Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.

Many events both personal and public have been deferred during the 15 plus months of the pandemic. Almost everyone has an example of a friend or family member who would have been sitting at what President Biden, during his memorial speech for the 500,000 victims of the virus referred to as the “empty chair” at a holiday gathering sans COVID-19.² For many in our country, part of the agonizing effort to awaken from the long nightmare of the pandemic is to resume the rhythm of rituals national, local, and personal that mark the year with meaning and offer rest and rejuvenation from the daily toil of duty. There are family dinners now cautiously resumed due to vaccinations; small celebrations of belated birthdays in family pods; socially distanced outdoor gatherings suspended in the cold communicable winter now gingerly possible with the warmth of spring.

As a nation, one of the events that was put on hold was the commemoration of the Vietnam War. On March 16, 2021, following guidance from the Centers for Disease Control and Prevention, the US Department of Veterans Affairs (VA) announced it was postponing commemoration events “until further notice.”³ Annually, the VA partners with the US Department of Defense, state, and local organizations to recognize “the service and sacrifices made by the nearly 3 million service members who served in Vietnam.”⁴

In 2012, President Barak Obama signed a proclamation establishing a 13-year commemoration of the 50th anniversary of the Vietnam War.⁵ Five years later, President Donald Trump signed the War Veterans Recognition Act of 2017, designating March 29 annually as National Vietnam War Veterans Day.⁶ Though many of the events planned for March and April could not take place, the Vietnam War Commemoration (https://www.vietnamwar50th.com) offers information and ideas for honoring and supporting Vietnam War veterans. As Memorial Day approaches in this year of so much loss and heroism, I encourage you to find a way to thank Vietnam veterans who may have received the opposite of gratitude when they initially returned home.

As my small contribution to the commemoration, this editorial will focus on the psychiatric disorder of memory: posttraumatic stress disorder (PTSD) and how the Vietnam War brought definition—albeit delayed—to the agonizing diagnosis that too many veterans experience.

The known clinical entity of PTSD is ancient. Narrative descriptions of the disorder are written in the Mesopotamian Epic of Gilgamesh and in Deuteronomy 20:1-9.⁷ American and European military physicians have given various names to the destructive effects of combat on body and mind from “soldier’s heart” in the American Civil War, to “shell shock” in World War I to “battle fatigue” during World War II.⁸ These were all descriptive diagnoses field practitioners used to grasp the psychosomatic decompensation they observed in service members who had been exposed to the horrors of war. The VA was the impetus and agent of the earliest attempts at scientific definition. The American Psychiatric Association further developed this nosology in 1952 with the diagnosis of gross stress reaction in the first Diagnostic and Statistical Manual of Mental Disorders (DSM)-1.⁹

The combat experience shaped the definition: the stressor had to be extreme, the civilian comparison would be a natural disaster; the reaction could occur only in a previously normal individual, it would be attributed to the extant psychiatric condition in anyone with a premorbid illness; and if it did not remit by 6 months, another primary psychiatric diagnosis must be assigned.

From our vantage point, this set of criteria is obviously woefully inadequate, yet it was at least a beginning of formal recognition of the experience that veterans endured in wartime and real progress compared with what happened next. When DSM-1 was revised in 1968, the diagnosis of gross stress reaction was eliminated without explanation. Researcher Andreasen and others speculate that its disappearance can be attributed to association of the diagnosis with war in a country that had been at peace since the end of the Korean War in 1953.¹⁰ Yet military historians among my readers will immediately counter that the Vietnam War began 2 years later and that the year of the revision saw major combat operations.

Many veterans living with the psychological and physical suffering of their service in Vietnam and the organizations that supported them advocated for the psychiatric profession to formally acknowledge post-Vietnam syndrome.¹¹ Five years after the end of the Vietnam War, the experts who authored DSM-III, decided to include a new stress-induced diagnosis.¹² Although the manual did not limit the traumatic experience to combat in Vietnam as some veterans wanted, there is no doubt that the criteria reflect the extensive research validating the illness narratives of thousands of service men and women.

