A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

A 78-year-old woman presented to the ambulatory care clinic for a painful tongue mass. She noticed the mass 2 months prior to presentation, and it had not grown in the interim. She had left-sided jaw pain when opening her mouth and persistent left-sided otalgia.

In the evaluation of tongue masses, ulcerations, or other surface abnormalities, exclusion of squamous cell carcinoma is the top priority. Additional tongue surface abnormalities include benign lesions such as geographic tongue, inflammatory conditions such as lichen planus, and infections such as syphilis.

The ear and jaw pain may reflect metastatic spread, neural invasion, or referred pain from the tongue. A vasculitis with predilection for the head, such as giant cell arteritis, could present with oral and ear pain. Jaw pain with mastication could reflect jaw claudication, but pain upon mouth opening is more commonly explained by temporomandibular joint dysfunction.

The patient had hypertension, hyperlipidemia, chronic kidney disease (estimated glomerular filtration rate of 42 mL/min), and diabetes mellitus. Four months prior she was diagnosed with a chronic obstructing left renal calculus on ultrasonography to evaluate chronic kidney disease. Two months prior heart failure with preserved ejection fraction was diagnosed. Stress cardiac magnetic resonance imaging (MRI) demonstrated normal ejection fraction, asymmetric septal hypertrophy, and stress-induced subendocardial perfusion defect. Her medications were metoprolol, lisinopril, simvastatin, meloxicam, and aspirin. She never used tobacco and did not consume alcohol. She was born in the Philippines and emigrated to the United States 15 years ago. She had not experienced fever, chills, hearing loss, tinnitus, cough, dysphonia, neck swelling, or joint pain. She had lost 3 kg in the previous 4 months.

The absence of tobacco and alcohol use reduces the probability of a squamous cell carcinoma, although human papillomavirus–associated squamous cell carcinoma of the tongue remains possible. Asymmetric septal hypertrophy is characteristic of hypertrophic cardiomyopathy or an infiltrative cardiomyopathy. Sarcoidosis can affect the heart and can account for the renal calculus (via hypercalcemia). Amyloid light-chain (AL) amyloidosis could involve the heart and the tongue, although in amyloidosis the cardiac MRI typically displays late gadolinium enhancement and ventricular wall thickening. The absence of tinnitus or hearing loss suggests that the left-sided otalgia is referred pain from the tongue and oral cavity rather than a primary otologic disease (eg, infection).

On physical examination, temperature was 37.2 °C, heart rate was 88 beats per minute, blood pressure was 134/62 mm Hg, and oxygen saturation was 99% while breathing ambient air. The patient’s weight was 40.4 kg (body mass index of 19.26 kg/m²). Intraoral examination revealed induration of the bilateral tongue, an erosive 1-cm pedunculated mass of the left dorsum, rough white coating on the right dorsum, and fullness of the right lateral surface with an erosion abutting tooth #2. The right submandibular salivary gland was firm. The otoscopic examination and remainder of the head and neck examination were normal. There was no cervical, supraclavicular, or axillary adenopathy. The cranial nerve, cardiovascular, pulmonary, abdominal, and skin examinations were normal.

The left-sided lingual mass and right-sided lingual erosion likely arise from the same process. Both are compatible with an infection (eg, syphilis or tuberculosis), cancer, autoimmune disease (eg, Crohn’s disease or sarcoidosis), or an infiltrative disease such as amyloidosis. Leukoplakia could reflect a candidal infection, dysplasia, squamous cell carcinoma, oral hairy leukoplakia, or hyperkeratosis. The isolated submandibular salivary gland could reflect sialadenitis from chronic salivary duct obstruction or a primary neoplasm, but more likely is caused by the same process causing the tongue abnormalities.

The white blood cell count was 8,600/μL; hemoglobin, 11.5 g/dL; mean corpuscular volume, 102.5 fL; and platelet count, 270,000/μL³. Serum sodium was 141 mEq/L; potassium, 4.1 mEq/L; chloride, 101 mEq/L; bicarbonate, 30 mEq/L; blood urea nitrogen, 19 mg/dL; creatinine, 0.7 mg/dL; and calcium, 10.4 mg/dL (reference range, 8.5-10.3). Total serum protein was 7.3 g/dL (reference range, 6.0-8.3); albumin was 3.7 g/dL. Liver biochemistry test results were normal. Serum folate and vitamin B₁₂ levels were normal. Serum ferritin was 423 ng/mL (reference range, 11-306); transferrin saturation, 21.4% (reference range, 15.0%-50.0%); and total iron-binding capacity, 323 µg/dL (reference range, 261-478). Parathyroid hormone (PTH) was 14 pg/mL (reference range, 15-65). HIV antibody was negative.

The calcium level is at the upper range of normal, whereas the PTH level is at the lower range of normal. The differential diagnosis for PTH-independent hypercalcemia includes hypercalcemia of malignancy and granulomatous disease such as sarcoidosis. Mild hypercalcemia could contribute to the nephrolithiasis. The iron studies exclude iron deficiency and are not suggestive of anemia of chronic disease. The triad of mild hypercalcemia, cardiomyopathy, and anemia is compatible with AL amyloidosis (perhaps with associated multiple myeloma) or sarcoidosis; both disorders can present as a mass. Imaging of the head and neck and biopsy of the tongue mass are the next steps.

The left dorsal tongue mass was excised in clinic. Histopathology revealed ulcerated squamous mucosa with inflammatory changes but no malignancy. Imaging of the head and neck was scheduled.

Neither cancer or granulomas were detected, but inadequate sampling or staining must be considered. Inflammatory changes are compatible with infection, autoimmunity, and cancer; the latter can feature reactive changes that obscure the malignant cells. The absence of granulomas lowers, but does not eliminate, the possibility of sarcoidosis, tuberculosis, fungal infection, and granulomatosis with polyangiitis. Actinomycosis is an invasive orofacial infection that disregards anatomic boundaries and is characterized by inflammatory histology; although infection of the tongue is possible, infection of the jaw and face is more typical. Immunoglobulin G4–related disease can present as an inflammatory and invasive disorder; however, the characteristic histopathologic findings (lymphoplasmacytic infiltrate, fibrosis, and phlebitis) are absent.

Culture of the tissue for mycobacteria or fungi (she is at increased risk for both given her previous residency in the Philippines) could increase the diagnostic yield. Another biopsy of the tongue or an adjacent structure—guided by imaging—may provide a more diagnostic tissue sample.

MRI of the head and neck demonstrated hyperintense signal and prominence of the right lateral pterygoid muscle (Figure 1A) and slight enlargement of a right submandibular gland (Figure 1B). No tongue abnormalities were identified. Radiograph of the chest did not reveal infiltrates, masses, or lymphadenopathy.

The absence of the tongue mass on the MRI likely reflects excision of the mass at the time of biopsy. The signal enhancement in the right lateral pterygoid muscle and submandibular gland is suggestive of an infiltrative process. Infiltration of the right lateral pterygoid muscle may also explain the patient’s pain when opening her mouth. Infiltrative processes can be neoplastic (eg, salivary gland tumor, sarcoma, lymphoma), infectious (eg, mycobacterial or fungal), cellular (eg, histiocytes, mast cells, plasma cells, eosinophils, granulomas), or related to inert substances such as amyloid or iron.

Seven weeks later, the patient presented to the hospital for scheduled percutaneous nephrolithotomy of the obstructing renal calculus. The physical examination was unchanged. The complete blood count and metabolic panel were unchanged apart from hemoglobin of 9.9 g/dL and calcium of 11.5 mg/dL. Coagulation studies were within normal limits.

A percutaneous nephroureteral stent was placed under conscious sedation. The patient then underwent rapid sequence induction of general anesthesia for the nephrolithotomy with fentanyl, propofol, and rocuronium. Within minutes of initiating mechanical ventilation, severe periorbital and perioral edema, copious oral cavity bleeding, and bilateral periorbital purpura occurred. Sugammadex (neuromuscular blockade reversal) and dexamethasone were administered. Examination of the oral cavity was limited by the brisk bleeding; the right sided tongue erosion was unchanged.

Bleeding is caused by thrombocytopenia, thrombocytopathy, coagulopathy, or disruption of vessel integrity. Oral cavity bleeding could arise from the tongue ulceration, but could also reflect pulmonary, nasal, or gastrointestinal hemorrhage. Angioedema arises from mast cell– or bradykinin-mediated pathways; mast cell degranulation may have been precipitated by the anesthetic agents, opiate, or a material in the nephroureteral stent.

The edema and bleeding are temporally related to multiple medications and mechanical ventilation. A latent bleeding diathesis may have manifested in the setting of increased tissue hydrostatic pressure or vessel permeability. Amyloidosis can lead to vessel fragility and coagulopathy, and periorbital bleeding is characteristic of AL amyloidosis.

The hypercalcemia, now more pronounced, raises concern for malignancy (including multiple myeloma) and granulomatous diseases like sarcoidosis, mycobacterial infections, and fungal infections. The declining hemoglobin could be explained by chronic blood loss, hemolysis, anemia of chronic disease, or a bone marrow process.

The cardiomyopathy, bleeding disorder, and multifocal disease in the oral cavity can be explained by AL amyloidosis; the hypercalcemia suggests concomitant multiple myeloma.

At the time of the bleeding event, the partial thromboplastin time, prothrombin time, and fibrinogen were within the reference ranges. Factor X activity level was normal. No schistocytes were observed on peripheral blood smear. Immunoglobulin G level was 1,425 mg/dL (reference range, 639-1,349); IgA and IgM levels were within the reference range. Serum lambda free light chains were 151.78 mg/dL (reference range, 0.46-2.71), and the ratio of kappa to lambda light chains was 0.01 (reference range, 0.49-2.54). Serum protein electrophoresis and immunofixation demonstrated a monoclonal paraprotein (IgG lambda) level of 1.2 g/dL. Congo red staining of the previously excised left dorsal tongue mass was negative for apple-green birefringence. Reexamination of the oral cavity revealed macroglossia and scalloping of the tongue (Figure 2).

Scalloping is characteristic of an infiltrative disorder that enlarges the tongue (macroglossia) and deforms its edges, which encounter the teeth. Macroglossia is seen in AL amyloidosis, acromegaly, and hypothyroidism. A monoclonal light chain, especially a lambda light chain, is characteristic of AL amyloidosis. The Congo red stain results can support the diagnosis when positive, but it has limited sensitivity. The tongue specimen can be sent for immunohistochemistry or mass spectrometry to evaluate for light chain deposition. A bone marrow biopsy can demonstrate a clonal plasma cell population. AL amyloidosis with concomitant multiple myeloma is the most likely diagnosis.

Bone marrow aspiration and core biopsy demonstrated 30% lambda-restricted plasma cells (Figure 3A-C). Congo red staining demonstrated apple-green birefringence of the bone marrow microvasculature (Figure 3D). Skeletal survey demonstrated widespread lytic bone disease involving the calvarium (Figure 4A), left humerus (Figure 4B), and left scapula (Figure 4B). Based on the monoclonal paraprotein, more than 10% monoclonal plasma cells, skeletal lesions, and hypercalcemia, she was diagnosed with IgG lambda multiple myeloma. Based on apple-green birefringence in the bone marrow and macroglossia, she was diagnosed with AL amyloidosis. The cardiac MRI findings were compatible with AL amyloidosis. ¹

After three cycles of bortezomib and dexamethasone therapy to concurrently treat AL amyloidosis and multiple myeloma, the serum lambda light chain level decreased to 1.49 mg/dL and the monoclonal paraprotein level decreased to 0.3 g/dL. The calcium level was 9.8 mg/dL, and the hemoglobin level was 11.7 g/dL. The patient’s tongue pain resolved, allowing for improved oral intake and a 5.7-kg weight gain. The patient underwent nephrolithotomy 4 months after her initial presentation. She resumed an active lifestyle and recently traveled to visit relatives in the Philippines.

Oral diseases affect general health and quality of life and can be a harbinger of systemic disease. Tooth loss, caries, periodontal disease, and poorly fitting dentures commonly affect speech and nutrition.² These common outpatient oral health issues can be the driving force for hospital admissions; for example, caries and periodontal disease can lead to suppurative odontogenic infection, endocarditis, brain abscess, and sepsis.

Tongue ulcerations, masses, and surface abnormalities often require consultation with a dentist or oral and maxillofacial surgeon to exclude squamous cell carcinoma.³ Other diagnostic considerations include benign neoplasms, trauma, inflammatory conditions (eg, sarcoidosis), infection (eg, syphilis, tuberculosis), and infiltrative processes such as amyloidosis.

Amyloidosis is a heterogeneous group of diseases caused by deposition of insoluble protein fibrils in tissues.^4,5 The three most encountered forms of amyloidosis are AL, AA, and ATTR. Each form is named after the culprit protein.⁴ AL amyloidosis arises when a small clonal population of plasma cells in the bone marrow overproduces immunoglobulin light chain monomers.^4,6 AA amyloidosis develops when the liver produces serum amyloid A protein (an acute phase reactant) in response to a chronic inflammatory condition such as rheumatoid arthritis or chronic intravenous drug injection.⁴ Transthyretin (TTR, also known as “prealbumin”) is a tetrameric protein that transports thyroxine and retinol; there are two forms of ATTR amyloidosis: hereditary and wild type. Hereditary ATTR amyloidosis develops from agglomeration of misfolded TTR monomers caused by mutations in the TTR gene. Wild-type ATTR amyloidosis is caused by age-related dissociation of the TTR tetramer into its constituent monomers that denature, misfold, and agglomerate into fibrils.⁵ Wild-type ATTR is now recognized as the most common form of amyloidosis, with 25% of myocardial autopsy specimens of patients 80 years or older demonstrating amyloid.⁷ The estimated incidence of AL amyloidosis is 10 cases per million person-years.⁸

Each amyloid protein homes in on specific anatomic sites.⁴ Characteristic combinations of organ dysfunction can suggest different forms of amyloidosis.⁹ Cardiac and peripheral nervous involvement (eg, carpal tunnel syndrome) is typical of both hereditary and wild-type ATTR amyloidosis; ATTR amyloidosis does not involve the kidney.⁴ AA amyloidosis most commonly manifests with proteinuria followed by declining glomerular filtration rate; heart failure is rare.⁴ The most common findings in AL amyloidosis are proteinuria, congestive heart failure, and sensory neuropathy.⁶ Gastrointestinal tract and hepatic involvement are each seen in nearly 20% of patients, and macroglossia is identified in approximately 10% of those with AL amyloidosis.^6,10

Chronic deposition of amyloid can lead to acute presentations. Approximately 30% of patients with AL amyloidosis develop abnormal bleeding.¹¹ Amyloid deposition in small blood vessels predisposes them to rupture. Bleeding events can be exacerbated by acquired coagulopathy due to plasma cell dyscrasia−associated thrombocytopenia, amyloid fibril adsorption of factor X, or hypofibrinogenemia.^11,12 Periorbital purpura following minor trauma or transient venous hypertension is characteristic of AL amyloidosis.^6,13 In this case, positive pressure ventilation and recumbent positioning increased hydrostatic pressure in the head and neck, causing rupture of the infiltrated small vessels around the eyes and in the oral cavity.¹⁴

Histological demonstration of tissue deposition of amyloid protein is the preferred method for amyloidosis diagnosis. Symptomatic sites or organs with dysfunction or radiologic changes are suitable for biopsy.⁶ If those sites are inaccessible or yield insufficient tissue quantity, abdominal fat pad aspiration or biopsy is indicated.¹⁵ Apple-green birefringence under polarized light of Congo red–stained tissue is characteristic, with sensitivity and specificity of approximately 80% and a positive predictive value of 85%.¹⁵ Immunoelectron microscopy is often performed simultaneously to confirm the diagnosis and determine the amyloid protein type.^4,16 Immunoelectron microscopy’s sensitivity is approximately 80%, and it has specificity and positive predictive value both approaching 100%.¹⁵ Mass spectrometry is particularly useful in cases where the amyloid subtype is not clinically apparent (eg, a patient with an autoimmune condition or chronic infection as well as light chain abnormality).⁶ Cardiac MRI findings that suggest amyloidosis include a thickened left ventricle and late gadolinium enhancement.¹ ATTR cardiac amyloidosis can be diagnosed using amyloid fibril–binding radiotracer technetium-99m-pyrophosphate scintigraphy; biopsy is often not necessary.^1,4 Gene sequencing to differentiate between hereditary and wild-type forms of ATTR amyloidosis is beneficial.

The primary objectives of amyloidosis management are to control symptoms and inhibit amyloid protein production.⁶ Outcomes in AL amyloidosis have improved due to early diagnosis, new chemotherapeutic agents to eradicate the plasma cell clone, and autologous stem cell transplantation.^6,17 Two new ATTR amyloidosis treatments are RNA interference therapies, which prevent TTR messenger RNA translation, and tafamidis, which stabilizes the TTR tetramer and prevents dissociation into its constituent monomers that precipitate in tissues.¹⁸ Both therapies can improve neuropathy-related quality of life.¹⁸ Tafamidis slows disease progression and decreases all-cause mortality in patients with hereditary and wild-type ATTR cardiac amyloidosis.¹⁹

Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical features.⁶ Multiple myeloma is characterized by marked expansion of a clonal plasma cell population within the bone marrow that aberrantly produces immunoglobulin. Conversely, the clonal plasma cell population responsible for producing the insoluble monoclonal light chain protein in AL amyloidosis typically constitutes less than 10% of the bone marrow.²⁰ Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis, which portends a poor outcome.²⁰

Amyloidosis is a rare group of diseases that arises when misfolded proteins aggregate in vital organs. The typical manifestations—congestive heart failure, neuropathy, chronic kidney disease, bleeding—are nearly always explained by more common conditions. Characteristic manifestations (like macroglossia) or associated diseases (like multiple myeloma) substantially increases the probability of AL amyloidosis. In a multisystem illness, the most common diseases must be excluded first, but this case reminds us that rare diseases, like amyloidosis, also warrant consideration as the story unfolds.

• Different amyloid proteins precipitate in different anatomic sites, which leads to specific multiorgan combinations. The most common amyloidosis, ATTR, tends to manifest as heart failure and peripheral sensory neuropathy, while the constellation of AL amyloidosis includes heart failure, neuropathy, and proteinuria.
• Bleeding occurs in 30% of patients with AL amyloidosis. It is precipitated by fragile small blood vessels and exacerbated by acquired coagulopathy from adsorption of coagulation factors.
• Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical tempos and presentations. Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis.

The authors thank Benjamin A Derman, MD, of the University of Chicago, Chicago, Illinois, for critical review of the manuscript.

A 78-year-old woman presented to the ambulatory care clinic for a painful tongue mass. She noticed the mass 2 months prior to presentation, and it had not grown in the interim. She had left-sided jaw pain when opening her mouth and persistent left-sided otalgia.

