primary outcome values and monthly process metrics (Figure, Appendix Figure 2, Appendix Figure 3). Chi-square tests were used to compare 30-day readmission rates before and after the intervention. Statistical modeling was used to determine differences in outcomes between referred patients seen and referred patients not seen by the TOCC. In these statistical models, the outcome measures were 30-day readmissions, 30-day ED visits, and 6-month mortality. Covariates included in the final analysis were age, gender, race, CAN score, rural-urban commuting area code, referral service (resident vs nonresident), and admission diagnosis. Admission diagnoses were sorted by the investigators into one of the following seven categories: cardiac, infectious, pulmonary, gastrointestinal, neurologic, renal, and other.

Mean (SD) or counts and percentages were used to describe the distribution of continuous and categorical variables, respectively. Kruskal-Wallis test, t test, or chi-square tests were used, as appropriate, across categories. Generalized linear models with a logistic link function were used to test for differences between patients who kept their appointment at the TOCC and those who did not keep their TOCC appointment (both unadjusted and adjusted for all of the covariates previously mentioned). In addition, generalized linear models were also used to compare outcomes between TOCC patients seen virtually vs those seen in-person (both unadjusted and adjusted for all the covariates previously mentioned). All statistical tests were considered significant at a two-sided P < .05. All analyses were performed using SAS software version 9.4 (SAS Institute Inc).

Magnitude Assessment

During the preimplementation period (February 2017-February 2018), there were 3014 patient discharges from ICVA and 343 readmissions, resulting in a readmission rate of 11.4%. Among patients with a hospital-admission diagnosis of cardiorespiratory disease, which included patients with CHF, there were 381 discharges and 46 readmissions, resulting in a readmission rate of 12.1%.

Primary Outcome

During the pilot phase, which was conducted from April 2018 to October 2018, 142 patients who met inclusion criteria (CHF diagnosis and a CAN score > 85) were discharged from ICVA, and 56 referrals to the TOCC were placed. The readmission rate among the cardiorespiratory cohort of veterans was 9.5%.

During the expansion of the intervention from February 2019 to February 2020, there were 2844 discharges from the ICVA and 291 readmissions, resulting in a readmission rate of 10.2%. However, there was a further decrease in the readmission rate after the third PDSA cycle was initiated in July 2019 (Appendix Figure 1). The readmission rate was 9.2% in the final 6 months of the intervention period, and 7.9% in the final 3 months. Of note, in the group of 1948 patients who did not meet the eligibility criteria to participate in our study, the readmission rate during the same time period was 8.6% (161 readmissions).

When comparing the 6 months following the third PDSA cycle to the magnitude assessment period, there was a relative readmission reduction of 19.3% (P = .04), and an absolute reduction of 2.2%. If the final 3 months of the intervention period are included, there was an absolute reduction of 3.5% and a relative reduction of 30.7% (P = .01). Notably, before the pilot phase, ICVA was in the fifth quintile for HWR among VA hospitals but improved to the second quintile by the end of the expansion phase.

Process Outcomes

Process metrics for TOCC referrals, the number of patients seen, and the number of virtual and in-person visits over time are shown in Appendix Figure 3. Rates of TOCC referrals and the number of TOCC visits were lower than anticipated during the first 5 months of the intervention. However, TOCC referrals increased significantly after we implemented the previously described changes as part of the third PDSA cycle. As a result, total, virtual, and in-person visits also significantly increased from July 2019 to February 2020. The proportion of patients choosing virtual vs in-person visits fluctuated over time, but virtual visits were generally chosen more often than in-person visits.

Statistical Modeling

Baseline Data

Cohort characteristics are shown in Table 1. The cohort, which reflected the ICVA population, was predominantly male (96%) and White (93%), with a mean age of 67 years. The population was approximately half urban and half rural in composition, and the most common reason for hospital admission was cardiac. Other than a small but statistically significant difference in CAN scores, there were no significant differences between patients who kept their TOCC appointment and those who did not. There were also no differences in baseline characteristics between patients who chose virtual follow-up and patients who chose in-person follow-up, including the proportion of urban and rural patients.

Outcomes

Patients who kept their TOCC appointments had a 30-day readmission rate of 9.6%, which was significantly lower than the 30-day readmission rate of 27% in the group that did not keep their TOCC appointment (P < .001). Similarly, the percentage of patients treated in the ED was 15% in the TOCC group compared to 31.2% in the group that canceled their appointment (P < .001) (Table 1). In the multivariable analysis, patients who were seen in the TOCC group had an OR for 30-day readmission of 0.35 (95% CI, 0.19-0.62, P < .001), and an OR for ED visits of 0.39 (95% CI, 0.23-0.65; P < .001) (Table 2). There was no statistically significant difference in 6-month mortality between the two groups. In the virtual group compared to the in-person group, there were no statistically significant differences in outcomes between the two groups in the unadjusted or adjusted analysis (Table 2).