The DSM-III criteria clearly had war in mind when it stipulated that the stressor had to be outside the range of usual human experience that would likely trigger significant symptoms in almost anyone as well as specifying chronic symptoms lasting more than 6 months. Despite the controversy about the diagnosis, Vietnam veterans helped bring the PTSD diagnosis to official psychiatric nomenclature and in a more recognizable form that began to capture the intensity of their reexperiencing of the trauma, the psychosocial difficulties numbing caused, and the pervasive interference of hyperarousal and vigilance many aspects and areas of life.¹³

The National Vietnam Veterans Longitudinal Study examined the course of PTSD over 25 years, using the newly formulated diagnostic criteria for PTSD.¹⁴ Results were reported to Congress in 2012 and showed that 11% of men and 7% of women who were in a war theater were still struggling with PTSD 40 years after the war. Of those, 37% met major depressive disorder criteria. Male veterans who in 1987 still met criteria for PTSD were twice as likely to have died than the comparator group of veterans without PTSD. Two-thirds of veterans with PTSD from war zone exposure discussed behavioral health or substance misuse concerns with a health care provider, and 37% of those were receiving VA care.¹⁴

Given these disturbing data, perhaps the best way we can pay homage to the aging Vietnam veterans is to support continued research into effective evidence-based treatments for PTSD and funding for the training and recruiting of mental health practitioners to all 3 branches of federal health care who can deliver that care compassionately and competently.

Many events both personal and public have been deferred during the 15 plus months of the pandemic. Almost everyone has an example of a friend or family member who would have been sitting at what President Biden, during his memorial speech for the 500,000 victims of the virus referred to as the “empty chair” at a holiday gathering sans COVID-19.² For many in our country, part of the agonizing effort to awaken from the long nightmare of the pandemic is to resume the rhythm of rituals national, local, and personal that mark the year with meaning and offer rest and rejuvenation from the daily toil of duty. There are family dinners now cautiously resumed due to vaccinations; small celebrations of belated birthdays in family pods; socially distanced outdoor gatherings suspended in the cold communicable winter now gingerly possible with the warmth of spring.

As a nation, one of the events that was put on hold was the commemoration of the Vietnam War. On March 16, 2021, following guidance from the Centers for Disease Control and Prevention, the US Department of Veterans Affairs (VA) announced it was postponing commemoration events “until further notice.”³ Annually, the VA partners with the US Department of Defense, state, and local organizations to recognize “the service and sacrifices made by the nearly 3 million service members who served in Vietnam.”⁴

In 2012, President Barak Obama signed a proclamation establishing a 13-year commemoration of the 50th anniversary of the Vietnam War.⁵ Five years later, President Donald Trump signed the War Veterans Recognition Act of 2017, designating March 29 annually as National Vietnam War Veterans Day.⁶ Though many of the events planned for March and April could not take place, the Vietnam War Commemoration (https://www.vietnamwar50th.com) offers information and ideas for honoring and supporting Vietnam War veterans. As Memorial Day approaches in this year of so much loss and heroism, I encourage you to find a way to thank Vietnam veterans who may have received the opposite of gratitude when they initially returned home.

As my small contribution to the commemoration, this editorial will focus on the psychiatric disorder of memory: posttraumatic stress disorder (PTSD) and how the Vietnam War brought definition—albeit delayed—to the agonizing diagnosis that too many veterans experience.

The known clinical entity of PTSD is ancient. Narrative descriptions of the disorder are written in the Mesopotamian Epic of Gilgamesh and in Deuteronomy 20:1-9.⁷ American and European military physicians have given various names to the destructive effects of combat on body and mind from “soldier’s heart” in the American Civil War, to “shell shock” in World War I to “battle fatigue” during World War II.⁸ These were all descriptive diagnoses field practitioners used to grasp the psychosomatic decompensation they observed in service members who had been exposed to the horrors of war. The VA was the impetus and agent of the earliest attempts at scientific definition. The American Psychiatric Association further developed this nosology in 1952 with the diagnosis of gross stress reaction in the first Diagnostic and Statistical Manual of Mental Disorders (DSM)-1.⁹

The combat experience shaped the definition: the stressor had to be extreme, the civilian comparison would be a natural disaster; the reaction could occur only in a previously normal individual, it would be attributed to the extant psychiatric condition in anyone with a premorbid illness; and if it did not remit by 6 months, another primary psychiatric diagnosis must be assigned.