In the evaluation of tongue masses, ulcerations, or other surface abnormalities, exclusion of squamous cell carcinoma is the top priority. Additional tongue surface abnormalities include benign lesions such as geographic tongue, inflammatory conditions such as lichen planus, and infections such as syphilis.

The ear and jaw pain may reflect metastatic spread, neural invasion, or referred pain from the tongue. A vasculitis with predilection for the head, such as giant cell arteritis, could present with oral and ear pain. Jaw pain with mastication could reflect jaw claudication, but pain upon mouth opening is more commonly explained by temporomandibular joint dysfunction.

The patient had hypertension, hyperlipidemia, chronic kidney disease (estimated glomerular filtration rate of 42 mL/min), and diabetes mellitus. Four months prior she was diagnosed with a chronic obstructing left renal calculus on ultrasonography to evaluate chronic kidney disease. Two months prior heart failure with preserved ejection fraction was diagnosed. Stress cardiac magnetic resonance imaging (MRI) demonstrated normal ejection fraction, asymmetric septal hypertrophy, and stress-induced subendocardial perfusion defect. Her medications were metoprolol, lisinopril, simvastatin, meloxicam, and aspirin. She never used tobacco and did not consume alcohol. She was born in the Philippines and emigrated to the United States 15 years ago. She had not experienced fever, chills, hearing loss, tinnitus, cough, dysphonia, neck swelling, or joint pain. She had lost 3 kg in the previous 4 months.

The absence of tobacco and alcohol use reduces the probability of a squamous cell carcinoma, although human papillomavirus–associated squamous cell carcinoma of the tongue remains possible. Asymmetric septal hypertrophy is characteristic of hypertrophic cardiomyopathy or an infiltrative cardiomyopathy. Sarcoidosis can affect the heart and can account for the renal calculus (via hypercalcemia). Amyloid light-chain (AL) amyloidosis could involve the heart and the tongue, although in amyloidosis the cardiac MRI typically displays late gadolinium enhancement and ventricular wall thickening. The absence of tinnitus or hearing loss suggests that the left-sided otalgia is referred pain from the tongue and oral cavity rather than a primary otologic disease (eg, infection).

On physical examination, temperature was 37.2 °C, heart rate was 88 beats per minute, blood pressure was 134/62 mm Hg, and oxygen saturation was 99% while breathing ambient air. The patient’s weight was 40.4 kg (body mass index of 19.26 kg/m²). Intraoral examination revealed induration of the bilateral tongue, an erosive 1-cm pedunculated mass of the left dorsum, rough white coating on the right dorsum, and fullness of the right lateral surface with an erosion abutting tooth #2. The right submandibular salivary gland was firm. The otoscopic examination and remainder of the head and neck examination were normal. There was no cervical, supraclavicular, or axillary adenopathy. The cranial nerve, cardiovascular, pulmonary, abdominal, and skin examinations were normal.

The left-sided lingual mass and right-sided lingual erosion likely arise from the same process. Both are compatible with an infection (eg, syphilis or tuberculosis), cancer, autoimmune disease (eg, Crohn’s disease or sarcoidosis), or an infiltrative disease such as amyloidosis. Leukoplakia could reflect a candidal infection, dysplasia, squamous cell carcinoma, oral hairy leukoplakia, or hyperkeratosis. The isolated submandibular salivary gland could reflect sialadenitis from chronic salivary duct obstruction or a primary neoplasm, but more likely is caused by the same process causing the tongue abnormalities.

The white blood cell count was 8,600/μL; hemoglobin, 11.5 g/dL; mean corpuscular volume, 102.5 fL; and platelet count, 270,000/μL³. Serum sodium was 141 mEq/L; potassium, 4.1 mEq/L; chloride, 101 mEq/L; bicarbonate, 30 mEq/L; blood urea nitrogen, 19 mg/dL; creatinine, 0.7 mg/dL; and calcium, 10.4 mg/dL (reference range, 8.5-10.3). Total serum protein was 7.3 g/dL (reference range, 6.0-8.3); albumin was 3.7 g/dL. Liver biochemistry test results were normal. Serum folate and vitamin B₁₂ levels were normal. Serum ferritin was 423 ng/mL (reference range, 11-306); transferrin saturation, 21.4% (reference range, 15.0%-50.0%); and total iron-binding capacity, 323 µg/dL (reference range, 261-478). Parathyroid hormone (PTH) was 14 pg/mL (reference range, 15-65). HIV antibody was negative.

The calcium level is at the upper range of normal, whereas the PTH level is at the lower range of normal. The differential diagnosis for PTH-independent hypercalcemia includes hypercalcemia of malignancy and granulomatous disease such as sarcoidosis. Mild hypercalcemia could contribute to the nephrolithiasis. The iron studies exclude iron deficiency and are not suggestive of anemia of chronic disease. The triad of mild hypercalcemia, cardiomyopathy, and anemia is compatible with AL amyloidosis (perhaps with associated multiple myeloma) or sarcoidosis; both disorders can present as a mass. Imaging of the head and neck and biopsy of the tongue mass are the next steps.

The left dorsal tongue mass was excised in clinic. Histopathology revealed ulcerated squamous mucosa with inflammatory changes but no malignancy. Imaging of the head and neck was scheduled.

Neither cancer or granulomas were detected, but inadequate sampling or staining must be considered. Inflammatory changes are compatible with infection, autoimmunity, and cancer; the latter can feature reactive changes that obscure the malignant cells. The absence of granulomas lowers, but does not eliminate, the possibility of sarcoidosis, tuberculosis, fungal infection, and granulomatosis with polyangiitis. Actinomycosis is an invasive orofacial infection that disregards anatomic boundaries and is characterized by inflammatory histology; although infection of the tongue is possible, infection of the jaw and face is more typical. Immunoglobulin G4–related disease can present as an inflammatory and invasive disorder; however, the characteristic histopathologic findings (lymphoplasmacytic infiltrate, fibrosis, and phlebitis) are absent.

Culture of the tissue for mycobacteria or fungi (she is at increased risk for both given her previous residency in the Philippines) could increase the diagnostic yield. Another biopsy of the tongue or an adjacent structure—guided by imaging—may provide a more diagnostic tissue sample.

MRI of the head and neck demonstrated hyperintense signal and prominence of the right lateral pterygoid muscle (Figure 1A) and slight enlargement of a right submandibular gland (Figure 1B). No tongue abnormalities were identified. Radiograph of the chest did not reveal infiltrates, masses, or lymphadenopathy.

The absence of the tongue mass on the MRI likely reflects excision of the mass at the time of biopsy. The signal enhancement in the right lateral pterygoid muscle and submandibular gland is suggestive of an infiltrative process. Infiltration of the right lateral pterygoid muscle may also explain the patient’s pain when opening her mouth. Infiltrative processes can be neoplastic (eg, salivary gland tumor, sarcoma, lymphoma), infectious (eg, mycobacterial or fungal), cellular (eg, histiocytes, mast cells, plasma cells, eosinophils, granulomas), or related to inert substances such as amyloid or iron.

Seven weeks later, the patient presented to the hospital for scheduled percutaneous nephrolithotomy of the obstructing renal calculus. The physical examination was unchanged. The complete blood count and metabolic panel were unchanged apart from hemoglobin of 9.9 g/dL and calcium of 11.5 mg/dL. Coagulation studies were within normal limits.

A percutaneous nephroureteral stent was placed under conscious sedation. The patient then underwent rapid sequence induction of general anesthesia for the nephrolithotomy with fentanyl, propofol, and rocuronium. Within minutes of initiating mechanical ventilation, severe periorbital and perioral edema, copious oral cavity bleeding, and bilateral periorbital purpura occurred. Sugammadex (neuromuscular blockade reversal) and dexamethasone were administered. Examination of the oral cavity was limited by the brisk bleeding; the right sided tongue erosion was unchanged.

Bleeding is caused by thrombocytopenia, thrombocytopathy, coagulopathy, or disruption of vessel integrity. Oral cavity bleeding could arise from the tongue ulceration, but could also reflect pulmonary, nasal, or gastrointestinal hemorrhage. Angioedema arises from mast cell– or bradykinin-mediated pathways; mast cell degranulation may have been precipitated by the anesthetic agents, opiate, or a material in the nephroureteral stent.

The edema and bleeding are temporally related to multiple medications and mechanical ventilation. A latent bleeding diathesis may have manifested in the setting of increased tissue hydrostatic pressure or vessel permeability. Amyloidosis can lead to vessel fragility and coagulopathy, and periorbital bleeding is characteristic of AL amyloidosis.

The hypercalcemia, now more pronounced, raises concern for malignancy (including multiple myeloma) and granulomatous diseases like sarcoidosis, mycobacterial infections, and fungal infections. The declining hemoglobin could be explained by chronic blood loss, hemolysis, anemia of chronic disease, or a bone marrow process.

The cardiomyopathy, bleeding disorder, and multifocal disease in the oral cavity can be explained by AL amyloidosis; the hypercalcemia suggests concomitant multiple myeloma.

At the time of the bleeding event, the partial thromboplastin time, prothrombin time, and fibrinogen were within the reference ranges. Factor X activity level was normal. No schistocytes were observed on peripheral blood smear. Immunoglobulin G level was 1,425 mg/dL (reference range, 639-1,349); IgA and IgM levels were within the reference range. Serum lambda free light chains were 151.78 mg/dL (reference range, 0.46-2.71), and the ratio of kappa to lambda light chains was 0.01 (reference range, 0.49-2.54). Serum protein electrophoresis and immunofixation demonstrated a monoclonal paraprotein (IgG lambda) level of 1.2 g/dL. Congo red staining of the previously excised left dorsal tongue mass was negative for apple-green birefringence. Reexamination of the oral cavity revealed macroglossia and scalloping of the tongue (Figure 2).

Scalloping is characteristic of an infiltrative disorder that enlarges the tongue (macroglossia) and deforms its edges, which encounter the teeth. Macroglossia is seen in AL amyloidosis, acromegaly, and hypothyroidism. A monoclonal light chain, especially a lambda light chain, is characteristic of AL amyloidosis. The Congo red stain results can support the diagnosis when positive, but it has limited sensitivity. The tongue specimen can be sent for immunohistochemistry or mass spectrometry to evaluate for light chain deposition. A bone marrow biopsy can demonstrate a clonal plasma cell population. AL amyloidosis with concomitant multiple myeloma is the most likely diagnosis.

Bone marrow aspiration and core biopsy demonstrated 30% lambda-restricted plasma cells (Figure 3A-C). Congo red staining demonstrated apple-green birefringence of the bone marrow microvasculature (Figure 3D). Skeletal survey demonstrated widespread lytic bone disease involving the calvarium (Figure 4A), left humerus (Figure 4B), and left scapula (Figure 4B). Based on the monoclonal paraprotein, more than 10% monoclonal plasma cells, skeletal lesions, and hypercalcemia, she was diagnosed with IgG lambda multiple myeloma. Based on apple-green birefringence in the bone marrow and macroglossia, she was diagnosed with AL amyloidosis. The cardiac MRI findings were compatible with AL amyloidosis. ¹

After three cycles of bortezomib and dexamethasone therapy to concurrently treat AL amyloidosis and multiple myeloma, the serum lambda light chain level decreased to 1.49 mg/dL and the monoclonal paraprotein level decreased to 0.3 g/dL. The calcium level was 9.8 mg/dL, and the hemoglobin level was 11.7 g/dL. The patient’s tongue pain resolved, allowing for improved oral intake and a 5.7-kg weight gain. The patient underwent nephrolithotomy 4 months after her initial presentation. She resumed an active lifestyle and recently traveled to visit relatives in the Philippines.

Oral diseases affect general health and quality of life and can be a harbinger of systemic disease. Tooth loss, caries, periodontal disease, and poorly fitting dentures commonly affect speech and nutrition.² These common outpatient oral health issues can be the driving force for hospital admissions; for example, caries and periodontal disease can lead to suppurative odontogenic infection, endocarditis, brain abscess, and sepsis.

Tongue ulcerations, masses, and surface abnormalities often require consultation with a dentist or oral and maxillofacial surgeon to exclude squamous cell carcinoma.³ Other diagnostic considerations include benign neoplasms, trauma, inflammatory conditions (eg, sarcoidosis), infection (eg, syphilis, tuberculosis), and infiltrative processes such as amyloidosis.

Amyloidosis is a heterogeneous group of diseases caused by deposition of insoluble protein fibrils in tissues.^4,5 The three most encountered forms of amyloidosis are AL, AA, and ATTR. Each form is named after the culprit protein.⁴ AL amyloidosis arises when a small clonal population of plasma cells in the bone marrow overproduces immunoglobulin light chain monomers.^4,6 AA amyloidosis develops when the liver produces serum amyloid A protein (an acute phase reactant) in response to a chronic inflammatory condition such as rheumatoid arthritis or chronic intravenous drug injection.⁴ Transthyretin (TTR, also known as “prealbumin”) is a tetrameric protein that transports thyroxine and retinol; there are two forms of ATTR amyloidosis: hereditary and wild type. Hereditary ATTR amyloidosis develops from agglomeration of misfolded TTR monomers caused by mutations in the TTR gene. Wild-type ATTR amyloidosis is caused by age-related dissociation of the TTR tetramer into its constituent monomers that denature, misfold, and agglomerate into fibrils.⁵ Wild-type ATTR is now recognized as the most common form of amyloidosis, with 25% of myocardial autopsy specimens of patients 80 years or older demonstrating amyloid.⁷ The estimated incidence of AL amyloidosis is 10 cases per million person-years.⁸

Each amyloid protein homes in on specific anatomic sites.⁴ Characteristic combinations of organ dysfunction can suggest different forms of amyloidosis.⁹ Cardiac and peripheral nervous involvement (eg, carpal tunnel syndrome) is typical of both hereditary and wild-type ATTR amyloidosis; ATTR amyloidosis does not involve the kidney.⁴ AA amyloidosis most commonly manifests with proteinuria followed by declining glomerular filtration rate; heart failure is rare.⁴ The most common findings in AL amyloidosis are proteinuria, congestive heart failure, and sensory neuropathy.⁶ Gastrointestinal tract and hepatic involvement are each seen in nearly 20% of patients, and macroglossia is identified in approximately 10% of those with AL amyloidosis.^6,10

Chronic deposition of amyloid can lead to acute presentations. Approximately 30% of patients with AL amyloidosis develop abnormal bleeding.¹¹ Amyloid deposition in small blood vessels predisposes them to rupture. Bleeding events can be exacerbated by acquired coagulopathy due to plasma cell dyscrasia−associated thrombocytopenia, amyloid fibril adsorption of factor X, or hypofibrinogenemia.^11,12 Periorbital purpura following minor trauma or transient venous hypertension is characteristic of AL amyloidosis.^6,13 In this case, positive pressure ventilation and recumbent positioning increased hydrostatic pressure in the head and neck, causing rupture of the infiltrated small vessels around the eyes and in the oral cavity.¹⁴

Histological demonstration of tissue deposition of amyloid protein is the preferred method for amyloidosis diagnosis. Symptomatic sites or organs with dysfunction or radiologic changes are suitable for biopsy.⁶ If those sites are inaccessible or yield insufficient tissue quantity, abdominal fat pad aspiration or biopsy is indicated.¹⁵ Apple-green birefringence under polarized light of Congo red–stained tissue is characteristic, with sensitivity and specificity of approximately 80% and a positive predictive value of 85%.¹⁵ Immunoelectron microscopy is often performed simultaneously to confirm the diagnosis and determine the amyloid protein type.^4,16 Immunoelectron microscopy’s sensitivity is approximately 80%, and it has specificity and positive predictive value both approaching 100%.¹⁵ Mass spectrometry is particularly useful in cases where the amyloid subtype is not clinically apparent (eg, a patient with an autoimmune condition or chronic infection as well as light chain abnormality).⁶ Cardiac MRI findings that suggest amyloidosis include a thickened left ventricle and late gadolinium enhancement.¹ ATTR cardiac amyloidosis can be diagnosed using amyloid fibril–binding radiotracer technetium-99m-pyrophosphate scintigraphy; biopsy is often not necessary.^1,4 Gene sequencing to differentiate between hereditary and wild-type forms of ATTR amyloidosis is beneficial.

The primary objectives of amyloidosis management are to control symptoms and inhibit amyloid protein production.⁶ Outcomes in AL amyloidosis have improved due to early diagnosis, new chemotherapeutic agents to eradicate the plasma cell clone, and autologous stem cell transplantation.^6,17 Two new ATTR amyloidosis treatments are RNA interference therapies, which prevent TTR messenger RNA translation, and tafamidis, which stabilizes the TTR tetramer and prevents dissociation into its constituent monomers that precipitate in tissues.¹⁸ Both therapies can improve neuropathy-related quality of life.¹⁸ Tafamidis slows disease progression and decreases all-cause mortality in patients with hereditary and wild-type ATTR cardiac amyloidosis.¹⁹

Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical features.⁶ Multiple myeloma is characterized by marked expansion of a clonal plasma cell population within the bone marrow that aberrantly produces immunoglobulin. Conversely, the clonal plasma cell population responsible for producing the insoluble monoclonal light chain protein in AL amyloidosis typically constitutes less than 10% of the bone marrow.²⁰ Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis, which portends a poor outcome.²⁰

Amyloidosis is a rare group of diseases that arises when misfolded proteins aggregate in vital organs. The typical manifestations—congestive heart failure, neuropathy, chronic kidney disease, bleeding—are nearly always explained by more common conditions. Characteristic manifestations (like macroglossia) or associated diseases (like multiple myeloma) substantially increases the probability of AL amyloidosis. In a multisystem illness, the most common diseases must be excluded first, but this case reminds us that rare diseases, like amyloidosis, also warrant consideration as the story unfolds.

• Different amyloid proteins precipitate in different anatomic sites, which leads to specific multiorgan combinations. The most common amyloidosis, ATTR, tends to manifest as heart failure and peripheral sensory neuropathy, while the constellation of AL amyloidosis includes heart failure, neuropathy, and proteinuria.
• Bleeding occurs in 30% of patients with AL amyloidosis. It is precipitated by fragile small blood vessels and exacerbated by acquired coagulopathy from adsorption of coagulation factors.
• Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical tempos and presentations. Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis.

The authors thank Benjamin A Derman, MD, of the University of Chicago, Chicago, Illinois, for critical review of the manuscript.

A 78-year-old woman presented to the ambulatory care clinic for a painful tongue mass. She noticed the mass 2 months prior to presentation, and it had not grown in the interim. She had left-sided jaw pain when opening her mouth and persistent left-sided otalgia.