In this quality improvement initiative, we found that a TOCC targeting high-risk patients and offering virtual follow-up visits significantly decreased the 30-day readmission rates among veterans at ICVA. Statistical comparisons of patients seen at the TOCC vs those not seen at the TOCC showed a dramatic reduction in 30-day readmissions and ED visits. Finally, virtual follow-ups were more popular than in-person visits, and patients who followed up virtually had equivalent outcomes to those with the more traditional follow-up.

In the expansion phase, eligibility was expanded to include any hospital indication but continued to focus on high-risk patients. Existing literature suggests that providing postdischarge care to all patients, including low- or medium-risk patients, may not be as impactful as enrolling high-risk patients only. For instance, a postdischarge clinic offered to all patients at a VA system in Colorado did not reduce readmission rates compared to PCP follow-up.²³ In contrast, a study of more than 10,000 high-risk urban patients demonstrated that postdischarge care resulted in a 9.3% reduction in readmission risk.²⁴ Our data are consistent with the previously published studies, as the average CAN score of patients seen in TOCC was 90, suggesting a high risk of readmission. In the final 12 months of the intervention, 15% of discharged patients were seen at the TOCC clinic, suggesting that targeted intervention within the small subset of high-risk patients was sufficient to achieve our primary aim. Of note, among patients who did not meet the inclusion criteria for TOCC referral (ie, patients not considered high risk [CAN score ≤ 85]), the rate of readmissions was 8.6%.

Most of the available research on the efficacy of postdischarge clinics was conducted in urban environments. Our ICVA population sees a large proportion of rural veterans, who account for just over 50% of the discharge population. In a study of more than 2 million Medicare patients discharged from US hospitals, the 30-day readmission rates and adjusted mortality rates were higher among patients in rural counties, and post–acute care seemed to have a greater impact in rural rather than urban settings.²⁵ Previous studies have demonstrated that virtual visits have the potential to improve readmission rates, especially in patients with CHF²⁶ and in patients at the highest risk for readmission.²⁷ In our study, the pilot phase offered only virtual visits, but we subsequently added an in-person option based on veteran feedback. Interestingly, over the next 12 months, virtual visits were more popular with both urban and rural veterans, and there were no differences in the number of rural patients in the in-person vs the virtual group. These findings suggest factors other than rurality influenced the decision to choose virtual follow-up visits over in-person visits. Future studies should seek to determine the extent to which factors such as age, race, educational level, and socioeconomic circumstances impact veterans’ follow-up decisions. Not only were outcomes among patients who chose virtual visits the same as those of patients who chose in-person visits, but both of these groups had better outcomes compared to the non-TOCC group (Table 2). This finding demonstrating the efficacy of virtual visits among rural and urban patients has taken on increased significance due to the COVID-19 pandemic, as virtual visits offer a safer option, one that minimizes physical contact.

Our quality improvement analysis included a statistical comparison of patients seen vs those not seen at the TOCC. Patients who were referred to the TOCC but chose not to keep their appointment were similar to those seen in TOCC in terms of age, CAN score, rurality, and hospital diagnosis, but readmission rates were substantially higher in this group even after adjustments for covariates (Table 2). Evaluating causality in interventions aimed to reduce hospital readmission rates is complicated.²⁸ Our findings add greater plausibility to the utility of TOCC in accounting for at least a portion of the reported decrease in ICVA 30-day readmissions.

Our study has several strengths, including an observation period longer than 2 years, a large population of discharged veterans within an integrated healthcare system, and a large proportion of patients living in rural areas. Another strength of our study is the innovative nature of the intervention, which features a multidisciplinary team and the option of virtual or in-person visits. Nevertheless, this study also has several important limitations. As a single-center study, our findings may not be generalizable to other institutions, especially those outside the VHA system. Similarly, our study population reflected that of the ICVA, which may limit generalizability to a more diverse population. While we attempted to account in our statistical modeling for baseline differences between referred patients seen by the TOCC and those referred but not seen, we cannot exclude residual confounding between the groups. Specifically, the comparison of patients who did and did not choose TOCC follow-up introduces the possibility of selection bias. Future randomized/controlled studies will need to evaluate whether TOCC is more effective than the standard of care to reduce readmissions. Finally, since the analysis period following the final PDSA cycle was compressed due to the onset of the COVID-19 pandemic in the United States, no data are available regarding the sustained impacts of changes made during this cycle.