From our vantage point, this set of criteria is obviously woefully inadequate, yet it was at least a beginning of formal recognition of the experience that veterans endured in wartime and real progress compared with what happened next. When DSM-1 was revised in 1968, the diagnosis of gross stress reaction was eliminated without explanation. Researcher Andreasen and others speculate that its disappearance can be attributed to association of the diagnosis with war in a country that had been at peace since the end of the Korean War in 1953.¹⁰ Yet military historians among my readers will immediately counter that the Vietnam War began 2 years later and that the year of the revision saw major combat operations.

Many veterans living with the psychological and physical suffering of their service in Vietnam and the organizations that supported them advocated for the psychiatric profession to formally acknowledge post-Vietnam syndrome.¹¹ Five years after the end of the Vietnam War, the experts who authored DSM-III, decided to include a new stress-induced diagnosis.¹² Although the manual did not limit the traumatic experience to combat in Vietnam as some veterans wanted, there is no doubt that the criteria reflect the extensive research validating the illness narratives of thousands of service men and women.

The DSM-III criteria clearly had war in mind when it stipulated that the stressor had to be outside the range of usual human experience that would likely trigger significant symptoms in almost anyone as well as specifying chronic symptoms lasting more than 6 months. Despite the controversy about the diagnosis, Vietnam veterans helped bring the PTSD diagnosis to official psychiatric nomenclature and in a more recognizable form that began to capture the intensity of their reexperiencing of the trauma, the psychosocial difficulties numbing caused, and the pervasive interference of hyperarousal and vigilance many aspects and areas of life.¹³

The National Vietnam Veterans Longitudinal Study examined the course of PTSD over 25 years, using the newly formulated diagnostic criteria for PTSD.¹⁴ Results were reported to Congress in 2012 and showed that 11% of men and 7% of women who were in a war theater were still struggling with PTSD 40 years after the war. Of those, 37% met major depressive disorder criteria. Male veterans who in 1987 still met criteria for PTSD were twice as likely to have died than the comparator group of veterans without PTSD. Two-thirds of veterans with PTSD from war zone exposure discussed behavioral health or substance misuse concerns with a health care provider, and 37% of those were receiving VA care.¹⁴

Given these disturbing data, perhaps the best way we can pay homage to the aging Vietnam veterans is to support continued research into effective evidence-based treatments for PTSD and funding for the training and recruiting of mental health practitioners to all 3 branches of federal health care who can deliver that care compassionately and competently.

Many events both personal and public have been deferred during the 15 plus months of the pandemic. Almost everyone has an example of a friend or family member who would have been sitting at what President Biden, during his memorial speech for the 500,000 victims of the virus referred to as the “empty chair” at a holiday gathering sans COVID-19.² For many in our country, part of the agonizing effort to awaken from the long nightmare of the pandemic is to resume the rhythm of rituals national, local, and personal that mark the year with meaning and offer rest and rejuvenation from the daily toil of duty. There are family dinners now cautiously resumed due to vaccinations; small celebrations of belated birthdays in family pods; socially distanced outdoor gatherings suspended in the cold communicable winter now gingerly possible with the warmth of spring.

As a nation, one of the events that was put on hold was the commemoration of the Vietnam War. On March 16, 2021, following guidance from the Centers for Disease Control and Prevention, the US Department of Veterans Affairs (VA) announced it was postponing commemoration events “until further notice.”³ Annually, the VA partners with the US Department of Defense, state, and local organizations to recognize “the service and sacrifices made by the nearly 3 million service members who served in Vietnam.”⁴

In 2012, President Barak Obama signed a proclamation establishing a 13-year commemoration of the 50th anniversary of the Vietnam War.⁵ Five years later, President Donald Trump signed the War Veterans Recognition Act of 2017, designating March 29 annually as National Vietnam War Veterans Day.⁶ Though many of the events planned for March and April could not take place, the Vietnam War Commemoration (https://www.vietnamwar50th.com) offers information and ideas for honoring and supporting Vietnam War veterans. As Memorial Day approaches in this year of so much loss and heroism, I encourage you to find a way to thank Vietnam veterans who may have received the opposite of gratitude when they initially returned home.

As my small contribution to the commemoration, this editorial will focus on the psychiatric disorder of memory: posttraumatic stress disorder (PTSD) and how the Vietnam War brought definition—albeit delayed—to the agonizing diagnosis that too many veterans experience.