In the evaluation of tongue masses, ulcerations, or other surface abnormalities, exclusion of squamous cell carcinoma is the top priority. Additional tongue surface abnormalities include benign lesions such as geographic tongue, inflammatory conditions such as lichen planus, and infections such as syphilis.

The ear and jaw pain may reflect metastatic spread, neural invasion, or referred pain from the tongue. A vasculitis with predilection for the head, such as giant cell arteritis, could present with oral and ear pain. Jaw pain with mastication could reflect jaw claudication, but pain upon mouth opening is more commonly explained by temporomandibular joint dysfunction.

The patient had hypertension, hyperlipidemia, chronic kidney disease (estimated glomerular filtration rate of 42 mL/min), and diabetes mellitus. Four months prior she was diagnosed with a chronic obstructing left renal calculus on ultrasonography to evaluate chronic kidney disease. Two months prior heart failure with preserved ejection fraction was diagnosed. Stress cardiac magnetic resonance imaging (MRI) demonstrated normal ejection fraction, asymmetric septal hypertrophy, and stress-induced subendocardial perfusion defect. Her medications were metoprolol, lisinopril, simvastatin, meloxicam, and aspirin. She never used tobacco and did not consume alcohol. She was born in the Philippines and emigrated to the United States 15 years ago. She had not experienced fever, chills, hearing loss, tinnitus, cough, dysphonia, neck swelling, or joint pain. She had lost 3 kg in the previous 4 months.

The absence of tobacco and alcohol use reduces the probability of a squamous cell carcinoma, although human papillomavirus–associated squamous cell carcinoma of the tongue remains possible. Asymmetric septal hypertrophy is characteristic of hypertrophic cardiomyopathy or an infiltrative cardiomyopathy. Sarcoidosis can affect the heart and can account for the renal calculus (via hypercalcemia). Amyloid light-chain (AL) amyloidosis could involve the heart and the tongue, although in amyloidosis the cardiac MRI typically displays late gadolinium enhancement and ventricular wall thickening. The absence of tinnitus or hearing loss suggests that the left-sided otalgia is referred pain from the tongue and oral cavity rather than a primary otologic disease (eg, infection).

On physical examination, temperature was 37.2 °C, heart rate was 88 beats per minute, blood pressure was 134/62 mm Hg, and oxygen saturation was 99% while breathing ambient air. The patient’s weight was 40.4 kg (body mass index of 19.26 kg/m²). Intraoral examination revealed induration of the bilateral tongue, an erosive 1-cm pedunculated mass of the left dorsum, rough white coating on the right dorsum, and fullness of the right lateral surface with an erosion abutting tooth #2. The right submandibular salivary gland was firm. The otoscopic examination and remainder of the head and neck examination were normal. There was no cervical, supraclavicular, or axillary adenopathy. The cranial nerve, cardiovascular, pulmonary, abdominal, and skin examinations were normal.

The left-sided lingual mass and right-sided lingual erosion likely arise from the same process. Both are compatible with an infection (eg, syphilis or tuberculosis), cancer, autoimmune disease (eg, Crohn’s disease or sarcoidosis), or an infiltrative disease such as amyloidosis. Leukoplakia could reflect a candidal infection, dysplasia, squamous cell carcinoma, oral hairy leukoplakia, or hyperkeratosis. The isolated submandibular salivary gland could reflect sialadenitis from chronic salivary duct obstruction or a primary neoplasm, but more likely is caused by the same process causing the tongue abnormalities.

The white blood cell count was 8,600/μL; hemoglobin, 11.5 g/dL; mean corpuscular volume, 102.5 fL; and platelet count, 270,000/μL³. Serum sodium was 141 mEq/L; potassium, 4.1 mEq/L; chloride, 101 mEq/L; bicarbonate, 30 mEq/L; blood urea nitrogen, 19 mg/dL; creatinine, 0.7 mg/dL; and calcium, 10.4 mg/dL (reference range, 8.5-10.3). Total serum protein was 7.3 g/dL (reference range, 6.0-8.3); albumin was 3.7 g/dL. Liver biochemistry test results were normal. Serum folate and vitamin B₁₂ levels were normal. Serum ferritin was 423 ng/mL (reference range, 11-306); transferrin saturation, 21.4% (reference range, 15.0%-50.0%); and total iron-binding capacity, 323 µg/dL (reference range, 261-478). Parathyroid hormone (PTH) was 14 pg/mL (reference range, 15-65). HIV antibody was negative.

The calcium level is at the upper range of normal, whereas the PTH level is at the lower range of normal. The differential diagnosis for PTH-independent hypercalcemia includes hypercalcemia of malignancy and granulomatous disease such as sarcoidosis. Mild hypercalcemia could contribute to the nephrolithiasis. The iron studies exclude iron deficiency and are not suggestive of anemia of chronic disease. The triad of mild hypercalcemia, cardiomyopathy, and anemia is compatible with AL amyloidosis (perhaps with associated multiple myeloma) or sarcoidosis; both disorders can present as a mass. Imaging of the head and neck and biopsy of the tongue mass are the next steps.

The left dorsal tongue mass was excised in clinic. Histopathology revealed ulcerated squamous mucosa with inflammatory changes but no malignancy. Imaging of the head and neck was scheduled.

Neither cancer or granulomas were detected, but inadequate sampling or staining must be considered. Inflammatory changes are compatible with infection, autoimmunity, and cancer; the latter can feature reactive changes that obscure the malignant cells. The absence of granulomas lowers, but does not eliminate, the possibility of sarcoidosis, tuberculosis, fungal infection, and granulomatosis with polyangiitis. Actinomycosis is an invasive orofacial infection that disregards anatomic boundaries and is characterized by inflammatory histology; although infection of the tongue is possible, infection of the jaw and face is more typical. Immunoglobulin G4–related disease can present as an inflammatory and invasive disorder; however, the characteristic histopathologic findings (lymphoplasmacytic infiltrate, fibrosis, and phlebitis) are absent.

Culture of the tissue for mycobacteria or fungi (she is at increased risk for both given her previous residency in the Philippines) could increase the diagnostic yield. Another biopsy of the tongue or an adjacent structure—guided by imaging—may provide a more diagnostic tissue sample.

MRI of the head and neck demonstrated hyperintense signal and prominence of the right lateral pterygoid muscle (Figure 1A) and slight enlargement of a right submandibular gland (Figure 1B). No tongue abnormalities were identified. Radiograph of the chest did not reveal infiltrates, masses, or lymphadenopathy.

The absence of the tongue mass on the MRI likely reflects excision of the mass at the time of biopsy. The signal enhancement in the right lateral pterygoid muscle and submandibular gland is suggestive of an infiltrative process. Infiltration of the right lateral pterygoid muscle may also explain the patient’s pain when opening her mouth. Infiltrative processes can be neoplastic (eg, salivary gland tumor, sarcoma, lymphoma), infectious (eg, mycobacterial or fungal), cellular (eg, histiocytes, mast cells, plasma cells, eosinophils, granulomas), or related to inert substances such as amyloid or iron.

Seven weeks later, the patient presented to the hospital for scheduled percutaneous nephrolithotomy of the obstructing renal calculus. The physical examination was unchanged. The complete blood count and metabolic panel were unchanged apart from hemoglobin of 9.9 g/dL and calcium of 11.5 mg/dL. Coagulation studies were within normal limits.

A percutaneous nephroureteral stent was placed under conscious sedation. The patient then underwent rapid sequence induction of general anesthesia for the nephrolithotomy with fentanyl, propofol, and rocuronium. Within minutes of initiating mechanical ventilation, severe periorbital and perioral edema, copious oral cavity bleeding, and bilateral periorbital purpura occurred. Sugammadex (neuromuscular blockade reversal) and dexamethasone were administered. Examination of the oral cavity was limited by the brisk bleeding; the right sided tongue erosion was unchanged.

Bleeding is caused by thrombocytopenia, thrombocytopathy, coagulopathy, or disruption of vessel integrity. Oral cavity bleeding could arise from the tongue ulceration, but could also reflect pulmonary, nasal, or gastrointestinal hemorrhage. Angioedema arises from mast cell– or bradykinin-mediated pathways; mast cell degranulation may have been precipitated by the anesthetic agents, opiate, or a material in the nephroureteral stent.

The edema and bleeding are temporally related to multiple medications and mechanical ventilation. A latent bleeding diathesis may have manifested in the setting of increased tissue hydrostatic pressure or vessel permeability. Amyloidosis can lead to vessel fragility and coagulopathy, and periorbital bleeding is characteristic of AL amyloidosis.

The hypercalcemia, now more pronounced, raises concern for malignancy (including multiple myeloma) and granulomatous diseases like sarcoidosis, mycobacterial infections, and fungal infections. The declining hemoglobin could be explained by chronic blood loss, hemolysis, anemia of chronic disease, or a bone marrow process.

The cardiomyopathy, bleeding disorder, and multifocal disease in the oral cavity can be explained by AL amyloidosis; the hypercalcemia suggests concomitant multiple myeloma.

At the time of the bleeding event, the partial thromboplastin time, prothrombin time, and fibrinogen were within the reference ranges. Factor X activity level was normal. No schistocytes were observed on peripheral blood smear. Immunoglobulin G level was 1,425 mg/dL (reference range, 639-1,349); IgA and IgM levels were within the reference range. Serum lambda free light chains were 151.78 mg/dL (reference range, 0.46-2.71), and the ratio of kappa to lambda light chains was 0.01 (reference range, 0.49-2.54). Serum protein electrophoresis and immunofixation demonstrated a monoclonal paraprotein (IgG lambda) level of 1.2 g/dL. Congo red staining of the previously excised left dorsal tongue mass was negative for apple-green birefringence. Reexamination of the oral cavity revealed macroglossia and scalloping of the tongue (Figure 2).

Scalloping is characteristic of an infiltrative disorder that enlarges the tongue (macroglossia) and deforms its edges, which encounter the teeth. Macroglossia is seen in AL amyloidosis, acromegaly, and hypothyroidism. A monoclonal light chain, especially a lambda light chain, is characteristic of AL amyloidosis. The Congo red stain results can support the diagnosis when positive, but it has limited sensitivity. The tongue specimen can be sent for immunohistochemistry or mass spectrometry to evaluate for light chain deposition. A bone marrow biopsy can demonstrate a clonal plasma cell population. AL amyloidosis with concomitant multiple myeloma is the most likely diagnosis.

Bone marrow aspiration and core biopsy demonstrated 30% lambda-restricted plasma cells (Figure 3A-C). Congo red staining demonstrated apple-green birefringence of the bone marrow microvasculature (Figure 3D). Skeletal survey demonstrated widespread lytic bone disease involving the calvarium (Figure 4A), left humerus (Figure 4B), and left scapula (Figure 4B). Based on the monoclonal paraprotein, more than 10% monoclonal plasma cells, skeletal lesions, and hypercalcemia, she was diagnosed with IgG lambda multiple myeloma. Based on apple-green birefringence in the bone marrow and macroglossia, she was diagnosed with AL amyloidosis. The cardiac MRI findings were compatible with AL amyloidosis. ¹

After three cycles of bortezomib and dexamethasone therapy to concurrently treat AL amyloidosis and multiple myeloma, the serum lambda light chain level decreased to 1.49 mg/dL and the monoclonal paraprotein level decreased to 0.3 g/dL. The calcium level was 9.8 mg/dL, and the hemoglobin level was 11.7 g/dL. The patient’s tongue pain resolved, allowing for improved oral intake and a 5.7-kg weight gain. The patient underwent nephrolithotomy 4 months after her initial presentation. She resumed an active lifestyle and recently traveled to visit relatives in the Philippines.

Oral diseases affect general health and quality of life and can be a harbinger of systemic disease. Tooth loss, caries, periodontal disease, and poorly fitting dentures commonly affect speech and nutrition.² These common outpatient oral health issues can be the driving force for hospital admissions; for example, caries and periodontal disease can lead to suppurative odontogenic infection, endocarditis, brain abscess, and sepsis.

Tongue ulcerations, masses, and surface abnormalities often require consultation with a dentist or oral and maxillofacial surgeon to exclude squamous cell carcinoma.³ Other diagnostic considerations include benign neoplasms, trauma, inflammatory conditions (eg, sarcoidosis), infection (eg, syphilis, tuberculosis), and infiltrative processes such as amyloidosis.

Amyloidosis is a heterogeneous group of diseases caused by deposition of insoluble protein fibrils in tissues.^4,5 The three most encountered forms of amyloidosis are AL, AA, and ATTR. Each form is named after the culprit protein.⁴ AL amyloidosis arises when a small clonal population of plasma cells in the bone marrow overproduces immunoglobulin light chain monomers.^4,6 AA amyloidosis develops when the liver produces serum amyloid A protein (an acute phase reactant) in response to a chronic inflammatory condition such as rheumatoid arthritis or chronic intravenous drug injection.⁴ Transthyretin (TTR, also known as “prealbumin”) is a tetrameric protein that transports thyroxine and retinol; there are two forms of ATTR amyloidosis: hereditary and wild type. Hereditary ATTR amyloidosis develops from agglomeration of misfolded TTR monomers caused by mutations in the TTR gene. Wild-type ATTR amyloidosis is caused by age-related dissociation of the TTR tetramer into its constituent monomers that denature, misfold, and agglomerate into fibrils.⁵ Wild-type ATTR is now recognized as the most common form of amyloidosis, with 25% of myocardial autopsy specimens of patients 80 years or older demonstrating amyloid.⁷ The estimated incidence of AL amyloidosis is 10 cases per million person-years.⁸

Each amyloid protein homes in on specific anatomic sites.⁴ Characteristic combinations of organ dysfunction can suggest different forms of amyloidosis.⁹ Cardiac and peripheral nervous involvement (eg, carpal tunnel syndrome) is typical of both hereditary and wild-type ATTR amyloidosis; ATTR amyloidosis does not involve the kidney.⁴ AA amyloidosis most commonly manifests with proteinuria followed by declining glomerular filtration rate; heart failure is rare.⁴ The most common findings in AL amyloidosis are proteinuria, congestive heart failure, and sensory neuropathy.⁶ Gastrointestinal tract and hepatic involvement are each seen in nearly 20% of patients, and macroglossia is identified in approximately 10% of those with AL amyloidosis.^6,10

Chronic deposition of amyloid can lead to acute presentations. Approximately 30% of patients with AL amyloidosis develop abnormal bleeding.¹¹ Amyloid deposition in small blood vessels predisposes them to rupture. Bleeding events can be exacerbated by acquired coagulopathy due to plasma cell dyscrasia−associated thrombocytopenia, amyloid fibril adsorption of factor X, or hypofibrinogenemia.^11,12 Periorbital purpura following minor trauma or transient venous hypertension is characteristic of AL amyloidosis.^6,13 In this case, positive pressure ventilation and recumbent positioning increased hydrostatic pressure in the head and neck, causing rupture of the infiltrated small vessels around the eyes and in the oral cavity.¹⁴

Histological demonstration of tissue deposition of amyloid protein is the preferred method for amyloidosis diagnosis. Symptomatic sites or organs with dysfunction or radiologic changes are suitable for biopsy.⁶ If those sites are inaccessible or yield insufficient tissue quantity, abdominal fat pad aspiration or biopsy is indicated.¹⁵ Apple-green birefringence under polarized light of Congo red–stained tissue is characteristic, with sensitivity and specificity of approximately 80% and a positive predictive value of 85%.¹⁵ Immunoelectron microscopy is often performed simultaneously to confirm the diagnosis and determine the amyloid protein type.^4,16 Immunoelectron microscopy’s sensitivity is approximately 80%, and it has specificity and positive predictive value both approaching 100%.¹⁵ Mass spectrometry is particularly useful in cases where the amyloid subtype is not clinically apparent (eg, a patient with an autoimmune condition or chronic infection as well as light chain abnormality).⁶ Cardiac MRI findings that suggest amyloidosis include a thickened left ventricle and late gadolinium enhancement.¹ ATTR cardiac amyloidosis can be diagnosed using amyloid fibril–binding radiotracer technetium-99m-pyrophosphate scintigraphy; biopsy is often not necessary.^1,4 Gene sequencing to differentiate between hereditary and wild-type forms of ATTR amyloidosis is beneficial.

The primary objectives of amyloidosis management are to control symptoms and inhibit amyloid protein production.⁶ Outcomes in AL amyloidosis have improved due to early diagnosis, new chemotherapeutic agents to eradicate the plasma cell clone, and autologous stem cell transplantation.^6,17 Two new ATTR amyloidosis treatments are RNA interference therapies, which prevent TTR messenger RNA translation, and tafamidis, which stabilizes the TTR tetramer and prevents dissociation into its constituent monomers that precipitate in tissues.¹⁸ Both therapies can improve neuropathy-related quality of life.¹⁸ Tafamidis slows disease progression and decreases all-cause mortality in patients with hereditary and wild-type ATTR cardiac amyloidosis.¹⁹

Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical features.⁶ Multiple myeloma is characterized by marked expansion of a clonal plasma cell population within the bone marrow that aberrantly produces immunoglobulin. Conversely, the clonal plasma cell population responsible for producing the insoluble monoclonal light chain protein in AL amyloidosis typically constitutes less than 10% of the bone marrow.²⁰ Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis, which portends a poor outcome.²⁰

Amyloidosis is a rare group of diseases that arises when misfolded proteins aggregate in vital organs. The typical manifestations—congestive heart failure, neuropathy, chronic kidney disease, bleeding—are nearly always explained by more common conditions. Characteristic manifestations (like macroglossia) or associated diseases (like multiple myeloma) substantially increases the probability of AL amyloidosis. In a multisystem illness, the most common diseases must be excluded first, but this case reminds us that rare diseases, like amyloidosis, also warrant consideration as the story unfolds.

• Different amyloid proteins precipitate in different anatomic sites, which leads to specific multiorgan combinations. The most common amyloidosis, ATTR, tends to manifest as heart failure and peripheral sensory neuropathy, while the constellation of AL amyloidosis includes heart failure, neuropathy, and proteinuria.
• Bleeding occurs in 30% of patients with AL amyloidosis. It is precipitated by fragile small blood vessels and exacerbated by acquired coagulopathy from adsorption of coagulation factors.
• Multiple myeloma and AL amyloidosis are both plasma cell dyscrasias involving the bone marrow, but they represent distinct disease processes with different clinical tempos and presentations. Multiple myeloma and AL amyloidosis may coexist in the same patient; nearly 15% of patients with multiple myeloma subsequently develop clinically overt AL amyloidosis.

The authors thank Benjamin A Derman, MD, of the University of Chicago, Chicago, Illinois, for critical review of the manuscript.