A multidisciplinary TOCC within the ICVA, featuring both virtual and in-person visits, reduced 30-day readmission rates by 19.3%; this approach to care was especially effective in patients with CHF. Virtual visits were the follow-up mode of choice for both urban and rural veterans, and there was no difference in outcomes between these two follow-up options. Future studies will focus on additional quality metrics, including cost-effectiveness and patient satisfaction.

While we agree that a well-honed physical exam is one of the most important diagnostic tools than an internist can use, we have several responses to Drs Kanjee and McNamara’s point that a routine physical exam is essential for hospitalized patients.¹ They argue that this exam might be helpful as a deliberate practice to improve skills for effective diagnostic exams. To this, we have two responses: the first is that the typical “routine” exam—a brief auscultation of the chest and abdomen—is performed frequently enough that additional practice should not be necessary for any practicing hospitalist. Performing a true full exam that would hone infrequently used skills, such as a full neurological exam, an orthopedic knee exam, or fundoscopy, comes at the expense of time spent talking to patients, as well as the potential harm of downstream testing cascades leading to adverse events. Second, we would argue that the real skill being developed is not “recognizing normal” but instead learning how to appropriately use physical diagnostic skills. Knowing precisely what exam maneuvers might be beneficial in a given hospitalized patient is incredibly complex, far more so than charts in evidence-based exam textbooks would suggest. It is this skill, not “recognizing normal,” that requires deliberate practice.

We agree that even during routine hospitalizations, daily exams may help detect complications of therapy, such as a patient with cellulitis on intravenous fluids developing volume overload. We are not against performing physical exams for diagnostic or monitoring purposes. In fact, it may be that most hospitalized patients would benefit from some sort of daily exam. However, rarely performed maneuvers, such as walking with patients or performing a validated delirium screen, are likely to have a higher yield than routine lung auscultation. It may also be true that hospitalized patients would benefit from certain screening exam maneuvers, but again, evidence is lacking, and decades of experience in the outpatient world would suggest the contrary.

Finally, and most ardently, we disagree that performing a routine daily physical exam can somehow inoculate against burnout. That is a view wholly unsupported by any evidence. The physical exam was originally developed as a diagnostic tool, not as a method to connect with patients. However, this traditional “routine” exam has been taught in medical schools as normal ever since, with very little serious interrogation of its utility or downstream effects. Increased cynicism about the exam’s usefulness, in our opinion, reflects physician cognizance of actual disutility of routine exams, rather than pining for a halcyon era that never existed. In fact, we believe a more hypothesis-driven diagnostic use of exams enriches physical diagnosis. For instance, listening to the chest of a patient with cellulitis on intravenous fluids is no longer “just listening,” it is an exercise specifically looking for a finding that affects management. Patient-centered care means tailoring all of our care—including the physical exam—to the needs of the patient. Doing a cursory, routine exam day after day for every patient with the goal of “recognizing normal” is not patient-centered, but rather physician-centered.

We do not doubt the importance of ritual, especially in such a stressful situation as a modern hospitalization. But rather than use a diagnostic procedure with downstream effects, we urge hospitalists to consider instead a ritual dating back to the time of Hippocrates—the compassionate physician sitting at the bedside, laying a hand on the shoulder, and listening to the patient’s concerns. That is authentic human connection rather than performance.

The authors of this point-counterpoint to thank Chris Smith, MD, and the members of the BIDMC Internal Medicine Residency Clinician Educator Track for thoughtful discussion around these topics.

While we agree that a well-honed physical exam is one of the most important diagnostic tools than an internist can use, we have several responses to Drs Kanjee and McNamara’s point that a routine physical exam is essential for hospitalized patients.¹ They argue that this exam might be helpful as a deliberate practice to improve skills for effective diagnostic exams. To this, we have two responses: the first is that the typical “routine” exam—a brief auscultation of the chest and abdomen—is performed frequently enough that additional practice should not be necessary for any practicing hospitalist. Performing a true full exam that would hone infrequently used skills, such as a full neurological exam, an orthopedic knee exam, or fundoscopy, comes at the expense of time spent talking to patients, as well as the potential harm of downstream testing cascades leading to adverse events. Second, we would argue that the real skill being developed is not “recognizing normal” but instead learning how to appropriately use physical diagnostic skills. Knowing precisely what exam maneuvers might be beneficial in a given hospitalized patient is incredibly complex, far more so than charts in evidence-based exam textbooks would suggest. It is this skill, not “recognizing normal,” that requires deliberate practice.

We agree that even during routine hospitalizations, daily exams may help detect complications of therapy, such as a patient with cellulitis on intravenous fluids developing volume overload. We are not against performing physical exams for diagnostic or monitoring purposes. In fact, it may be that most hospitalized patients would benefit from some sort of daily exam. However, rarely performed maneuvers, such as walking with patients or performing a validated delirium screen, are likely to have a higher yield than routine lung auscultation. It may also be true that hospitalized patients would benefit from certain screening exam maneuvers, but again, evidence is lacking, and decades of experience in the outpatient world would suggest the contrary.