The known clinical entity of PTSD is ancient. Narrative descriptions of the disorder are written in the Mesopotamian Epic of Gilgamesh and in Deuteronomy 20:1-9.⁷ American and European military physicians have given various names to the destructive effects of combat on body and mind from “soldier’s heart” in the American Civil War, to “shell shock” in World War I to “battle fatigue” during World War II.⁸ These were all descriptive diagnoses field practitioners used to grasp the psychosomatic decompensation they observed in service members who had been exposed to the horrors of war. The VA was the impetus and agent of the earliest attempts at scientific definition. The American Psychiatric Association further developed this nosology in 1952 with the diagnosis of gross stress reaction in the first Diagnostic and Statistical Manual of Mental Disorders (DSM)-1.⁹

The combat experience shaped the definition: the stressor had to be extreme, the civilian comparison would be a natural disaster; the reaction could occur only in a previously normal individual, it would be attributed to the extant psychiatric condition in anyone with a premorbid illness; and if it did not remit by 6 months, another primary psychiatric diagnosis must be assigned.

From our vantage point, this set of criteria is obviously woefully inadequate, yet it was at least a beginning of formal recognition of the experience that veterans endured in wartime and real progress compared with what happened next. When DSM-1 was revised in 1968, the diagnosis of gross stress reaction was eliminated without explanation. Researcher Andreasen and others speculate that its disappearance can be attributed to association of the diagnosis with war in a country that had been at peace since the end of the Korean War in 1953.¹⁰ Yet military historians among my readers will immediately counter that the Vietnam War began 2 years later and that the year of the revision saw major combat operations.

Many veterans living with the psychological and physical suffering of their service in Vietnam and the organizations that supported them advocated for the psychiatric profession to formally acknowledge post-Vietnam syndrome.¹¹ Five years after the end of the Vietnam War, the experts who authored DSM-III, decided to include a new stress-induced diagnosis.¹² Although the manual did not limit the traumatic experience to combat in Vietnam as some veterans wanted, there is no doubt that the criteria reflect the extensive research validating the illness narratives of thousands of service men and women.

The DSM-III criteria clearly had war in mind when it stipulated that the stressor had to be outside the range of usual human experience that would likely trigger significant symptoms in almost anyone as well as specifying chronic symptoms lasting more than 6 months. Despite the controversy about the diagnosis, Vietnam veterans helped bring the PTSD diagnosis to official psychiatric nomenclature and in a more recognizable form that began to capture the intensity of their reexperiencing of the trauma, the psychosocial difficulties numbing caused, and the pervasive interference of hyperarousal and vigilance many aspects and areas of life.¹³

The National Vietnam Veterans Longitudinal Study examined the course of PTSD over 25 years, using the newly formulated diagnostic criteria for PTSD.¹⁴ Results were reported to Congress in 2012 and showed that 11% of men and 7% of women who were in a war theater were still struggling with PTSD 40 years after the war. Of those, 37% met major depressive disorder criteria. Male veterans who in 1987 still met criteria for PTSD were twice as likely to have died than the comparator group of veterans without PTSD. Two-thirds of veterans with PTSD from war zone exposure discussed behavioral health or substance misuse concerns with a health care provider, and 37% of those were receiving VA care.¹⁴

Given these disturbing data, perhaps the best way we can pay homage to the aging Vietnam veterans is to support continued research into effective evidence-based treatments for PTSD and funding for the training and recruiting of mental health practitioners to all 3 branches of federal health care who can deliver that care compassionately and competently.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Society is having a moment of reflection about the role of law enforcement and correctional facilities in addressing societal problems. During this moment, psychiatry is being asked by courts to arbitrate who qualifies and ultimately deserves certain judgments.

In particular, we are asked to assess how dangerous an individual may be using violent risk assessment tools and measures of antisocial disorders. As such, we are tasked with pointing out the negative factors of defendants. Alternatively, psychiatry is also asked to explain, using biopsychosocial determinants, what led an individual to act in a deviant manner. As such, we are tasked with pointing out mitigating factors of defendants. In this article, we attempt to look at limitations in both paradigms to encourage a more prudent forensic approach.
 