Since its inception in the mid-1990s, the hospitalist model of care has enjoyed robust growth in the United States, increasing to around 20,000 providers by the end of its first decade.^1,2 Since then, it has far outstripped early predictions of adoption, currently standing at more than 50,000 hospitalist providers.² Although driven by numerous factors, including system-based management needs, provision of inpatient care for unassigned patients, and demands for improved patient safety and satisfaction, this meteoric growth has been driven largely by cost pressures particular to the US healthcare system.^1,2 Nonetheless, the growing complexity of healthcare systems, substantial fiscal pressures, and increasing healthcare demands from aging populations are worldwide challenges to which countries outside North America also seek solutions. Countries that have initiated hospitalist care have localized adoption, evolving the model to meet their unique fiscal and system-based needs and patients’ expectations.

While there has been keen interest in the hospitalist model in Asia, there has not yet been widespread adoption, despite numerous data demonstrating that this model is associated with lower length of stay (LOS), as well as lower costs and improved patient safety.^3,4 This article explores hospitalist care adoption experiences in Singapore, Taiwan, Korea, and Japan, focusing on stakeholder demand for hospitalist care, respective adoption, outcomes, and associated challenges to date.

Stakeholder Demand for Hospitalist Care

Historically in Singapore, family physicians provided primary care and internal medicine subspecialists provided inpatient care.⁵ Present-day trends, including an aging population, increasing rates of chronic diseases, and multisystem health issues, have stressed the historical model, leading to care fragmentation, long LOS (>9 days), and reduced patient satisfaction.^5,6 Additionally, as 80% of hospital care is government funded, public hospitals are under pressure to reduce healthcare expenditures.⁵

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet patient needs and healthcare system challenges, the hospitalist model has evolved through several iterations in Singapore. The first model, implemented at Singapore General Hospital, utilized family physicians as hospitalists to coordinate inpatient care and integrate care between hospital and community settings.^3,5 This model resulted in shorter LOS and reduced costs for patients cared for by family physician hospitalists.³ Despite these benefits, the family physician hospitalist model did not spread, partly due to biases favoring subspecialist care for hospitalized patients.⁷

The next iteration utilized general internal medicine (GIM) specialists. Traditionally, GIM specialists cared for a small number of low-acuity hospitalized patients. Recognizing the emerging need for holistic inpatient care, the Singapore Ministry of Health supported advances in generalist care, including a financial bonus and a revamped GIM training program. This spawned hospitalist-type models nationwide. At the National University Hospital (NUH), for example, GIM physicians were recruited to care for “specialty” patients in the acute medical unit and increase their ward coverage to include complex multimorbid patients. Additionally, NUH launched the enhanced complex care program, providing integrated inpatient and outpatient care to high-utilizing, complex patients. Overall, the NUH GIM division grew by 70% (faculty) and 60% (trainees) over 5 years. Currently, fueled by government enthusiasm for generalist care, hospitalist-type models are evident at newly minted hospitals across Singapore.

Although physicians act as hospitalists, the term hospitalist is not embraced in Singapore, thus limiting its potential to develop clinical- and system-improvement competencies and establish professional identity. This may be due to the strong UK-based cultural foundations and continued systemic bias favoring subspecialists.⁸

Stakeholder Demand for Hospitalist Care

Under its national health insurance (NHI) system, Taiwan has relatively low copayments for medical services, with acute patients paying 10% of costs for a ≤30-day hospitalization, causing demand for inpatient care to remain strong.^4,9 The NHI system has also led to increased numbers of patients accessing care in emergency departments (EDs), where costs may be as low as US $16 (NT $450), causing long waits for evaluation and transfer to wards.^9,10 There remains an insufficient number of hospital-based physicians to manage this high patient volume, a situation exacerbated by low reimbursements.⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

In order to address rising admissions, inefficient ED management, and physician shortages, a hospitalist care program was first introduced in Taiwan in 2002, followed by the establishment of a hospitalist-run ward in National Taiwan University Hospital in 2009.¹¹ Subsequent studies from Taiwan have found that hospitalist-run wards had lower admission costs, shorter LOS, and more do-not-resuscitate consent, and also had similar in-hospital mortality and readmission rates compared to specialist-run wards.^4,12 Reflecting these successes, the Taiwan Association of Hospital Medicine (TAHM) was established in 2018, and since January 2021, the Ministry of Health and Welfare of Taiwan has mandated hospital medicine programs as an accreditation requirement for all medical centers, with a dual role of educating residents and providing inpatient care.

Despite growing opportunities, Taiwan has seen a modest increase in the number of hospitalists, rising from three in 2009 to around 300 by January 2021. An indistinct professional identity and career path are the main barriers. Given this, TAHM is trying to strengthen hospitalist professionalism by introducing both hard and soft skills, such as utilizing point-of-care ultrasonography and implementing the concepts of Choosing Wisely^® and shared decision-making.

Stakeholder Demand for Hospitalist Care

Korea has experienced a chronic physician shortage, with just 2.4 physicians per 1,000 people (World Bank, 2017), leading to significant physician burnout. Designed to protect trainee well-being, the 2015 Improvement of Training Conditions and Status of Medical Residents Act limited resident work hours while reducing internal medicine and general surgery training periods, further exacerbating physician shortages.¹³ In addition, Korea’s current NHI system—including its’ healthcare insurance reimbursements scheme, established in 1989 when Korea’s per capita gross domestic product was less than US $5,000—provides low reimbursements to healthcare providers.¹⁴ Along with increased attention to patient safety and healthcare-related consumer expectations, the hospitalist system in Korea aims to maintain improvements to residents’ well-being, while increasing hospital revenue and meeting patient demand for improved services.¹⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

Along with the Ministry of Health and Welfare, the Korean Health Insurance Review and Assessment Service launched a hospitalist pilot program in general medicine and surgery in 2016.¹⁵ Services for hospitalist-managed inpatients are charged on a new schedule covered by the NHI system, including facility fees, which are charged per diem, and separate hospitalist fees.¹⁴ New hospital medicine programs are utilized, in part, to recruit new physicians to manage a large volume of inpatients. Previous studies found that these new hospitalist care systems also improved patient safety, quality of care, and overall patient satisfaction, while being associated with shorter LOS and fewer unnecessary intensive care unit admissions.^16,17 After a successful pilot, the revamped reimbursement system for hospitalist care officially started in January 2021.

Although Korea had only 250 registered hospitalists by August 2020, this is likely a substantial underestimate, as only hospital medicine teams with more than two hospitalists were allowed formal registration during the pilot period. Wider registration is currently underway for the new official reimbursement system.

Stakeholder Demand for Hospitalist Care

Hospitals in Japan are organized into highly compartmentalized subspecialties. Providing quality inpatient care to senior patients, who account for more than 28% of the population, and managing smooth transitions from hospital to long-term- care facilities remain challenging. In addition, given generous caps on maximum monthly out-of-pocket payments under its NHI system, LOS for Japanese hospitals are as long as 16.1 days.¹⁸ Nonetheless, given rising financial burdens associated with long-term care, hospitals are under government pressure to further shorten LOS and transition patients to local long-term-care facilities after treatment for acute symptoms.

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet these challenges, an increasing number of Japanese hospitals have established departments of general medicine to triage and manage patients with multiple comorbidities and to coordinate patient care across relevant specialties. The Japanese Society of Hospital General Medicine (JSHGM) was established in 2010, and currently has 1,890 members from 896 medical institutions. In 2018, general medicine was recognized by the Japanese Board of Medical Specialties as a formal specialty for certification. Currently, JSHGM is working with the Japan Primary Care Association and other organizations to establish a specialty certification system for hospitalist physicians and raise awareness of hospital medicine. A Japanese study of elderly patients with chronic aspiration pneumonia found that care by hospitalists resulted in shorter LOS and lower costs than specialist care.¹⁹ Recently, hospitalists have played a central role in COVID-19 management, opening fever intake clinics and establishing collaborative guidelines with infectious disease experts and other specialists.

Yet, different from the prototypical hospitalist first defined by Wachter and Goldman, Japanese general medicine hospitalists continue to have substantial outpatient responsibilities, albeit in the hospital setting. Out of 81 university hospitals, 69 now have a department of hospital general medicine, though only 20 have inpatient services.²⁰ In addition, a medical culture in which patients continue to see their surgery attendings long after surgery remains strong. Clear definitions regarding hospitalists’ roles need to be established, while promoting changes toward inpatient care for both patients and subspecialists.

The four Asian countries reviewed here have all established universal access to healthcare, with Taiwan, Korea, and Japan having strong NHI systems and Singapore providing significant healthcare subsidies for those in need. Nonetheless, they also face similar challenges, including the growing complexity of healthcare systems, substantial fiscal pressures, increased healthcare demands caused by aging populations, and increased expectations regarding stakeholder well-being. As such, these countries share common driving forces that are propelling the adoption of hospitalist care models, such as lack of a sufficient physician workforce on inpatient wards; need for extra resources to shorten ED wait times prior to inpatient admission; need for providing quality care to multimorbid senior patients across highly segmented hospital departments and coordinating medical services between hospitals and outpatient care facilities; and government pressure on cutting costs, especially by shortening inpatient LOS. Some common barriers among these Asian countries include unclear definitions of hospitalists’ roles and degree of collaboration with subspecialty departments, and social and systemic biases favoring subspecialty care for inpatients.

The four Asian countries reviewed here have chosen to adopt the hospitalist model as a supplement to already established, specialty-driven inpatient care systems; as such, further comparative outcome studies focusing on cost, care quality, and patient safety and satisfaction are warranted to bolster professional hospitalist roles, further facilitate government/policy-level support for hospital care systems, and promote future training and certification systems appropriate to each country’s unique healthcare system and medical culture. Similarly, evidence-driven educational outreach programs are warranted to facilitate patient understanding of the role of hospitalists in their care.For countries interested in establishing hospital medicine programs, the adoption experiences in Singapore, Taiwan, Korea, and Japan provide valuable insights regarding how to establish hospitalist models to meet country-specific healthcare challenges while successfully functioning in the context of their unique medical-system frameworks.

Since its inception in the mid-1990s, the hospitalist model of care has enjoyed robust growth in the United States, increasing to around 20,000 providers by the end of its first decade.^1,2 Since then, it has far outstripped early predictions of adoption, currently standing at more than 50,000 hospitalist providers.² Although driven by numerous factors, including system-based management needs, provision of inpatient care for unassigned patients, and demands for improved patient safety and satisfaction, this meteoric growth has been driven largely by cost pressures particular to the US healthcare system.^1,2 Nonetheless, the growing complexity of healthcare systems, substantial fiscal pressures, and increasing healthcare demands from aging populations are worldwide challenges to which countries outside North America also seek solutions. Countries that have initiated hospitalist care have localized adoption, evolving the model to meet their unique fiscal and system-based needs and patients’ expectations.

While there has been keen interest in the hospitalist model in Asia, there has not yet been widespread adoption, despite numerous data demonstrating that this model is associated with lower length of stay (LOS), as well as lower costs and improved patient safety.^3,4 This article explores hospitalist care adoption experiences in Singapore, Taiwan, Korea, and Japan, focusing on stakeholder demand for hospitalist care, respective adoption, outcomes, and associated challenges to date.

Stakeholder Demand for Hospitalist Care

Historically in Singapore, family physicians provided primary care and internal medicine subspecialists provided inpatient care.⁵ Present-day trends, including an aging population, increasing rates of chronic diseases, and multisystem health issues, have stressed the historical model, leading to care fragmentation, long LOS (>9 days), and reduced patient satisfaction.^5,6 Additionally, as 80% of hospital care is government funded, public hospitals are under pressure to reduce healthcare expenditures.⁵

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet patient needs and healthcare system challenges, the hospitalist model has evolved through several iterations in Singapore. The first model, implemented at Singapore General Hospital, utilized family physicians as hospitalists to coordinate inpatient care and integrate care between hospital and community settings.^3,5 This model resulted in shorter LOS and reduced costs for patients cared for by family physician hospitalists.³ Despite these benefits, the family physician hospitalist model did not spread, partly due to biases favoring subspecialist care for hospitalized patients.⁷

The next iteration utilized general internal medicine (GIM) specialists. Traditionally, GIM specialists cared for a small number of low-acuity hospitalized patients. Recognizing the emerging need for holistic inpatient care, the Singapore Ministry of Health supported advances in generalist care, including a financial bonus and a revamped GIM training program. This spawned hospitalist-type models nationwide. At the National University Hospital (NUH), for example, GIM physicians were recruited to care for “specialty” patients in the acute medical unit and increase their ward coverage to include complex multimorbid patients. Additionally, NUH launched the enhanced complex care program, providing integrated inpatient and outpatient care to high-utilizing, complex patients. Overall, the NUH GIM division grew by 70% (faculty) and 60% (trainees) over 5 years. Currently, fueled by government enthusiasm for generalist care, hospitalist-type models are evident at newly minted hospitals across Singapore.

Although physicians act as hospitalists, the term hospitalist is not embraced in Singapore, thus limiting its potential to develop clinical- and system-improvement competencies and establish professional identity. This may be due to the strong UK-based cultural foundations and continued systemic bias favoring subspecialists.⁸

Stakeholder Demand for Hospitalist Care

Under its national health insurance (NHI) system, Taiwan has relatively low copayments for medical services, with acute patients paying 10% of costs for a ≤30-day hospitalization, causing demand for inpatient care to remain strong.^4,9 The NHI system has also led to increased numbers of patients accessing care in emergency departments (EDs), where costs may be as low as US $16 (NT $450), causing long waits for evaluation and transfer to wards.^9,10 There remains an insufficient number of hospital-based physicians to manage this high patient volume, a situation exacerbated by low reimbursements.⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

In order to address rising admissions, inefficient ED management, and physician shortages, a hospitalist care program was first introduced in Taiwan in 2002, followed by the establishment of a hospitalist-run ward in National Taiwan University Hospital in 2009.¹¹ Subsequent studies from Taiwan have found that hospitalist-run wards had lower admission costs, shorter LOS, and more do-not-resuscitate consent, and also had similar in-hospital mortality and readmission rates compared to specialist-run wards.^4,12 Reflecting these successes, the Taiwan Association of Hospital Medicine (TAHM) was established in 2018, and since January 2021, the Ministry of Health and Welfare of Taiwan has mandated hospital medicine programs as an accreditation requirement for all medical centers, with a dual role of educating residents and providing inpatient care.

Despite growing opportunities, Taiwan has seen a modest increase in the number of hospitalists, rising from three in 2009 to around 300 by January 2021. An indistinct professional identity and career path are the main barriers. Given this, TAHM is trying to strengthen hospitalist professionalism by introducing both hard and soft skills, such as utilizing point-of-care ultrasonography and implementing the concepts of Choosing Wisely^® and shared decision-making.

Stakeholder Demand for Hospitalist Care

Korea has experienced a chronic physician shortage, with just 2.4 physicians per 1,000 people (World Bank, 2017), leading to significant physician burnout. Designed to protect trainee well-being, the 2015 Improvement of Training Conditions and Status of Medical Residents Act limited resident work hours while reducing internal medicine and general surgery training periods, further exacerbating physician shortages.¹³ In addition, Korea’s current NHI system—including its’ healthcare insurance reimbursements scheme, established in 1989 when Korea’s per capita gross domestic product was less than US $5,000—provides low reimbursements to healthcare providers.¹⁴ Along with increased attention to patient safety and healthcare-related consumer expectations, the hospitalist system in Korea aims to maintain improvements to residents’ well-being, while increasing hospital revenue and meeting patient demand for improved services.¹⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

Along with the Ministry of Health and Welfare, the Korean Health Insurance Review and Assessment Service launched a hospitalist pilot program in general medicine and surgery in 2016.¹⁵ Services for hospitalist-managed inpatients are charged on a new schedule covered by the NHI system, including facility fees, which are charged per diem, and separate hospitalist fees.¹⁴ New hospital medicine programs are utilized, in part, to recruit new physicians to manage a large volume of inpatients. Previous studies found that these new hospitalist care systems also improved patient safety, quality of care, and overall patient satisfaction, while being associated with shorter LOS and fewer unnecessary intensive care unit admissions.^16,17 After a successful pilot, the revamped reimbursement system for hospitalist care officially started in January 2021.

Although Korea had only 250 registered hospitalists by August 2020, this is likely a substantial underestimate, as only hospital medicine teams with more than two hospitalists were allowed formal registration during the pilot period. Wider registration is currently underway for the new official reimbursement system.

Stakeholder Demand for Hospitalist Care

Hospitals in Japan are organized into highly compartmentalized subspecialties. Providing quality inpatient care to senior patients, who account for more than 28% of the population, and managing smooth transitions from hospital to long-term- care facilities remain challenging. In addition, given generous caps on maximum monthly out-of-pocket payments under its NHI system, LOS for Japanese hospitals are as long as 16.1 days.¹⁸ Nonetheless, given rising financial burdens associated with long-term care, hospitals are under government pressure to further shorten LOS and transition patients to local long-term-care facilities after treatment for acute symptoms.

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet these challenges, an increasing number of Japanese hospitals have established departments of general medicine to triage and manage patients with multiple comorbidities and to coordinate patient care across relevant specialties. The Japanese Society of Hospital General Medicine (JSHGM) was established in 2010, and currently has 1,890 members from 896 medical institutions. In 2018, general medicine was recognized by the Japanese Board of Medical Specialties as a formal specialty for certification. Currently, JSHGM is working with the Japan Primary Care Association and other organizations to establish a specialty certification system for hospitalist physicians and raise awareness of hospital medicine. A Japanese study of elderly patients with chronic aspiration pneumonia found that care by hospitalists resulted in shorter LOS and lower costs than specialist care.¹⁹ Recently, hospitalists have played a central role in COVID-19 management, opening fever intake clinics and establishing collaborative guidelines with infectious disease experts and other specialists.

Yet, different from the prototypical hospitalist first defined by Wachter and Goldman, Japanese general medicine hospitalists continue to have substantial outpatient responsibilities, albeit in the hospital setting. Out of 81 university hospitals, 69 now have a department of hospital general medicine, though only 20 have inpatient services.²⁰ In addition, a medical culture in which patients continue to see their surgery attendings long after surgery remains strong. Clear definitions regarding hospitalists’ roles need to be established, while promoting changes toward inpatient care for both patients and subspecialists.

The four Asian countries reviewed here have all established universal access to healthcare, with Taiwan, Korea, and Japan having strong NHI systems and Singapore providing significant healthcare subsidies for those in need. Nonetheless, they also face similar challenges, including the growing complexity of healthcare systems, substantial fiscal pressures, increased healthcare demands caused by aging populations, and increased expectations regarding stakeholder well-being. As such, these countries share common driving forces that are propelling the adoption of hospitalist care models, such as lack of a sufficient physician workforce on inpatient wards; need for extra resources to shorten ED wait times prior to inpatient admission; need for providing quality care to multimorbid senior patients across highly segmented hospital departments and coordinating medical services between hospitals and outpatient care facilities; and government pressure on cutting costs, especially by shortening inpatient LOS. Some common barriers among these Asian countries include unclear definitions of hospitalists’ roles and degree of collaboration with subspecialty departments, and social and systemic biases favoring subspecialty care for inpatients.