Finally, and most ardently, we disagree that performing a routine daily physical exam can somehow inoculate against burnout. That is a view wholly unsupported by any evidence. The physical exam was originally developed as a diagnostic tool, not as a method to connect with patients. However, this traditional “routine” exam has been taught in medical schools as normal ever since, with very little serious interrogation of its utility or downstream effects. Increased cynicism about the exam’s usefulness, in our opinion, reflects physician cognizance of actual disutility of routine exams, rather than pining for a halcyon era that never existed. In fact, we believe a more hypothesis-driven diagnostic use of exams enriches physical diagnosis. For instance, listening to the chest of a patient with cellulitis on intravenous fluids is no longer “just listening,” it is an exercise specifically looking for a finding that affects management. Patient-centered care means tailoring all of our care—including the physical exam—to the needs of the patient. Doing a cursory, routine exam day after day for every patient with the goal of “recognizing normal” is not patient-centered, but rather physician-centered.

We do not doubt the importance of ritual, especially in such a stressful situation as a modern hospitalization. But rather than use a diagnostic procedure with downstream effects, we urge hospitalists to consider instead a ritual dating back to the time of Hippocrates—the compassionate physician sitting at the bedside, laying a hand on the shoulder, and listening to the patient’s concerns. That is authentic human connection rather than performance.

The authors of this point-counterpoint to thank Chris Smith, MD, and the members of the BIDMC Internal Medicine Residency Clinician Educator Track for thoughtful discussion around these topics.

While we agree that a well-honed physical exam is one of the most important diagnostic tools than an internist can use, we have several responses to Drs Kanjee and McNamara’s point that a routine physical exam is essential for hospitalized patients.¹ They argue that this exam might be helpful as a deliberate practice to improve skills for effective diagnostic exams. To this, we have two responses: the first is that the typical “routine” exam—a brief auscultation of the chest and abdomen—is performed frequently enough that additional practice should not be necessary for any practicing hospitalist. Performing a true full exam that would hone infrequently used skills, such as a full neurological exam, an orthopedic knee exam, or fundoscopy, comes at the expense of time spent talking to patients, as well as the potential harm of downstream testing cascades leading to adverse events. Second, we would argue that the real skill being developed is not “recognizing normal” but instead learning how to appropriately use physical diagnostic skills. Knowing precisely what exam maneuvers might be beneficial in a given hospitalized patient is incredibly complex, far more so than charts in evidence-based exam textbooks would suggest. It is this skill, not “recognizing normal,” that requires deliberate practice.

We agree that even during routine hospitalizations, daily exams may help detect complications of therapy, such as a patient with cellulitis on intravenous fluids developing volume overload. We are not against performing physical exams for diagnostic or monitoring purposes. In fact, it may be that most hospitalized patients would benefit from some sort of daily exam. However, rarely performed maneuvers, such as walking with patients or performing a validated delirium screen, are likely to have a higher yield than routine lung auscultation. It may also be true that hospitalized patients would benefit from certain screening exam maneuvers, but again, evidence is lacking, and decades of experience in the outpatient world would suggest the contrary.

Finally, and most ardently, we disagree that performing a routine daily physical exam can somehow inoculate against burnout. That is a view wholly unsupported by any evidence. The physical exam was originally developed as a diagnostic tool, not as a method to connect with patients. However, this traditional “routine” exam has been taught in medical schools as normal ever since, with very little serious interrogation of its utility or downstream effects. Increased cynicism about the exam’s usefulness, in our opinion, reflects physician cognizance of actual disutility of routine exams, rather than pining for a halcyon era that never existed. In fact, we believe a more hypothesis-driven diagnostic use of exams enriches physical diagnosis. For instance, listening to the chest of a patient with cellulitis on intravenous fluids is no longer “just listening,” it is an exercise specifically looking for a finding that affects management. Patient-centered care means tailoring all of our care—including the physical exam—to the needs of the patient. Doing a cursory, routine exam day after day for every patient with the goal of “recognizing normal” is not patient-centered, but rather physician-centered.

We do not doubt the importance of ritual, especially in such a stressful situation as a modern hospitalization. But rather than use a diagnostic procedure with downstream effects, we urge hospitalists to consider instead a ritual dating back to the time of Hippocrates—the compassionate physician sitting at the bedside, laying a hand on the shoulder, and listening to the patient’s concerns. That is authentic human connection rather than performance.

The authors of this point-counterpoint to thank Chris Smith, MD, and the members of the BIDMC Internal Medicine Residency Clinician Educator Track for thoughtful discussion around these topics.