Negative factors

A conundrum for the forensic psychiatry evaluator is that diagnostic criteria are not designed for the rigors and needs of court. The criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM) are not composed of rigid rules with validity markers to measure their veracity but leave room for clinical judgment, variance across individuals, and future research and treatment needs.

There are some benefits to having room for clinical judgment, but it can also lead to overdiagnosis.¹ This problem is particularly reflected in the diagnosis of antisocial personality disorder (ASPD), the criteria of which includes failure to conform to social norms, deceitfulness, impulsivity, irritability, recklessness, irresponsibility, and lack of remorse. Each of these criteria is ripe for subjectivity by an inexperienced or biased reviewer.

Mitigating factors

On the other side, the defense expert also faces significant challenges, though the tools are different. Contrary to the prosecuting expert who loads an arsenal of subjective assessment tools, the defense expert will point to childhood trauma and mental illness as extenuating explanations for a crime. Having suffered abuse as a child is advanced to justify someone’s subsequent violence. This problem is reflected in the diagnosis of posttraumatic stress disorder (PTSD). An unscrupulous expert may simply allow an evaluee to endorse symptoms without clinical correlates or rigorous validation to advance this narrative.

For example, psychiatrists commonly ascribe the DSM criteria A for PTSD, “directly experiencing the traumatic event(s),” to a smaller slight in life. Some experts suggest that a medical diagnosis, even if not life-threatening but perceived as such, could warrant the diagnosis.¹⁰ This would expand our understanding of trauma and its consequences significantly. Yet already, a survey of Detroit area residents in 1998 found that 89.6% of the interviewees reported having experienced a significant trauma and that the average number of traumatic experiences was 4.8.¹¹ The meaning of a diagnosis that can be applied to almost 90% of a population has unclear usefulness, especially if meant to diminish guilt and responsibility.

More recently, citing Adverse Childhood Experiences (ACEs) has been a common method of supporting mitigating evaluations. Using the ACEs questionnaires, researchers have supported the idea that social programs are a key player in an improved criminal justice system. The ACEs study identified 10 forms of childhood trauma in 17,000 patients, including abuse, neglect, abandonment, household dysfunction, and exposure to violence, that were strongly associated with negative psychological outcomes, engagement in high-risk behaviors, significant medical consequences, and even early death.¹² However, similarly to past trauma, the prevalence of ACEs in the forensic population is the norm, not the exception.
 

Additional thoughts

Of particular concern is when diagnostic criteria intersect or seemingly contradict one another. For example, acts such as an outburst of anger may be interpreted by one evaluator as a sign of deviance, irritability, or recklessness – and meeting antisocial personality disorder criteria. Whereas another evaluator may interpret the same incident as hypervigilance, exaggerated startle response, or self-destructive behavior in PTSD.

An incident of not assisting someone in need may be interpreted as lack of remorse and glibness from antisocial characteristics or avoidance and detachment from others as a reaction to past trauma. Flashbacks from trauma can be interpreted by some as violent fantasies. Even the experience of trauma can be viewed as a risk factor for future violence. In some ways, our perspectives are influenced by our examination of someone’s history through the lens of sociopathy or empathy.
 

In summary

Psychiatry is entrusted by courts to comment on negative and mitigating factors. Negative factors hinge in part on our subjective impression of sociopathy, and mitigating factors hinge, in part, on our empathy for a defendant’s trauma. Psychiatry should recognize the limitations of both sides and humble itself in providing balanced evaluations to courts.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Amendolara is a first-year psychiatry resident at University of California, San Diego. He spent years advocating for survivors of rape and domestic violence at the Crime Victims Treatment Center in New York and conducted public health research at Lourdes Center for Public Health in Camden, N.J. Dr. Amendolara has no disclosures. Dr. Ngo is a second-year child neurology resident at University of California, Los Angeles. She received a master’s degree in narrative medicine from Columbia University, New York. She has no disclosures.

References

1. Frances A. Saving Normal: An Insider’s Revolt Against Out-of-Control Psychiatric Diagnosis, DSM-5, Big Pharma and the Medicalization of Ordinary Life. Harper Collins, 2013.