The four Asian countries reviewed here have chosen to adopt the hospitalist model as a supplement to already established, specialty-driven inpatient care systems; as such, further comparative outcome studies focusing on cost, care quality, and patient safety and satisfaction are warranted to bolster professional hospitalist roles, further facilitate government/policy-level support for hospital care systems, and promote future training and certification systems appropriate to each country’s unique healthcare system and medical culture. Similarly, evidence-driven educational outreach programs are warranted to facilitate patient understanding of the role of hospitalists in their care.For countries interested in establishing hospital medicine programs, the adoption experiences in Singapore, Taiwan, Korea, and Japan provide valuable insights regarding how to establish hospitalist models to meet country-specific healthcare challenges while successfully functioning in the context of their unique medical-system frameworks.

Since its inception in the mid-1990s, the hospitalist model of care has enjoyed robust growth in the United States, increasing to around 20,000 providers by the end of its first decade.^1,2 Since then, it has far outstripped early predictions of adoption, currently standing at more than 50,000 hospitalist providers.² Although driven by numerous factors, including system-based management needs, provision of inpatient care for unassigned patients, and demands for improved patient safety and satisfaction, this meteoric growth has been driven largely by cost pressures particular to the US healthcare system.^1,2 Nonetheless, the growing complexity of healthcare systems, substantial fiscal pressures, and increasing healthcare demands from aging populations are worldwide challenges to which countries outside North America also seek solutions. Countries that have initiated hospitalist care have localized adoption, evolving the model to meet their unique fiscal and system-based needs and patients’ expectations.

While there has been keen interest in the hospitalist model in Asia, there has not yet been widespread adoption, despite numerous data demonstrating that this model is associated with lower length of stay (LOS), as well as lower costs and improved patient safety.^3,4 This article explores hospitalist care adoption experiences in Singapore, Taiwan, Korea, and Japan, focusing on stakeholder demand for hospitalist care, respective adoption, outcomes, and associated challenges to date.

Stakeholder Demand for Hospitalist Care

Historically in Singapore, family physicians provided primary care and internal medicine subspecialists provided inpatient care.⁵ Present-day trends, including an aging population, increasing rates of chronic diseases, and multisystem health issues, have stressed the historical model, leading to care fragmentation, long LOS (>9 days), and reduced patient satisfaction.^5,6 Additionally, as 80% of hospital care is government funded, public hospitals are under pressure to reduce healthcare expenditures.⁵

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet patient needs and healthcare system challenges, the hospitalist model has evolved through several iterations in Singapore. The first model, implemented at Singapore General Hospital, utilized family physicians as hospitalists to coordinate inpatient care and integrate care between hospital and community settings.^3,5 This model resulted in shorter LOS and reduced costs for patients cared for by family physician hospitalists.³ Despite these benefits, the family physician hospitalist model did not spread, partly due to biases favoring subspecialist care for hospitalized patients.⁷

The next iteration utilized general internal medicine (GIM) specialists. Traditionally, GIM specialists cared for a small number of low-acuity hospitalized patients. Recognizing the emerging need for holistic inpatient care, the Singapore Ministry of Health supported advances in generalist care, including a financial bonus and a revamped GIM training program. This spawned hospitalist-type models nationwide. At the National University Hospital (NUH), for example, GIM physicians were recruited to care for “specialty” patients in the acute medical unit and increase their ward coverage to include complex multimorbid patients. Additionally, NUH launched the enhanced complex care program, providing integrated inpatient and outpatient care to high-utilizing, complex patients. Overall, the NUH GIM division grew by 70% (faculty) and 60% (trainees) over 5 years. Currently, fueled by government enthusiasm for generalist care, hospitalist-type models are evident at newly minted hospitals across Singapore.

Although physicians act as hospitalists, the term hospitalist is not embraced in Singapore, thus limiting its potential to develop clinical- and system-improvement competencies and establish professional identity. This may be due to the strong UK-based cultural foundations and continued systemic bias favoring subspecialists.⁸

Stakeholder Demand for Hospitalist Care

Under its national health insurance (NHI) system, Taiwan has relatively low copayments for medical services, with acute patients paying 10% of costs for a ≤30-day hospitalization, causing demand for inpatient care to remain strong.^4,9 The NHI system has also led to increased numbers of patients accessing care in emergency departments (EDs), where costs may be as low as US $16 (NT $450), causing long waits for evaluation and transfer to wards.^9,10 There remains an insufficient number of hospital-based physicians to manage this high patient volume, a situation exacerbated by low reimbursements.⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

In order to address rising admissions, inefficient ED management, and physician shortages, a hospitalist care program was first introduced in Taiwan in 2002, followed by the establishment of a hospitalist-run ward in National Taiwan University Hospital in 2009.¹¹ Subsequent studies from Taiwan have found that hospitalist-run wards had lower admission costs, shorter LOS, and more do-not-resuscitate consent, and also had similar in-hospital mortality and readmission rates compared to specialist-run wards.^4,12 Reflecting these successes, the Taiwan Association of Hospital Medicine (TAHM) was established in 2018, and since January 2021, the Ministry of Health and Welfare of Taiwan has mandated hospital medicine programs as an accreditation requirement for all medical centers, with a dual role of educating residents and providing inpatient care.

Despite growing opportunities, Taiwan has seen a modest increase in the number of hospitalists, rising from three in 2009 to around 300 by January 2021. An indistinct professional identity and career path are the main barriers. Given this, TAHM is trying to strengthen hospitalist professionalism by introducing both hard and soft skills, such as utilizing point-of-care ultrasonography and implementing the concepts of Choosing Wisely^® and shared decision-making.

Stakeholder Demand for Hospitalist Care

Korea has experienced a chronic physician shortage, with just 2.4 physicians per 1,000 people (World Bank, 2017), leading to significant physician burnout. Designed to protect trainee well-being, the 2015 Improvement of Training Conditions and Status of Medical Residents Act limited resident work hours while reducing internal medicine and general surgery training periods, further exacerbating physician shortages.¹³ In addition, Korea’s current NHI system—including its’ healthcare insurance reimbursements scheme, established in 1989 when Korea’s per capita gross domestic product was less than US $5,000—provides low reimbursements to healthcare providers.¹⁴ Along with increased attention to patient safety and healthcare-related consumer expectations, the hospitalist system in Korea aims to maintain improvements to residents’ well-being, while increasing hospital revenue and meeting patient demand for improved services.¹⁴

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

Along with the Ministry of Health and Welfare, the Korean Health Insurance Review and Assessment Service launched a hospitalist pilot program in general medicine and surgery in 2016.¹⁵ Services for hospitalist-managed inpatients are charged on a new schedule covered by the NHI system, including facility fees, which are charged per diem, and separate hospitalist fees.¹⁴ New hospital medicine programs are utilized, in part, to recruit new physicians to manage a large volume of inpatients. Previous studies found that these new hospitalist care systems also improved patient safety, quality of care, and overall patient satisfaction, while being associated with shorter LOS and fewer unnecessary intensive care unit admissions.^16,17 After a successful pilot, the revamped reimbursement system for hospitalist care officially started in January 2021.

Although Korea had only 250 registered hospitalists by August 2020, this is likely a substantial underestimate, as only hospital medicine teams with more than two hospitalists were allowed formal registration during the pilot period. Wider registration is currently underway for the new official reimbursement system.

Stakeholder Demand for Hospitalist Care

Hospitals in Japan are organized into highly compartmentalized subspecialties. Providing quality inpatient care to senior patients, who account for more than 28% of the population, and managing smooth transitions from hospital to long-term- care facilities remain challenging. In addition, given generous caps on maximum monthly out-of-pocket payments under its NHI system, LOS for Japanese hospitals are as long as 16.1 days.¹⁸ Nonetheless, given rising financial burdens associated with long-term care, hospitals are under government pressure to further shorten LOS and transition patients to local long-term-care facilities after treatment for acute symptoms.

Adoption of Hospitalist Care, Outcomes, and Challenges Faced

To meet these challenges, an increasing number of Japanese hospitals have established departments of general medicine to triage and manage patients with multiple comorbidities and to coordinate patient care across relevant specialties. The Japanese Society of Hospital General Medicine (JSHGM) was established in 2010, and currently has 1,890 members from 896 medical institutions. In 2018, general medicine was recognized by the Japanese Board of Medical Specialties as a formal specialty for certification. Currently, JSHGM is working with the Japan Primary Care Association and other organizations to establish a specialty certification system for hospitalist physicians and raise awareness of hospital medicine. A Japanese study of elderly patients with chronic aspiration pneumonia found that care by hospitalists resulted in shorter LOS and lower costs than specialist care.¹⁹ Recently, hospitalists have played a central role in COVID-19 management, opening fever intake clinics and establishing collaborative guidelines with infectious disease experts and other specialists.

Yet, different from the prototypical hospitalist first defined by Wachter and Goldman, Japanese general medicine hospitalists continue to have substantial outpatient responsibilities, albeit in the hospital setting. Out of 81 university hospitals, 69 now have a department of hospital general medicine, though only 20 have inpatient services.²⁰ In addition, a medical culture in which patients continue to see their surgery attendings long after surgery remains strong. Clear definitions regarding hospitalists’ roles need to be established, while promoting changes toward inpatient care for both patients and subspecialists.

The four Asian countries reviewed here have all established universal access to healthcare, with Taiwan, Korea, and Japan having strong NHI systems and Singapore providing significant healthcare subsidies for those in need. Nonetheless, they also face similar challenges, including the growing complexity of healthcare systems, substantial fiscal pressures, increased healthcare demands caused by aging populations, and increased expectations regarding stakeholder well-being. As such, these countries share common driving forces that are propelling the adoption of hospitalist care models, such as lack of a sufficient physician workforce on inpatient wards; need for extra resources to shorten ED wait times prior to inpatient admission; need for providing quality care to multimorbid senior patients across highly segmented hospital departments and coordinating medical services between hospitals and outpatient care facilities; and government pressure on cutting costs, especially by shortening inpatient LOS. Some common barriers among these Asian countries include unclear definitions of hospitalists’ roles and degree of collaboration with subspecialty departments, and social and systemic biases favoring subspecialty care for inpatients.

The four Asian countries reviewed here have chosen to adopt the hospitalist model as a supplement to already established, specialty-driven inpatient care systems; as such, further comparative outcome studies focusing on cost, care quality, and patient safety and satisfaction are warranted to bolster professional hospitalist roles, further facilitate government/policy-level support for hospital care systems, and promote future training and certification systems appropriate to each country’s unique healthcare system and medical culture. Similarly, evidence-driven educational outreach programs are warranted to facilitate patient understanding of the role of hospitalists in their care.For countries interested in establishing hospital medicine programs, the adoption experiences in Singapore, Taiwan, Korea, and Japan provide valuable insights regarding how to establish hospitalist models to meet country-specific healthcare challenges while successfully functioning in the context of their unique medical-system frameworks.

The prospect of facing a medical malpractice claim is a source of apprehension for physicians that affects physician behavior, including leading to defensive medicine.^1-3 Overall, annual defensive medicine costs have been estimated at $45.6 billion,⁴ and surveys of hospitalists indicate that 13.0% to 37.5% of hospitalist healthcare costs involve defensive medicine.^5,6 Despite the impact of malpractice concerns on hospitalist practice and the unprecedented growth of the field of hospital medicine, relatively few studies have examined the liability environment surrounding hospitalist practice.^7,8 The specific issue of malpractice claims rates faced by hospitalists has received even less attention in the medical literature.⁸

A better understanding of the contributing factors and other attributes of malpractice claims can help guide patient safety initiatives and inform hospitalists’ level of concern regarding liability. Although most medical errors do not result in a malpractice claim,^9,10 the majority of malpractice claims in which there is an indemnity payment involve medical injury due to clinician error.¹¹ Even malpractice claims that do not result in an indemnity payment represent opportunities to identify patient safety and risk management vulnerabilities.¹²

We used a national malpractice claims database to analyze the characteristics of claims made against hospitalists, including claims rates. In addition to claims rates, we also analyzed the other types of providers named in hospitalist claims given the importance of interdisciplinary collaboration to hospital medicine.^13,14 To provide context for understanding hospitalist liability data, we present data on other specialties. We also describe a model to predict whether hospitalist malpractice claims will close with an indemnity payment.

Data Sources and Elements

This analysis used a repository of malpractice claims maintained by CRICO, the captive malpractice insurer of the Harvard-affiliated medical institutions. This database, the Comparative Benchmarking System, aggregates malpractice claims from multiple other malpractice carriers (both commercial and captive). This database comprises approximately 31% of all malpractice claims in the United States (both paid and unpaid) according to a comparison with claims in the National Practitioner Data Bank (NPDB), which is a government-run database to which all paid malpractice claims against physicians must be reported.¹⁵ To compile this national database, trained nurse coders, who have access to the medical records and legal documents from each case, abstract information into coded fields, such as the type of allegation, contributing factors, and injury severity. The information in these coded fields is based on a taxonomy that was developed specifically for use in malpractice cases. The nurse coders participate in regular meetings in which cases are discussed to ensure that they are applying the coding and taxonomy uniformly.

Injury severity was based on a widely used scale developed for malpractice claims by the National Association of Insurance Commissioners.¹⁶ Low injury severity included emotional injury and temporary insignificant injury. Medium injury severity included temporary minor, temporary major, and permanent minor injury. High injury severity included permanent significant injury through death. Because this study used a database assembled for operational and patient safety purposes and was not human subjects research, institutional review board approval was not needed.

Study Cohort

Malpractice claims included formal lawsuits or written requests for compensation for negligent medical care. Hospitalist malpractice claims were defined as those in which the nurse coders determined that the internal medicine hospitalist service was the clinical service that was primarily responsible for the care of the patient at the time of the clinical event giving rise to the claim. Malpractice claims closed during the period 2009-2018 were included, regardless of whether an indemnity payment was made. Claims against select other medical specialties (nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry), defined by the specialty of the physician named in the claim, were included for comparison with the characteristics of the claims against hospitalists. Physician specialty was available for all physicians in the study cohort; however, given that malpractice cases were aggregated from multiple different insurers, full demographic information (eg, age and sex) was not available for all physicians.

Statistical Analysis

Malpractice claims rates were treated as Poisson rates and compared using a Z-test. Malpractice claims rates are expressed as claims per 100 physician-years. Each physician-year represents 1 year of coverage of one physician by the medical malpractice carrier whose data were used. Physician-years represent the duration of time physicians practiced during which they were insured by the malpractice carrier and, as such, could have been subject to a malpractice claim that would have been included in our data. Claims rates are based on the subset of the malpractice claims in the study for which the number of physician-years of coverage is available, representing 8.2% of hospitalist claims and 11.6% of all claims.

Comparisons of the percentages of cases closing with an indemnity payment, as well as the percentages of cases in different allegation type and clinical severity categories, were made using the Fisher exact test. Indemnity payment amounts were inflation-adjusted to 2018 dollars using the Consumer Price Index. Comparisons of indemnity payment amounts between physician specialties were carried out using the Wilcoxon rank sum test given that the distribution of the payment amounts appeared nonnormal; this was confirmed with the Shapiro-Wilk test. A multivariable logistic regression model was developed to predict the binary outcome of whether a hospitalist case would close with an indemnity payment (compared with no payment), based on the 1,216 hospitalist claims. The predictors used in this regression model were chosen a priori based on hypotheses about what factors drive the likelihood that a case closes with payment. Both the unadjusted and adjusted odds ratios for the predictors are presented. The adjusted model is adjusted for all the other predictors contained in the model. All reported P values are two-sided. The statistical analysis was carried out using JMP Pro version 15 (SAS Institute Inc) and Minitab version 19 (Minitab LLC).

We identified 1,216 hospital medicine malpractice claims from our database. Claims rates were calculated from the subset of our data for which physician-years were available—including 5,140 physician-years encompassing 100 claims, representing 8.2% of all hospitalist claims studied. An additional 18,644 malpractice claims from five other specialties—nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry—were analyzed to provide context for the hospitalist claims.

The malpractice claims rate for hospitalists was significantly higher than the rate for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years; P < .001), though they were not significantly different from the rate for nonhospitalist general internal medicine physicians (1.95 vs 1.92 claims per 100 physician-years; P = .93) (Table 1). Compared with emergency medicine physicians, with whom hospitalists are sometimes compared due to both specialties being defined by their site of practice and the absence of longitudinal patient relationships, hospitalists had a significantly lower claims rate (1.95 vs 4.07 claims per 100 physician-years; P < .001).

An assessment of the temporal trends in the claims rates, based on a comparison between the two halves of the study period (2014-2018 vs 2009-2013), showed that the claims rate for hospitalists was increasing, but at a rate that did not reach statistical significance (Table 1). In contrast, the claims rates for the five other specialties assessed decreased over time, and the decreases were significant for four of these five other specialties (internal medicine subspecialties, emergency medicine, neurosurgery, and psychiatry).

Multiple claims against a single physician were uncommon in our hospitalist malpractice claims data. Among the 100 claims that were used to calculate the claims rates, one physician was named in 2 claims, and all the other physicians were named in only a single claim. Among all of the 1,216 hospitalist malpractice claims we analyzed, there were eight physicians who were named in more than 1 claim, seven of whom were named in 2 claims, and one of whom was named in 3 claims.

The median indemnity payment for hospitalist claims was $231,454 (interquartile range [IQR], $100,000-$503,015), similar to the median indemnity payment for neurosurgery ($233,723; IQR, $85,292-$697,872), though significantly greater than the median indemnity payment for the other four specialties studied (Table 2). Among the hospitalist claims, 29.9% resulted in an indemnity payment, not significantly different from the rate for nonhospitalist general internal medicine, internal medicine subspecialties, or neurosurgery, but significantly lower than the rate for emergency medicine (33.8%; P = .011). No significant temporal trend in the percentage of hospitalist claims that resulted in an indemnity payment was observed.

We performed a multivariable logistic regression analysis to assess the effect of different factors on the likelihood of a hospitalist case closing with an indemnity payment, compared with no payment (Table 3). In the multivariable model, the presence of an error in clinical judgment had an adjusted odds ratio (AOR) of 5.01 (95% CI, 3.37-7.45; P < .001) for a claim closing with payment, the largest effect found. The presence of problems with communication (AOR, 1.89; 95% CI, 1.42-2.51; P < .001), the clinical environment (eg, weekend/holiday or clinical busyness; AOR, 1.70; 95% CI, 1.20-2.40; P = .0026), and documentation (AOR, 1.65; 95% CI, 1.18-2.31; P = .0038) were also positive predictors of claims closing with payment. Greater patient age (per decade) was a negative predictor of the likelihood of a claim closing with payment (AOR, 0.92; 95% CI, 0.86-0.998), though it was of borderline statistical significance (P = .044).

We also assessed multiple clinical attributes of hospitalist malpractice claims, including the major allegation type and injury severity (Appendix Table). Among the 1,216 hospitalist malpractice claims studied, the most common allegation types were for errors related to medical treatment (n = 482; 39.6%), diagnosis (n = 446; 36.7%), and medications (n = 157; 12.9%). Among the hospitalist claims, 888 (73.0%) involved high-severity injury, and 674 (55.4%) involved the death of the patient. The percentages of cases involving high-severity injury and death were significantly greater for hospitalists, compared with that of the other specialties studied (P < .001 for all pairwise comparisons). Of the six specialties studied, hospital medicine was the only one in which the percentage of cases involving death exceeded 50%.

Hospital medicine is typically team-based, and we evaluated which other services were named in claims with hospital medicine as the primary responsible service. The clinician groups most commonly named in hospitalist claims were nursing (n = 269; 22.1%), followed by emergency medicine (n = 91; 7.5%), general surgery (n = 51; 4.2%), cardiology (n = 49; 4.0%), and orthopedic surgery (n = 46; 3.8%) (Appendix Figure). During the first 2 years of the study period, no physician assistants (PAs) or nurse practitioners (NPs) were named in hospitalist claims. Over the study period, the proportion of hospitalist cases also naming PAs and NPs increased steadily, reaching 6.9% and 6.2% of claims, respectively, in 2018 (Figure) (P < .001 for NPs and P = .037 for PAs based on a comparison between the two halves of the study period).

We found that the average annual claims rate for hospitalists was similar to that for nonhospitalist general internists (1.95 vs 1.92 claims per 100 physician-years) but significantly greater than that for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years). Hospitalist claims rates showed a notable temporal trend—a nonsignificant increase—over the study period (2009-2018). This contrasts with the five other specialties studied, all of which had decreasing claims rates, four of which were significant. An analysis of a different national malpractice claims database, the NPDB, found that the rate of paid malpractice claims overall decreased 55.7% during the period 1992-2014, again contrasting with the trend we found for hospitalist claims rates.¹⁷

We posit several explanations for why the malpractice claims rate trend for hospitalists has diverged from that of other specialties. There has been a large expansion in the number of hospitalists in the United States.¹⁸ With this increasing demand, many young physicians have entered the hospital medicine field. In a survey of general internal medicine physicians conducted by the Society of General Internal Medicine, 73% of hospitalists were aged 25 to 44 years, significantly greater than the 45% in this age range among nonhospitalist general internal medicine physicians.¹⁹ Hospitalists in their first year of practice have higher mortality rates than more experienced hospitalists.²⁰ Therefore, the relative inexperience of hospitalists, driven by this high demand, could be putting them at increased risk of medical errors and resulting malpractice claims. The higher mortality rate among hospitalists in their first year of practice could be due to a lack of familiarity with the systems of care, such as managing test results and obtaining appropriate consults.²⁰ This possibility suggests that enhanced training and mentorship could be valuable as a strategy to both improve the quality of care and reduce medicolegal risk. The increasing demand for hospitalists could also be affecting the qualification level of physicians entering the field.

Our analysis also showed that the severity of injury in hospitalist claims was greater than that for the other specialties studied. In addition, the percentage of claims involving death was greater for hospitalists than that for the other specialties. The increased acuity of inpatients, compared with that of outpatients—and the trend, at least for some conditions, of increased inpatient acuity over time^21,22— could account for the high injury severity seen among hospitalist claims. Given the positive correlation between injury severity and the size of indemnity payments made on malpractice claims,¹² the high injury severity seen in hospitalist claims was very likely a driver of the high indemnity payments observed among the hospitalist claims.

The relationship between injury severity and financial outcomes is supported by the results of our multivariable regression model (Table 3). Compared with medium-severity injury claims, both death and high-severity injury cases were significantly more likely to close with an indemnity payment (compared with no payment), with AORs of 1.79 (95% CI, 1.21-2.65) and 2.44 (95% CI, 1.54-3.87), respectively.

The most striking finding in our regression model was the magnitude of the effect of an error in clinical judgement. Cases coded with this contributing factor had five times the AOR of closing with payment (compared with no payment) (AOR, 5.01; 95% CI, 3.37-7.45). A clinical judgment call may be difficult to defend when it is ultimately associated with a bad patient outcome. The importance of clinical judgment in our analysis suggests a risk management strategy: clearly and contemporaneously documenting the rationale behind one’s clinical decision-making. This may help make a claim more defensible in the event of an adverse outcome by demonstrating that the clinician was acting reasonably based on the information available at the time. The importance of specifying a rationale for a clinical decision may be especially important in the era of electronic health records (EHRs). EHRs are not structured as chronologically linear charts, which can make it challenging during a trial to retrospectively show what information was available to the physician at the time the clinical decision was made. The importance of clinical judgment also affirms the importance of effective clinical decision support as a patient safety tool.²³

More broadly, it is notable that several contributing factors, including errors in clinical judgment (as discussed previously), problems with communication, and issues with the clinical environment, were significantly associated with malpractice cases closing with payment. This demonstrates that systematically examining malpractice claims to determine the underlying contributing factors can generate predictive analytics, as well as suggest risk management and patient safety strategies.

Interdisciplinary collaboration, as a component of systems-based practice, is a core principle of hospital medicine,¹³ and so we analyzed the involvement of other clinicians in hospitalist claims. Of the five specialties most frequently named in claims with hospitalists, two were surgical services: general surgery (n = 51; 4.2%) and orthopedic surgery (n = 46; 3.8%). With hospitalists being asked to play an increasing role in the care of surgical patients, they may be providing care to patient populations with whom they have less experience, which could put them at risk of adverse outcomes, leading to malpractice claims.^24,25 Hospitalists need to be attuned to the liability risks related to the care of patients requiring surgical management and ensure areas of responsibility are clearly delineated between the hospital medicine and surgical services.²⁶ We also found that hospitalist claims increasingly involve PAs and NPs, likely reflecting their increasing role in providing care on hospitalist services.^27,28The naming of these other services and provider types does not necessarily mean a breakdown in interdisciplinary collaboration occurred. Rather, these findings highlight the importance of including these surgical services, PAs, and NPs as integral participants in the patient safety and risk management efforts undertaken by hospitalists.

A prior analysis of claims rates for hospitalists that covered injury dates from 1997 to 2011 found that hospitalists had a relatively low claims rate, significantly lower than that for other internal medicine physicians.⁸ In addition to covering an earlier time period, that analysis based its claims rates on data from academic medical centers covered by a single insurer, and physicians at academic medical centers generally have lower claims rates, likely due, at least in part, to their spending a smaller proportion of their time on patient care, compared with nonacademic physicians.²⁹ Another analysis of hospitalist closed claims, which shared some cases with the cohort we analyzed, was performed by The Doctors Company, a commercial liability insurer.⁷ That analysis astutely emphasized the importance of breakdowns in diagnostic processes as a factor underlying hospitalist claims.

Our study has several limitations. First, although our database of malpractice claims includes approximately 31% of all the claims in the country and includes claims from every state, it may not be nationally representative. Another limitation relates to calculating the claims rates for physicians. Detailed information on the number of years of clinical activity, which is necessary to calculate claims rates, was available for only a subset of our data (8.2% of the hospitalist cases and 11.6% of all cases), so claims rates are based on this subset of our data (among which academic centers are overrepresented). Therefore, the claims rates should be interpreted with caution, especially regarding their application to the community hospital setting. The institutions included in the subset of our data used for determining claims rates were stable over time, so the use of a subset of our data for calculating claims rates reduces the generalizability of our claims rates but should not be a source of bias.

Potentially offsetting strengths of our claims database and study include the availability of unpaid claims (which outnumber paid claims roughly 2:1)^11,12; the presence of information on contributing factors and other case characteristics obtained through structured manual review of the cases; and the availability of the specialties of the clinicians involved. These features distinguish the database we used from the NPDB, another national database of malpractice claims, which does not include unpaid claims and which does not include information on contributing factors or physician specialty.

First described in 1996, the hospitalist field is the fastest growing specialty in modern medical history.^18,30 Therefore, an understanding of the malpractice risk of hospitalists is important and can shed light on the patient safety environment in hospitals. Our analysis showed that hospitalist malpractice claims rates remain roughly stable, in contrast to most other specialties, which have seen a fall in malpractice claims rates.¹⁷ In addition, unlike a previous analysis,⁸ we found that claims rates for hospitalists were essentially equal to those of other general internal medicine physicians (not lower, as had been previously reported), and higher than those of the internal medicine subspecialties. Hospitalist claims also have relatively high severity of injury. Potential factors driving these trends include the increasing demand for hospitalists, which results in a higher proportion of less-experienced physicians entering the field, and the expanding clinical scope of hospitalists, which may lead to their managing patients with conditions with which they may be less comfortable. Overall, our analysis suggests that the malpractice environment for hospitalists is becoming less favorable, and therefore, hospitalists should explore opportunities for mitigating liability risk and enhancing patient safety.

The prospect of facing a medical malpractice claim is a source of apprehension for physicians that affects physician behavior, including leading to defensive medicine.^1-3 Overall, annual defensive medicine costs have been estimated at $45.6 billion,⁴ and surveys of hospitalists indicate that 13.0% to 37.5% of hospitalist healthcare costs involve defensive medicine.^5,6 Despite the impact of malpractice concerns on hospitalist practice and the unprecedented growth of the field of hospital medicine, relatively few studies have examined the liability environment surrounding hospitalist practice.^7,8 The specific issue of malpractice claims rates faced by hospitalists has received even less attention in the medical literature.⁸

A better understanding of the contributing factors and other attributes of malpractice claims can help guide patient safety initiatives and inform hospitalists’ level of concern regarding liability. Although most medical errors do not result in a malpractice claim,^9,10 the majority of malpractice claims in which there is an indemnity payment involve medical injury due to clinician error.¹¹ Even malpractice claims that do not result in an indemnity payment represent opportunities to identify patient safety and risk management vulnerabilities.¹²

We used a national malpractice claims database to analyze the characteristics of claims made against hospitalists, including claims rates. In addition to claims rates, we also analyzed the other types of providers named in hospitalist claims given the importance of interdisciplinary collaboration to hospital medicine.^13,14 To provide context for understanding hospitalist liability data, we present data on other specialties. We also describe a model to predict whether hospitalist malpractice claims will close with an indemnity payment.

Data Sources and Elements

This analysis used a repository of malpractice claims maintained by CRICO, the captive malpractice insurer of the Harvard-affiliated medical institutions. This database, the Comparative Benchmarking System, aggregates malpractice claims from multiple other malpractice carriers (both commercial and captive). This database comprises approximately 31% of all malpractice claims in the United States (both paid and unpaid) according to a comparison with claims in the National Practitioner Data Bank (NPDB), which is a government-run database to which all paid malpractice claims against physicians must be reported.¹⁵ To compile this national database, trained nurse coders, who have access to the medical records and legal documents from each case, abstract information into coded fields, such as the type of allegation, contributing factors, and injury severity. The information in these coded fields is based on a taxonomy that was developed specifically for use in malpractice cases. The nurse coders participate in regular meetings in which cases are discussed to ensure that they are applying the coding and taxonomy uniformly.

Injury severity was based on a widely used scale developed for malpractice claims by the National Association of Insurance Commissioners.¹⁶ Low injury severity included emotional injury and temporary insignificant injury. Medium injury severity included temporary minor, temporary major, and permanent minor injury. High injury severity included permanent significant injury through death. Because this study used a database assembled for operational and patient safety purposes and was not human subjects research, institutional review board approval was not needed.

Study Cohort

Malpractice claims included formal lawsuits or written requests for compensation for negligent medical care. Hospitalist malpractice claims were defined as those in which the nurse coders determined that the internal medicine hospitalist service was the clinical service that was primarily responsible for the care of the patient at the time of the clinical event giving rise to the claim. Malpractice claims closed during the period 2009-2018 were included, regardless of whether an indemnity payment was made. Claims against select other medical specialties (nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry), defined by the specialty of the physician named in the claim, were included for comparison with the characteristics of the claims against hospitalists. Physician specialty was available for all physicians in the study cohort; however, given that malpractice cases were aggregated from multiple different insurers, full demographic information (eg, age and sex) was not available for all physicians.

Statistical Analysis

Malpractice claims rates were treated as Poisson rates and compared using a Z-test. Malpractice claims rates are expressed as claims per 100 physician-years. Each physician-year represents 1 year of coverage of one physician by the medical malpractice carrier whose data were used. Physician-years represent the duration of time physicians practiced during which they were insured by the malpractice carrier and, as such, could have been subject to a malpractice claim that would have been included in our data. Claims rates are based on the subset of the malpractice claims in the study for which the number of physician-years of coverage is available, representing 8.2% of hospitalist claims and 11.6% of all claims.

Comparisons of the percentages of cases closing with an indemnity payment, as well as the percentages of cases in different allegation type and clinical severity categories, were made using the Fisher exact test. Indemnity payment amounts were inflation-adjusted to 2018 dollars using the Consumer Price Index. Comparisons of indemnity payment amounts between physician specialties were carried out using the Wilcoxon rank sum test given that the distribution of the payment amounts appeared nonnormal; this was confirmed with the Shapiro-Wilk test. A multivariable logistic regression model was developed to predict the binary outcome of whether a hospitalist case would close with an indemnity payment (compared with no payment), based on the 1,216 hospitalist claims. The predictors used in this regression model were chosen a priori based on hypotheses about what factors drive the likelihood that a case closes with payment. Both the unadjusted and adjusted odds ratios for the predictors are presented. The adjusted model is adjusted for all the other predictors contained in the model. All reported P values are two-sided. The statistical analysis was carried out using JMP Pro version 15 (SAS Institute Inc) and Minitab version 19 (Minitab LLC).

We identified 1,216 hospital medicine malpractice claims from our database. Claims rates were calculated from the subset of our data for which physician-years were available—including 5,140 physician-years encompassing 100 claims, representing 8.2% of all hospitalist claims studied. An additional 18,644 malpractice claims from five other specialties—nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry—were analyzed to provide context for the hospitalist claims.

The malpractice claims rate for hospitalists was significantly higher than the rate for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years; P < .001), though they were not significantly different from the rate for nonhospitalist general internal medicine physicians (1.95 vs 1.92 claims per 100 physician-years; P = .93) (Table 1). Compared with emergency medicine physicians, with whom hospitalists are sometimes compared due to both specialties being defined by their site of practice and the absence of longitudinal patient relationships, hospitalists had a significantly lower claims rate (1.95 vs 4.07 claims per 100 physician-years; P < .001).

An assessment of the temporal trends in the claims rates, based on a comparison between the two halves of the study period (2014-2018 vs 2009-2013), showed that the claims rate for hospitalists was increasing, but at a rate that did not reach statistical significance (Table 1). In contrast, the claims rates for the five other specialties assessed decreased over time, and the decreases were significant for four of these five other specialties (internal medicine subspecialties, emergency medicine, neurosurgery, and psychiatry).

Multiple claims against a single physician were uncommon in our hospitalist malpractice claims data. Among the 100 claims that were used to calculate the claims rates, one physician was named in 2 claims, and all the other physicians were named in only a single claim. Among all of the 1,216 hospitalist malpractice claims we analyzed, there were eight physicians who were named in more than 1 claim, seven of whom were named in 2 claims, and one of whom was named in 3 claims.

The median indemnity payment for hospitalist claims was $231,454 (interquartile range [IQR], $100,000-$503,015), similar to the median indemnity payment for neurosurgery ($233,723; IQR, $85,292-$697,872), though significantly greater than the median indemnity payment for the other four specialties studied (Table 2). Among the hospitalist claims, 29.9% resulted in an indemnity payment, not significantly different from the rate for nonhospitalist general internal medicine, internal medicine subspecialties, or neurosurgery, but significantly lower than the rate for emergency medicine (33.8%; P = .011). No significant temporal trend in the percentage of hospitalist claims that resulted in an indemnity payment was observed.

We performed a multivariable logistic regression analysis to assess the effect of different factors on the likelihood of a hospitalist case closing with an indemnity payment, compared with no payment (Table 3). In the multivariable model, the presence of an error in clinical judgment had an adjusted odds ratio (AOR) of 5.01 (95% CI, 3.37-7.45; P < .001) for a claim closing with payment, the largest effect found. The presence of problems with communication (AOR, 1.89; 95% CI, 1.42-2.51; P < .001), the clinical environment (eg, weekend/holiday or clinical busyness; AOR, 1.70; 95% CI, 1.20-2.40; P = .0026), and documentation (AOR, 1.65; 95% CI, 1.18-2.31; P = .0038) were also positive predictors of claims closing with payment. Greater patient age (per decade) was a negative predictor of the likelihood of a claim closing with payment (AOR, 0.92; 95% CI, 0.86-0.998), though it was of borderline statistical significance (P = .044).

We also assessed multiple clinical attributes of hospitalist malpractice claims, including the major allegation type and injury severity (Appendix Table). Among the 1,216 hospitalist malpractice claims studied, the most common allegation types were for errors related to medical treatment (n = 482; 39.6%), diagnosis (n = 446; 36.7%), and medications (n = 157; 12.9%). Among the hospitalist claims, 888 (73.0%) involved high-severity injury, and 674 (55.4%) involved the death of the patient. The percentages of cases involving high-severity injury and death were significantly greater for hospitalists, compared with that of the other specialties studied (P < .001 for all pairwise comparisons). Of the six specialties studied, hospital medicine was the only one in which the percentage of cases involving death exceeded 50%.

Hospital medicine is typically team-based, and we evaluated which other services were named in claims with hospital medicine as the primary responsible service. The clinician groups most commonly named in hospitalist claims were nursing (n = 269; 22.1%), followed by emergency medicine (n = 91; 7.5%), general surgery (n = 51; 4.2%), cardiology (n = 49; 4.0%), and orthopedic surgery (n = 46; 3.8%) (Appendix Figure). During the first 2 years of the study period, no physician assistants (PAs) or nurse practitioners (NPs) were named in hospitalist claims. Over the study period, the proportion of hospitalist cases also naming PAs and NPs increased steadily, reaching 6.9% and 6.2% of claims, respectively, in 2018 (Figure) (P < .001 for NPs and P = .037 for PAs based on a comparison between the two halves of the study period).