2. Key Substance Use and Mental Health Indicators in the United States. National Survey on Drug Use and Health. 2018.

3. Wong SCP and Gordon A. Psychol Public Policy Law. 2006;12(3):279-309.

4. Douglas KS et al. Mental Health Law & Policy Institute. About the Historical Clinical Risk Management-20, Version 3.

5. Angwin J et al. ProPublica. 2016 May 23.

6. Dressel J and Farid H. Sci Adv. 2018;4(1). doi: 10.1126/sciady.aao5580.

7. Freedman R et al. Am J Psychiatry. 2013 Jan;170(1):1-5.

8. Lillie B. The complexities of the psychopath test: A Q&A with Ron Jonson. TEDBlog. 2012 Aug 15.

9. Larsen RR et al. Psychol Public Policy Law. 2020;26(3):297-311.

10. Cordova MJ. Psychiatric Times. 2020 Jul 31;37(7).

11. Breslau N et al. Arch Gen Psychiatry. 1998;55(7):626-32.

12. Reavis JA et al. Perm J. 2013 Spring;17(2):44-8.

Society is having a moment of reflection about the role of law enforcement and correctional facilities in addressing societal problems. During this moment, psychiatry is being asked by courts to arbitrate who qualifies and ultimately deserves certain judgments.

In particular, we are asked to assess how dangerous an individual may be using violent risk assessment tools and measures of antisocial disorders. As such, we are tasked with pointing out the negative factors of defendants. Alternatively, psychiatry is also asked to explain, using biopsychosocial determinants, what led an individual to act in a deviant manner. As such, we are tasked with pointing out mitigating factors of defendants. In this article, we attempt to look at limitations in both paradigms to encourage a more prudent forensic approach.
 

Negative factors

A conundrum for the forensic psychiatry evaluator is that diagnostic criteria are not designed for the rigors and needs of court. The criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM) are not composed of rigid rules with validity markers to measure their veracity but leave room for clinical judgment, variance across individuals, and future research and treatment needs.

There are some benefits to having room for clinical judgment, but it can also lead to overdiagnosis.¹ This problem is particularly reflected in the diagnosis of antisocial personality disorder (ASPD), the criteria of which includes failure to conform to social norms, deceitfulness, impulsivity, irritability, recklessness, irresponsibility, and lack of remorse. Each of these criteria is ripe for subjectivity by an inexperienced or biased reviewer.

Mitigating factors

On the other side, the defense expert also faces significant challenges, though the tools are different. Contrary to the prosecuting expert who loads an arsenal of subjective assessment tools, the defense expert will point to childhood trauma and mental illness as extenuating explanations for a crime. Having suffered abuse as a child is advanced to justify someone’s subsequent violence. This problem is reflected in the diagnosis of posttraumatic stress disorder (PTSD). An unscrupulous expert may simply allow an evaluee to endorse symptoms without clinical correlates or rigorous validation to advance this narrative.

For example, psychiatrists commonly ascribe the DSM criteria A for PTSD, “directly experiencing the traumatic event(s),” to a smaller slight in life. Some experts suggest that a medical diagnosis, even if not life-threatening but perceived as such, could warrant the diagnosis.¹⁰ This would expand our understanding of trauma and its consequences significantly. Yet already, a survey of Detroit area residents in 1998 found that 89.6% of the interviewees reported having experienced a significant trauma and that the average number of traumatic experiences was 4.8.¹¹ The meaning of a diagnosis that can be applied to almost 90% of a population has unclear usefulness, especially if meant to diminish guilt and responsibility.

More recently, citing Adverse Childhood Experiences (ACEs) has been a common method of supporting mitigating evaluations. Using the ACEs questionnaires, researchers have supported the idea that social programs are a key player in an improved criminal justice system. The ACEs study identified 10 forms of childhood trauma in 17,000 patients, including abuse, neglect, abandonment, household dysfunction, and exposure to violence, that were strongly associated with negative psychological outcomes, engagement in high-risk behaviors, significant medical consequences, and even early death.¹² However, similarly to past trauma, the prevalence of ACEs in the forensic population is the norm, not the exception.
 

Additional thoughts

Of particular concern is when diagnostic criteria intersect or seemingly contradict one another. For example, acts such as an outburst of anger may be interpreted by one evaluator as a sign of deviance, irritability, or recklessness – and meeting antisocial personality disorder criteria. Whereas another evaluator may interpret the same incident as hypervigilance, exaggerated startle response, or self-destructive behavior in PTSD.