We found that the average annual claims rate for hospitalists was similar to that for nonhospitalist general internists (1.95 vs 1.92 claims per 100 physician-years) but significantly greater than that for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years). Hospitalist claims rates showed a notable temporal trend—a nonsignificant increase—over the study period (2009-2018). This contrasts with the five other specialties studied, all of which had decreasing claims rates, four of which were significant. An analysis of a different national malpractice claims database, the NPDB, found that the rate of paid malpractice claims overall decreased 55.7% during the period 1992-2014, again contrasting with the trend we found for hospitalist claims rates.¹⁷

We posit several explanations for why the malpractice claims rate trend for hospitalists has diverged from that of other specialties. There has been a large expansion in the number of hospitalists in the United States.¹⁸ With this increasing demand, many young physicians have entered the hospital medicine field. In a survey of general internal medicine physicians conducted by the Society of General Internal Medicine, 73% of hospitalists were aged 25 to 44 years, significantly greater than the 45% in this age range among nonhospitalist general internal medicine physicians.¹⁹ Hospitalists in their first year of practice have higher mortality rates than more experienced hospitalists.²⁰ Therefore, the relative inexperience of hospitalists, driven by this high demand, could be putting them at increased risk of medical errors and resulting malpractice claims. The higher mortality rate among hospitalists in their first year of practice could be due to a lack of familiarity with the systems of care, such as managing test results and obtaining appropriate consults.²⁰ This possibility suggests that enhanced training and mentorship could be valuable as a strategy to both improve the quality of care and reduce medicolegal risk. The increasing demand for hospitalists could also be affecting the qualification level of physicians entering the field.

Our analysis also showed that the severity of injury in hospitalist claims was greater than that for the other specialties studied. In addition, the percentage of claims involving death was greater for hospitalists than that for the other specialties. The increased acuity of inpatients, compared with that of outpatients—and the trend, at least for some conditions, of increased inpatient acuity over time^21,22— could account for the high injury severity seen among hospitalist claims. Given the positive correlation between injury severity and the size of indemnity payments made on malpractice claims,¹² the high injury severity seen in hospitalist claims was very likely a driver of the high indemnity payments observed among the hospitalist claims.

The relationship between injury severity and financial outcomes is supported by the results of our multivariable regression model (Table 3). Compared with medium-severity injury claims, both death and high-severity injury cases were significantly more likely to close with an indemnity payment (compared with no payment), with AORs of 1.79 (95% CI, 1.21-2.65) and 2.44 (95% CI, 1.54-3.87), respectively.

The most striking finding in our regression model was the magnitude of the effect of an error in clinical judgement. Cases coded with this contributing factor had five times the AOR of closing with payment (compared with no payment) (AOR, 5.01; 95% CI, 3.37-7.45). A clinical judgment call may be difficult to defend when it is ultimately associated with a bad patient outcome. The importance of clinical judgment in our analysis suggests a risk management strategy: clearly and contemporaneously documenting the rationale behind one’s clinical decision-making. This may help make a claim more defensible in the event of an adverse outcome by demonstrating that the clinician was acting reasonably based on the information available at the time. The importance of specifying a rationale for a clinical decision may be especially important in the era of electronic health records (EHRs). EHRs are not structured as chronologically linear charts, which can make it challenging during a trial to retrospectively show what information was available to the physician at the time the clinical decision was made. The importance of clinical judgment also affirms the importance of effective clinical decision support as a patient safety tool.²³

More broadly, it is notable that several contributing factors, including errors in clinical judgment (as discussed previously), problems with communication, and issues with the clinical environment, were significantly associated with malpractice cases closing with payment. This demonstrates that systematically examining malpractice claims to determine the underlying contributing factors can generate predictive analytics, as well as suggest risk management and patient safety strategies.

Interdisciplinary collaboration, as a component of systems-based practice, is a core principle of hospital medicine,¹³ and so we analyzed the involvement of other clinicians in hospitalist claims. Of the five specialties most frequently named in claims with hospitalists, two were surgical services: general surgery (n = 51; 4.2%) and orthopedic surgery (n = 46; 3.8%). With hospitalists being asked to play an increasing role in the care of surgical patients, they may be providing care to patient populations with whom they have less experience, which could put them at risk of adverse outcomes, leading to malpractice claims.^24,25 Hospitalists need to be attuned to the liability risks related to the care of patients requiring surgical management and ensure areas of responsibility are clearly delineated between the hospital medicine and surgical services.²⁶ We also found that hospitalist claims increasingly involve PAs and NPs, likely reflecting their increasing role in providing care on hospitalist services.^27,28The naming of these other services and provider types does not necessarily mean a breakdown in interdisciplinary collaboration occurred. Rather, these findings highlight the importance of including these surgical services, PAs, and NPs as integral participants in the patient safety and risk management efforts undertaken by hospitalists.

A prior analysis of claims rates for hospitalists that covered injury dates from 1997 to 2011 found that hospitalists had a relatively low claims rate, significantly lower than that for other internal medicine physicians.⁸ In addition to covering an earlier time period, that analysis based its claims rates on data from academic medical centers covered by a single insurer, and physicians at academic medical centers generally have lower claims rates, likely due, at least in part, to their spending a smaller proportion of their time on patient care, compared with nonacademic physicians.²⁹ Another analysis of hospitalist closed claims, which shared some cases with the cohort we analyzed, was performed by The Doctors Company, a commercial liability insurer.⁷ That analysis astutely emphasized the importance of breakdowns in diagnostic processes as a factor underlying hospitalist claims.

Our study has several limitations. First, although our database of malpractice claims includes approximately 31% of all the claims in the country and includes claims from every state, it may not be nationally representative. Another limitation relates to calculating the claims rates for physicians. Detailed information on the number of years of clinical activity, which is necessary to calculate claims rates, was available for only a subset of our data (8.2% of the hospitalist cases and 11.6% of all cases), so claims rates are based on this subset of our data (among which academic centers are overrepresented). Therefore, the claims rates should be interpreted with caution, especially regarding their application to the community hospital setting. The institutions included in the subset of our data used for determining claims rates were stable over time, so the use of a subset of our data for calculating claims rates reduces the generalizability of our claims rates but should not be a source of bias.

Potentially offsetting strengths of our claims database and study include the availability of unpaid claims (which outnumber paid claims roughly 2:1)^11,12; the presence of information on contributing factors and other case characteristics obtained through structured manual review of the cases; and the availability of the specialties of the clinicians involved. These features distinguish the database we used from the NPDB, another national database of malpractice claims, which does not include unpaid claims and which does not include information on contributing factors or physician specialty.

First described in 1996, the hospitalist field is the fastest growing specialty in modern medical history.^18,30 Therefore, an understanding of the malpractice risk of hospitalists is important and can shed light on the patient safety environment in hospitals. Our analysis showed that hospitalist malpractice claims rates remain roughly stable, in contrast to most other specialties, which have seen a fall in malpractice claims rates.¹⁷ In addition, unlike a previous analysis,⁸ we found that claims rates for hospitalists were essentially equal to those of other general internal medicine physicians (not lower, as had been previously reported), and higher than those of the internal medicine subspecialties. Hospitalist claims also have relatively high severity of injury. Potential factors driving these trends include the increasing demand for hospitalists, which results in a higher proportion of less-experienced physicians entering the field, and the expanding clinical scope of hospitalists, which may lead to their managing patients with conditions with which they may be less comfortable. Overall, our analysis suggests that the malpractice environment for hospitalists is becoming less favorable, and therefore, hospitalists should explore opportunities for mitigating liability risk and enhancing patient safety.

The prospect of facing a medical malpractice claim is a source of apprehension for physicians that affects physician behavior, including leading to defensive medicine.^1-3 Overall, annual defensive medicine costs have been estimated at $45.6 billion,⁴ and surveys of hospitalists indicate that 13.0% to 37.5% of hospitalist healthcare costs involve defensive medicine.^5,6 Despite the impact of malpractice concerns on hospitalist practice and the unprecedented growth of the field of hospital medicine, relatively few studies have examined the liability environment surrounding hospitalist practice.^7,8 The specific issue of malpractice claims rates faced by hospitalists has received even less attention in the medical literature.⁸

A better understanding of the contributing factors and other attributes of malpractice claims can help guide patient safety initiatives and inform hospitalists’ level of concern regarding liability. Although most medical errors do not result in a malpractice claim,^9,10 the majority of malpractice claims in which there is an indemnity payment involve medical injury due to clinician error.¹¹ Even malpractice claims that do not result in an indemnity payment represent opportunities to identify patient safety and risk management vulnerabilities.¹²

We used a national malpractice claims database to analyze the characteristics of claims made against hospitalists, including claims rates. In addition to claims rates, we also analyzed the other types of providers named in hospitalist claims given the importance of interdisciplinary collaboration to hospital medicine.^13,14 To provide context for understanding hospitalist liability data, we present data on other specialties. We also describe a model to predict whether hospitalist malpractice claims will close with an indemnity payment.

Data Sources and Elements

This analysis used a repository of malpractice claims maintained by CRICO, the captive malpractice insurer of the Harvard-affiliated medical institutions. This database, the Comparative Benchmarking System, aggregates malpractice claims from multiple other malpractice carriers (both commercial and captive). This database comprises approximately 31% of all malpractice claims in the United States (both paid and unpaid) according to a comparison with claims in the National Practitioner Data Bank (NPDB), which is a government-run database to which all paid malpractice claims against physicians must be reported.¹⁵ To compile this national database, trained nurse coders, who have access to the medical records and legal documents from each case, abstract information into coded fields, such as the type of allegation, contributing factors, and injury severity. The information in these coded fields is based on a taxonomy that was developed specifically for use in malpractice cases. The nurse coders participate in regular meetings in which cases are discussed to ensure that they are applying the coding and taxonomy uniformly.

Injury severity was based on a widely used scale developed for malpractice claims by the National Association of Insurance Commissioners.¹⁶ Low injury severity included emotional injury and temporary insignificant injury. Medium injury severity included temporary minor, temporary major, and permanent minor injury. High injury severity included permanent significant injury through death. Because this study used a database assembled for operational and patient safety purposes and was not human subjects research, institutional review board approval was not needed.

Study Cohort

Malpractice claims included formal lawsuits or written requests for compensation for negligent medical care. Hospitalist malpractice claims were defined as those in which the nurse coders determined that the internal medicine hospitalist service was the clinical service that was primarily responsible for the care of the patient at the time of the clinical event giving rise to the claim. Malpractice claims closed during the period 2009-2018 were included, regardless of whether an indemnity payment was made. Claims against select other medical specialties (nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry), defined by the specialty of the physician named in the claim, were included for comparison with the characteristics of the claims against hospitalists. Physician specialty was available for all physicians in the study cohort; however, given that malpractice cases were aggregated from multiple different insurers, full demographic information (eg, age and sex) was not available for all physicians.

Statistical Analysis

Malpractice claims rates were treated as Poisson rates and compared using a Z-test. Malpractice claims rates are expressed as claims per 100 physician-years. Each physician-year represents 1 year of coverage of one physician by the medical malpractice carrier whose data were used. Physician-years represent the duration of time physicians practiced during which they were insured by the malpractice carrier and, as such, could have been subject to a malpractice claim that would have been included in our data. Claims rates are based on the subset of the malpractice claims in the study for which the number of physician-years of coverage is available, representing 8.2% of hospitalist claims and 11.6% of all claims.

Comparisons of the percentages of cases closing with an indemnity payment, as well as the percentages of cases in different allegation type and clinical severity categories, were made using the Fisher exact test. Indemnity payment amounts were inflation-adjusted to 2018 dollars using the Consumer Price Index. Comparisons of indemnity payment amounts between physician specialties were carried out using the Wilcoxon rank sum test given that the distribution of the payment amounts appeared nonnormal; this was confirmed with the Shapiro-Wilk test. A multivariable logistic regression model was developed to predict the binary outcome of whether a hospitalist case would close with an indemnity payment (compared with no payment), based on the 1,216 hospitalist claims. The predictors used in this regression model were chosen a priori based on hypotheses about what factors drive the likelihood that a case closes with payment. Both the unadjusted and adjusted odds ratios for the predictors are presented. The adjusted model is adjusted for all the other predictors contained in the model. All reported P values are two-sided. The statistical analysis was carried out using JMP Pro version 15 (SAS Institute Inc) and Minitab version 19 (Minitab LLC).

We identified 1,216 hospital medicine malpractice claims from our database. Claims rates were calculated from the subset of our data for which physician-years were available—including 5,140 physician-years encompassing 100 claims, representing 8.2% of all hospitalist claims studied. An additional 18,644 malpractice claims from five other specialties—nonhospitalist general internal medicine, internal medicine subspecialists, emergency medicine, neurosurgery, and psychiatry—were analyzed to provide context for the hospitalist claims.

The malpractice claims rate for hospitalists was significantly higher than the rate for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years; P < .001), though they were not significantly different from the rate for nonhospitalist general internal medicine physicians (1.95 vs 1.92 claims per 100 physician-years; P = .93) (Table 1). Compared with emergency medicine physicians, with whom hospitalists are sometimes compared due to both specialties being defined by their site of practice and the absence of longitudinal patient relationships, hospitalists had a significantly lower claims rate (1.95 vs 4.07 claims per 100 physician-years; P < .001).

An assessment of the temporal trends in the claims rates, based on a comparison between the two halves of the study period (2014-2018 vs 2009-2013), showed that the claims rate for hospitalists was increasing, but at a rate that did not reach statistical significance (Table 1). In contrast, the claims rates for the five other specialties assessed decreased over time, and the decreases were significant for four of these five other specialties (internal medicine subspecialties, emergency medicine, neurosurgery, and psychiatry).

Multiple claims against a single physician were uncommon in our hospitalist malpractice claims data. Among the 100 claims that were used to calculate the claims rates, one physician was named in 2 claims, and all the other physicians were named in only a single claim. Among all of the 1,216 hospitalist malpractice claims we analyzed, there were eight physicians who were named in more than 1 claim, seven of whom were named in 2 claims, and one of whom was named in 3 claims.

The median indemnity payment for hospitalist claims was $231,454 (interquartile range [IQR], $100,000-$503,015), similar to the median indemnity payment for neurosurgery ($233,723; IQR, $85,292-$697,872), though significantly greater than the median indemnity payment for the other four specialties studied (Table 2). Among the hospitalist claims, 29.9% resulted in an indemnity payment, not significantly different from the rate for nonhospitalist general internal medicine, internal medicine subspecialties, or neurosurgery, but significantly lower than the rate for emergency medicine (33.8%; P = .011). No significant temporal trend in the percentage of hospitalist claims that resulted in an indemnity payment was observed.

We performed a multivariable logistic regression analysis to assess the effect of different factors on the likelihood of a hospitalist case closing with an indemnity payment, compared with no payment (Table 3). In the multivariable model, the presence of an error in clinical judgment had an adjusted odds ratio (AOR) of 5.01 (95% CI, 3.37-7.45; P < .001) for a claim closing with payment, the largest effect found. The presence of problems with communication (AOR, 1.89; 95% CI, 1.42-2.51; P < .001), the clinical environment (eg, weekend/holiday or clinical busyness; AOR, 1.70; 95% CI, 1.20-2.40; P = .0026), and documentation (AOR, 1.65; 95% CI, 1.18-2.31; P = .0038) were also positive predictors of claims closing with payment. Greater patient age (per decade) was a negative predictor of the likelihood of a claim closing with payment (AOR, 0.92; 95% CI, 0.86-0.998), though it was of borderline statistical significance (P = .044).

We also assessed multiple clinical attributes of hospitalist malpractice claims, including the major allegation type and injury severity (Appendix Table). Among the 1,216 hospitalist malpractice claims studied, the most common allegation types were for errors related to medical treatment (n = 482; 39.6%), diagnosis (n = 446; 36.7%), and medications (n = 157; 12.9%). Among the hospitalist claims, 888 (73.0%) involved high-severity injury, and 674 (55.4%) involved the death of the patient. The percentages of cases involving high-severity injury and death were significantly greater for hospitalists, compared with that of the other specialties studied (P < .001 for all pairwise comparisons). Of the six specialties studied, hospital medicine was the only one in which the percentage of cases involving death exceeded 50%.

Hospital medicine is typically team-based, and we evaluated which other services were named in claims with hospital medicine as the primary responsible service. The clinician groups most commonly named in hospitalist claims were nursing (n = 269; 22.1%), followed by emergency medicine (n = 91; 7.5%), general surgery (n = 51; 4.2%), cardiology (n = 49; 4.0%), and orthopedic surgery (n = 46; 3.8%) (Appendix Figure). During the first 2 years of the study period, no physician assistants (PAs) or nurse practitioners (NPs) were named in hospitalist claims. Over the study period, the proportion of hospitalist cases also naming PAs and NPs increased steadily, reaching 6.9% and 6.2% of claims, respectively, in 2018 (Figure) (P < .001 for NPs and P = .037 for PAs based on a comparison between the two halves of the study period).

We found that the average annual claims rate for hospitalists was similar to that for nonhospitalist general internists (1.95 vs 1.92 claims per 100 physician-years) but significantly greater than that for internal medicine subspecialists (1.95 vs 1.30 claims per 100 physician-years). Hospitalist claims rates showed a notable temporal trend—a nonsignificant increase—over the study period (2009-2018). This contrasts with the five other specialties studied, all of which had decreasing claims rates, four of which were significant. An analysis of a different national malpractice claims database, the NPDB, found that the rate of paid malpractice claims overall decreased 55.7% during the period 1992-2014, again contrasting with the trend we found for hospitalist claims rates.¹⁷

We posit several explanations for why the malpractice claims rate trend for hospitalists has diverged from that of other specialties. There has been a large expansion in the number of hospitalists in the United States.¹⁸ With this increasing demand, many young physicians have entered the hospital medicine field. In a survey of general internal medicine physicians conducted by the Society of General Internal Medicine, 73% of hospitalists were aged 25 to 44 years, significantly greater than the 45% in this age range among nonhospitalist general internal medicine physicians.¹⁹ Hospitalists in their first year of practice have higher mortality rates than more experienced hospitalists.²⁰ Therefore, the relative inexperience of hospitalists, driven by this high demand, could be putting them at increased risk of medical errors and resulting malpractice claims. The higher mortality rate among hospitalists in their first year of practice could be due to a lack of familiarity with the systems of care, such as managing test results and obtaining appropriate consults.²⁰ This possibility suggests that enhanced training and mentorship could be valuable as a strategy to both improve the quality of care and reduce medicolegal risk. The increasing demand for hospitalists could also be affecting the qualification level of physicians entering the field.

Our analysis also showed that the severity of injury in hospitalist claims was greater than that for the other specialties studied. In addition, the percentage of claims involving death was greater for hospitalists than that for the other specialties. The increased acuity of inpatients, compared with that of outpatients—and the trend, at least for some conditions, of increased inpatient acuity over time^21,22— could account for the high injury severity seen among hospitalist claims. Given the positive correlation between injury severity and the size of indemnity payments made on malpractice claims,¹² the high injury severity seen in hospitalist claims was very likely a driver of the high indemnity payments observed among the hospitalist claims.