An incident of not assisting someone in need may be interpreted as lack of remorse and glibness from antisocial characteristics or avoidance and detachment from others as a reaction to past trauma. Flashbacks from trauma can be interpreted by some as violent fantasies. Even the experience of trauma can be viewed as a risk factor for future violence. In some ways, our perspectives are influenced by our examination of someone’s history through the lens of sociopathy or empathy.
 

In summary

Psychiatry is entrusted by courts to comment on negative and mitigating factors. Negative factors hinge in part on our subjective impression of sociopathy, and mitigating factors hinge, in part, on our empathy for a defendant’s trauma. Psychiatry should recognize the limitations of both sides and humble itself in providing balanced evaluations to courts.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Amendolara is a first-year psychiatry resident at University of California, San Diego. He spent years advocating for survivors of rape and domestic violence at the Crime Victims Treatment Center in New York and conducted public health research at Lourdes Center for Public Health in Camden, N.J. Dr. Amendolara has no disclosures. Dr. Ngo is a second-year child neurology resident at University of California, Los Angeles. She received a master’s degree in narrative medicine from Columbia University, New York. She has no disclosures.

References

1. Frances A. Saving Normal: An Insider’s Revolt Against Out-of-Control Psychiatric Diagnosis, DSM-5, Big Pharma and the Medicalization of Ordinary Life. Harper Collins, 2013.

2. Key Substance Use and Mental Health Indicators in the United States. National Survey on Drug Use and Health. 2018.

3. Wong SCP and Gordon A. Psychol Public Policy Law. 2006;12(3):279-309.

4. Douglas KS et al. Mental Health Law & Policy Institute. About the Historical Clinical Risk Management-20, Version 3.

5. Angwin J et al. ProPublica. 2016 May 23.

6. Dressel J and Farid H. Sci Adv. 2018;4(1). doi: 10.1126/sciady.aao5580.

7. Freedman R et al. Am J Psychiatry. 2013 Jan;170(1):1-5.

8. Lillie B. The complexities of the psychopath test: A Q&A with Ron Jonson. TEDBlog. 2012 Aug 15.

9. Larsen RR et al. Psychol Public Policy Law. 2020;26(3):297-311.

10. Cordova MJ. Psychiatric Times. 2020 Jul 31;37(7).

11. Breslau N et al. Arch Gen Psychiatry. 1998;55(7):626-32.

12. Reavis JA et al. Perm J. 2013 Spring;17(2):44-8.

Society is having a moment of reflection about the role of law enforcement and correctional facilities in addressing societal problems. During this moment, psychiatry is being asked by courts to arbitrate who qualifies and ultimately deserves certain judgments.

In particular, we are asked to assess how dangerous an individual may be using violent risk assessment tools and measures of antisocial disorders. As such, we are tasked with pointing out the negative factors of defendants. Alternatively, psychiatry is also asked to explain, using biopsychosocial determinants, what led an individual to act in a deviant manner. As such, we are tasked with pointing out mitigating factors of defendants. In this article, we attempt to look at limitations in both paradigms to encourage a more prudent forensic approach.
 

Negative factors

A conundrum for the forensic psychiatry evaluator is that diagnostic criteria are not designed for the rigors and needs of court. The criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM) are not composed of rigid rules with validity markers to measure their veracity but leave room for clinical judgment, variance across individuals, and future research and treatment needs.

There are some benefits to having room for clinical judgment, but it can also lead to overdiagnosis.¹ This problem is particularly reflected in the diagnosis of antisocial personality disorder (ASPD), the criteria of which includes failure to conform to social norms, deceitfulness, impulsivity, irritability, recklessness, irresponsibility, and lack of remorse. Each of these criteria is ripe for subjectivity by an inexperienced or biased reviewer.

Mitigating factors

On the other side, the defense expert also faces significant challenges, though the tools are different. Contrary to the prosecuting expert who loads an arsenal of subjective assessment tools, the defense expert will point to childhood trauma and mental illness as extenuating explanations for a crime. Having suffered abuse as a child is advanced to justify someone’s subsequent violence. This problem is reflected in the diagnosis of posttraumatic stress disorder (PTSD). An unscrupulous expert may simply allow an evaluee to endorse symptoms without clinical correlates or rigorous validation to advance this narrative.

For example, psychiatrists commonly ascribe the DSM criteria A for PTSD, “directly experiencing the traumatic event(s),” to a smaller slight in life. Some experts suggest that a medical diagnosis, even if not life-threatening but perceived as such, could warrant the diagnosis.¹⁰ This would expand our understanding of trauma and its consequences significantly. Yet already, a survey of Detroit area residents in 1998 found that 89.6% of the interviewees reported having experienced a significant trauma and that the average number of traumatic experiences was 4.8.¹¹ The meaning of a diagnosis that can be applied to almost 90% of a population has unclear usefulness, especially if meant to diminish guilt and responsibility.

More recently, citing Adverse Childhood Experiences (ACEs) has been a common method of supporting mitigating evaluations. Using the ACEs questionnaires, researchers have supported the idea that social programs are a key player in an improved criminal justice system. The ACEs study identified 10 forms of childhood trauma in 17,000 patients, including abuse, neglect, abandonment, household dysfunction, and exposure to violence, that were strongly associated with negative psychological outcomes, engagement in high-risk behaviors, significant medical consequences, and even early death.¹² However, similarly to past trauma, the prevalence of ACEs in the forensic population is the norm, not the exception.
 

Additional thoughts

Of particular concern is when diagnostic criteria intersect or seemingly contradict one another. For example, acts such as an outburst of anger may be interpreted by one evaluator as a sign of deviance, irritability, or recklessness – and meeting antisocial personality disorder criteria. Whereas another evaluator may interpret the same incident as hypervigilance, exaggerated startle response, or self-destructive behavior in PTSD.

An incident of not assisting someone in need may be interpreted as lack of remorse and glibness from antisocial characteristics or avoidance and detachment from others as a reaction to past trauma. Flashbacks from trauma can be interpreted by some as violent fantasies. Even the experience of trauma can be viewed as a risk factor for future violence. In some ways, our perspectives are influenced by our examination of someone’s history through the lens of sociopathy or empathy.
 

In summary

Psychiatry is entrusted by courts to comment on negative and mitigating factors. Negative factors hinge in part on our subjective impression of sociopathy, and mitigating factors hinge, in part, on our empathy for a defendant’s trauma. Psychiatry should recognize the limitations of both sides and humble itself in providing balanced evaluations to courts.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Amendolara is a first-year psychiatry resident at University of California, San Diego. He spent years advocating for survivors of rape and domestic violence at the Crime Victims Treatment Center in New York and conducted public health research at Lourdes Center for Public Health in Camden, N.J. Dr. Amendolara has no disclosures. Dr. Ngo is a second-year child neurology resident at University of California, Los Angeles. She received a master’s degree in narrative medicine from Columbia University, New York. She has no disclosures.

References

1. Frances A. Saving Normal: An Insider’s Revolt Against Out-of-Control Psychiatric Diagnosis, DSM-5, Big Pharma and the Medicalization of Ordinary Life. Harper Collins, 2013.

2. Key Substance Use and Mental Health Indicators in the United States. National Survey on Drug Use and Health. 2018.

3. Wong SCP and Gordon A. Psychol Public Policy Law. 2006;12(3):279-309.

4. Douglas KS et al. Mental Health Law & Policy Institute. About the Historical Clinical Risk Management-20, Version 3.

5. Angwin J et al. ProPublica. 2016 May 23.

6. Dressel J and Farid H. Sci Adv. 2018;4(1). doi: 10.1126/sciady.aao5580.

7. Freedman R et al. Am J Psychiatry. 2013 Jan;170(1):1-5.

8. Lillie B. The complexities of the psychopath test: A Q&A with Ron Jonson. TEDBlog. 2012 Aug 15.

9. Larsen RR et al. Psychol Public Policy Law. 2020;26(3):297-311.

10. Cordova MJ. Psychiatric Times. 2020 Jul 31;37(7).

11. Breslau N et al. Arch Gen Psychiatry. 1998;55(7):626-32.

12. Reavis JA et al. Perm J. 2013 Spring;17(2):44-8.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

• What is your diagnosis?
• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

• What is your diagnosis?
• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

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• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.