The relationship between injury severity and financial outcomes is supported by the results of our multivariable regression model (Table 3). Compared with medium-severity injury claims, both death and high-severity injury cases were significantly more likely to close with an indemnity payment (compared with no payment), with AORs of 1.79 (95% CI, 1.21-2.65) and 2.44 (95% CI, 1.54-3.87), respectively.

The most striking finding in our regression model was the magnitude of the effect of an error in clinical judgement. Cases coded with this contributing factor had five times the AOR of closing with payment (compared with no payment) (AOR, 5.01; 95% CI, 3.37-7.45). A clinical judgment call may be difficult to defend when it is ultimately associated with a bad patient outcome. The importance of clinical judgment in our analysis suggests a risk management strategy: clearly and contemporaneously documenting the rationale behind one’s clinical decision-making. This may help make a claim more defensible in the event of an adverse outcome by demonstrating that the clinician was acting reasonably based on the information available at the time. The importance of specifying a rationale for a clinical decision may be especially important in the era of electronic health records (EHRs). EHRs are not structured as chronologically linear charts, which can make it challenging during a trial to retrospectively show what information was available to the physician at the time the clinical decision was made. The importance of clinical judgment also affirms the importance of effective clinical decision support as a patient safety tool.²³

More broadly, it is notable that several contributing factors, including errors in clinical judgment (as discussed previously), problems with communication, and issues with the clinical environment, were significantly associated with malpractice cases closing with payment. This demonstrates that systematically examining malpractice claims to determine the underlying contributing factors can generate predictive analytics, as well as suggest risk management and patient safety strategies.

Interdisciplinary collaboration, as a component of systems-based practice, is a core principle of hospital medicine,¹³ and so we analyzed the involvement of other clinicians in hospitalist claims. Of the five specialties most frequently named in claims with hospitalists, two were surgical services: general surgery (n = 51; 4.2%) and orthopedic surgery (n = 46; 3.8%). With hospitalists being asked to play an increasing role in the care of surgical patients, they may be providing care to patient populations with whom they have less experience, which could put them at risk of adverse outcomes, leading to malpractice claims.^24,25 Hospitalists need to be attuned to the liability risks related to the care of patients requiring surgical management and ensure areas of responsibility are clearly delineated between the hospital medicine and surgical services.²⁶ We also found that hospitalist claims increasingly involve PAs and NPs, likely reflecting their increasing role in providing care on hospitalist services.^27,28The naming of these other services and provider types does not necessarily mean a breakdown in interdisciplinary collaboration occurred. Rather, these findings highlight the importance of including these surgical services, PAs, and NPs as integral participants in the patient safety and risk management efforts undertaken by hospitalists.

A prior analysis of claims rates for hospitalists that covered injury dates from 1997 to 2011 found that hospitalists had a relatively low claims rate, significantly lower than that for other internal medicine physicians.⁸ In addition to covering an earlier time period, that analysis based its claims rates on data from academic medical centers covered by a single insurer, and physicians at academic medical centers generally have lower claims rates, likely due, at least in part, to their spending a smaller proportion of their time on patient care, compared with nonacademic physicians.²⁹ Another analysis of hospitalist closed claims, which shared some cases with the cohort we analyzed, was performed by The Doctors Company, a commercial liability insurer.⁷ That analysis astutely emphasized the importance of breakdowns in diagnostic processes as a factor underlying hospitalist claims.

Our study has several limitations. First, although our database of malpractice claims includes approximately 31% of all the claims in the country and includes claims from every state, it may not be nationally representative. Another limitation relates to calculating the claims rates for physicians. Detailed information on the number of years of clinical activity, which is necessary to calculate claims rates, was available for only a subset of our data (8.2% of the hospitalist cases and 11.6% of all cases), so claims rates are based on this subset of our data (among which academic centers are overrepresented). Therefore, the claims rates should be interpreted with caution, especially regarding their application to the community hospital setting. The institutions included in the subset of our data used for determining claims rates were stable over time, so the use of a subset of our data for calculating claims rates reduces the generalizability of our claims rates but should not be a source of bias.

Potentially offsetting strengths of our claims database and study include the availability of unpaid claims (which outnumber paid claims roughly 2:1)^11,12; the presence of information on contributing factors and other case characteristics obtained through structured manual review of the cases; and the availability of the specialties of the clinicians involved. These features distinguish the database we used from the NPDB, another national database of malpractice claims, which does not include unpaid claims and which does not include information on contributing factors or physician specialty.

First described in 1996, the hospitalist field is the fastest growing specialty in modern medical history.^18,30 Therefore, an understanding of the malpractice risk of hospitalists is important and can shed light on the patient safety environment in hospitals. Our analysis showed that hospitalist malpractice claims rates remain roughly stable, in contrast to most other specialties, which have seen a fall in malpractice claims rates.¹⁷ In addition, unlike a previous analysis,⁸ we found that claims rates for hospitalists were essentially equal to those of other general internal medicine physicians (not lower, as had been previously reported), and higher than those of the internal medicine subspecialties. Hospitalist claims also have relatively high severity of injury. Potential factors driving these trends include the increasing demand for hospitalists, which results in a higher proportion of less-experienced physicians entering the field, and the expanding clinical scope of hospitalists, which may lead to their managing patients with conditions with which they may be less comfortable. Overall, our analysis suggests that the malpractice environment for hospitalists is becoming less favorable, and therefore, hospitalists should explore opportunities for mitigating liability risk and enhancing patient safety.

As a physician living with bipolar disorder, I am more intimately familiar with the psychiatric ward than I would like to admit. Despite a decade of medication and weekly therapy, I live with a disease which flares, not unlike many of the patients I care for.

–Justin L Bullock, MD, MPH

Mental health conditions are common among physicians. Approximately 28% of residents experience depression or depressive symptoms during their training,¹ and many will not seek mental health care due to fear of medical licensing implications.² These fears are well-founded. Executive directors of 13 of 35 state medical boards indicated that diagnosis of mental illness alone was sufficient for sanctioning physicians.³ Another study found that two-thirds of state licensing applications pose questions about providers’ mental health that violate the American with Disabilities Act.² What happens when a physician discloses and trusts the system to support their mental health–related needs? We address this question through the story of one trainee (JLB) recounting his experience with help-seeking and a fitness-for-duty (FFD) evaluation and conclude with recommendations to improve FFD processes.

Once again, I found myself sitting on a sheetless hospital bed with a baggy hospital gown draping my bony shoulders as I described my aborted suicide attempt to an attending psychiatrist. After a brief pause, the psychiatrist told me that they did not want to cause problems for my medical license and would drop my psychiatric hold. Even though they were the third psychiatrist to say this to me, their words caught me off guard given my recent attempt. I believe these psychiatrists factored my medical career into their clinical care because they understood that the simple act of being psychiatrically hospitalized placed my medical career in peril. After I completed a month-long outpatient treatment program, a psychiatrist and therapist cleared me to return to work.

I feel no shame about living with bipolar disorder and have always been transparent with my institution; the reason behind my absence was no secret. But before I could return to work, my case had to be reviewed by my institution’s Physician Well-being Committee. This committee was presented to me as a group that would help determine how to best support my return to work. However, before I had an opportunity to speak with the committee, I was informed that I would have to undergo a formal FFD evaluation. 

A FFD evaluation is indicated when there are credible reports of physician impairment or professional misconduct. Its purpose is to ensure that physicians can perform their essential job functions and that they are not a risk to patient safety. The Federation of State Medical Boards cautions that illness should not be conflated with impairment.⁴ Indeed, physicians with mental illness can function safely, thrive, and benefit patients and peers, especially when accommodations or modification reduce workplace barriers.^5,6

I can best describe FFD as a 2-month-long stigmatized interrogation. I was forced to provide hair, blood, and urine samples for drug tests, complete an extensive multi-day psychiatric interview—including questions about my childhood trauma—and given a personality test. I was asked to disclose all of my private mental health records and feared I would be penalized if I refused to answer any questions. Multiple people, including my program director, confirmed that there were no performance or professionalism concerns. My suicide attempt happened outside of work; in my eyes, I had a mental illness which had been appropriately treated, not a workplace issue. I voiced my concern that the committee discriminated against me based on my mental illness. The committee told me that their decision to conduct a FFD was warranted because I had a condition that could affect my cognition, despite the lack of evidence that it actually had. My institution’s Office for Prevention of Harassment and Discrimination concurred that this was legal practice.

All of this happened despite my transparency regarding my bipolar disorder. Before I began residency, I disclosed my illness to my institution’s disability office, and I requested and received workplace accommodations. I have appropriately called-out of work whenever I felt that my bipolar could interfere with my focus on patient care. I have been openly bipolar and at the same institution for 6 years. In that time, I have received multiple teaching awards and a graduation award for exemplifying the qualities of a true physician—all while managing bipolar flares, including four hospitalizations. To destigmatize mental illness, I have discussed suicidality and getting help multiple times in front of hundreds of medical students.

The FFD evaluation found no evidence of a substance use disorder, nonadherence to treatment, or danger to my patients. Despite no adverse findings, and a record of well-managed mental illness and ongoing treatment, if I wanted to return to residency, I had to sign an agreement stipulating frequent monitoring by a “case-manager” and worksite “mentor.” I felt stigmatized and penalized for getting help. As I spoke out publicly against this process, I learned that my FFD experience is neither unique nor uncommon. Mental illness is deeply stigmatized within medicine. As a gay Black bipolar man, I hold multiple marginalized identities that inform and shape my experiences, yet the FFD committee did not have a single psychiatrist nor a single Black member. Instead, to make decisions on my case, they relied on the recommendations of the external psychiatrist, who met me for two days. In addition to the therapy and medications I had been taking for years, in order to return to work, I had to agree to a new type of therapy for the remainder of residency. I was incredulous that my employers felt it was appropriate to dictate my specific psychiatric care when I already had my own providers and my own care plan. My voice was not heard in this process, and despite my objections and the institutional mentors who spoke up for me, the FFD committee would not permit me to work without agreeing to their unmodified terms.

Institutions face the challenging task of simultaneously navigating physician illness, patient safety, and institutional liability. In our opinion, many institutions excessively scrutinize physicians with mental illness and initiate FFD evaluations for reasons that are disproportionately skewed toward minimizing institutional liability. Moreover, in the absence of demonstrated physician workplace impairment, institutions should have systems in place to work collaboratively with the physician to ensure that they have access to professional treatment and appropriate workplace accommodations. It is possible to be simultaneously disabled and completely competent; creative and supportive accommodation processes allow physicians with disabilities to thrive, and their patients to benefit from the care of a physician with personal experience navigating disability. If a physician’s mental illness, despite accommodations, begins to impact workplace safety, a FFD evaluation may be initiated; unfortunately, the FFD evaluation itself may become a source of further harm.

FFD evaluations often situate the physician as incapable of managing their own mental illness, suggesting that they must be closely monitored and restricted even when physicians come forward independently.⁷ These beliefs and concurrent policies can propagate harmful, inaccurate biases against physicians who live with mental illness. These biases are compounded by the structural racism endemic in healthcare and academic medicine.⁸ Dehumanization in medicine adds fuel to this fire, projecting the ideal physician persona as an invulnerable, infallible superhuman who can witness intense suffering and work inhumane hours without impact upon the their mental health and well-being. Altogether, these factors increase fear and discourage help-seeking among physicians with mental illness (Appendix Figure), ultimately harming physicians and patients in the process.⁹ Given that the FFD process involves evaluation, treatment, surveillance, and restrictions for individuals with stigmatized health conditions, these processes risk amplifying the impacts of trauma, racism, and oppression unless specifically designed to be antiracist, anti-oppressive, and trauma-informed. 

To encourage physician help-seeking, especially for stigmatized conditions, we must dismantle systems that traumatize physicians with mental illness (Appendix Figure) and build systems that invite and support courageous vulnerability and help-seeking.^5,6 Institutions can provide evaluation and oversight of physicians while also adopting trauma-informed care principles. A trauma-informed approach to FFD would ask: How can we create systems that are informed by a genuine understanding of suffering to promote healing and avoid re-traumatization? Trauma-informed care emphasizes safety, trustworthiness, transparency, cultural humility (an antiracist, anti-oppression framework), collaboration, peer support, and patient empowerment.¹⁰ FFD evaluations differ by institution and by state, with some being performed internally and others utilizing external state physician health programs. We believe our recommendations below apply independent of context (Table).

Institutional Changes

All institutions must publish a detailed description of the FFD process, including its purpose, the definition of impairment or potential impairment, and the steps of the FFD evaluation. The FFD evaluation should be as limited in scope as possible, without invasive inquiry about the physician’s life-long history. Physicians should be invited to include a peer-support person throughout the entire process. The FFD “return to work agreement” should incorporate meaningful input from the physician as the expert in their own experience and, if already in treatment, informed by their healthcare providers. Given the stigmatization of mental health conditions and inherent power differentials in FFD processes, it is paramount that committees be diverse (including but not limited to race/ethnicity, gender, sexual orientation, and mental illness) and comprised of physicians trained in trauma-informed processes who treat the conditions affecting the individual undergoing the FFD evaluation. Finally, trustworthiness requires accountability: We recommend that all FFD systems establish an external oversight body that is equipped to effect change in real time if a physician reports a potential process violation and that collects anonymous feedback from physicians to inform required continuous quality improvement.

State and Federal Changes

It is difficult to effect meaningful change without accurate measurement of physician suicide. Therefore, we recommend mandatory reporting of physician suicide and suspected suicide to publicly available, de-identified state registries. We call for each state medical licensing board to limit licensing questions to current impairment due to mental illness, substance use disorders, or other health condition, as recommended by the Federation of State Medical Boards.⁴ There is a critical need for federal legislation to fund improvements in workplace safety and enhanced access to mental health treatment on demand for physicians.

Especially in these extraordinary times, as physicians are being exposed to such high burdens of stress, suffering, loss, and moral injury, we must de-stigmatize mental illness, encourage help-seeking, and provide physicians struggling with mental illness with timely and compassionate support. By creating systems that are healing and supportive for physicians, we enhance healing for all.

Bipolar is my sun and my storm. As a physician, I am not ashamed of that. For my own health and that of my patients, I must work in a system where it is safe to come forward when I am struggling.

As I fought against what I felt was a toxic and injurious process, I was fortunate to not stand alone. More than 600 residents from 18 departments at my institution signed a petition in support of reforming the FFD process informed by my experience. My institution is in the early stages of responding to this display of strength and unity with a diverse taskforce dedicated to improving the Physician Well-being Committee and FFD process.

As I accompany my patients on their healing journeys, my own experience with recovery allows me to hold the hope of healing for them. My family, friends, mentors, and providers held these rays of hope for me when I was lost in my own darkness. I now know that being cured from disease is just one form of healing. My proximity to death grounds me as some of my patients approach the end of life. Notably, some of my primary care patients have read my story online and come to their appointments to tell me that they are proud to have me as their doctor, “bipolar and all.”

As a physician living with bipolar disorder, I am more intimately familiar with the psychiatric ward than I would like to admit. Despite a decade of medication and weekly therapy, I live with a disease which flares, not unlike many of the patients I care for.

–Justin L Bullock, MD, MPH

Mental health conditions are common among physicians. Approximately 28% of residents experience depression or depressive symptoms during their training,¹ and many will not seek mental health care due to fear of medical licensing implications.² These fears are well-founded. Executive directors of 13 of 35 state medical boards indicated that diagnosis of mental illness alone was sufficient for sanctioning physicians.³ Another study found that two-thirds of state licensing applications pose questions about providers’ mental health that violate the American with Disabilities Act.² What happens when a physician discloses and trusts the system to support their mental health–related needs? We address this question through the story of one trainee (JLB) recounting his experience with help-seeking and a fitness-for-duty (FFD) evaluation and conclude with recommendations to improve FFD processes.

Once again, I found myself sitting on a sheetless hospital bed with a baggy hospital gown draping my bony shoulders as I described my aborted suicide attempt to an attending psychiatrist. After a brief pause, the psychiatrist told me that they did not want to cause problems for my medical license and would drop my psychiatric hold. Even though they were the third psychiatrist to say this to me, their words caught me off guard given my recent attempt. I believe these psychiatrists factored my medical career into their clinical care because they understood that the simple act of being psychiatrically hospitalized placed my medical career in peril. After I completed a month-long outpatient treatment program, a psychiatrist and therapist cleared me to return to work.

I feel no shame about living with bipolar disorder and have always been transparent with my institution; the reason behind my absence was no secret. But before I could return to work, my case had to be reviewed by my institution’s Physician Well-being Committee. This committee was presented to me as a group that would help determine how to best support my return to work. However, before I had an opportunity to speak with the committee, I was informed that I would have to undergo a formal FFD evaluation. 

A FFD evaluation is indicated when there are credible reports of physician impairment or professional misconduct. Its purpose is to ensure that physicians can perform their essential job functions and that they are not a risk to patient safety. The Federation of State Medical Boards cautions that illness should not be conflated with impairment.⁴ Indeed, physicians with mental illness can function safely, thrive, and benefit patients and peers, especially when accommodations or modification reduce workplace barriers.^5,6

I can best describe FFD as a 2-month-long stigmatized interrogation. I was forced to provide hair, blood, and urine samples for drug tests, complete an extensive multi-day psychiatric interview—including questions about my childhood trauma—and given a personality test. I was asked to disclose all of my private mental health records and feared I would be penalized if I refused to answer any questions. Multiple people, including my program director, confirmed that there were no performance or professionalism concerns. My suicide attempt happened outside of work; in my eyes, I had a mental illness which had been appropriately treated, not a workplace issue. I voiced my concern that the committee discriminated against me based on my mental illness. The committee told me that their decision to conduct a FFD was warranted because I had a condition that could affect my cognition, despite the lack of evidence that it actually had. My institution’s Office for Prevention of Harassment and Discrimination concurred that this was legal practice.

All of this happened despite my transparency regarding my bipolar disorder. Before I began residency, I disclosed my illness to my institution’s disability office, and I requested and received workplace accommodations. I have appropriately called-out of work whenever I felt that my bipolar could interfere with my focus on patient care. I have been openly bipolar and at the same institution for 6 years. In that time, I have received multiple teaching awards and a graduation award for exemplifying the qualities of a true physician—all while managing bipolar flares, including four hospitalizations. To destigmatize mental illness, I have discussed suicidality and getting help multiple times in front of hundreds of medical students.

The FFD evaluation found no evidence of a substance use disorder, nonadherence to treatment, or danger to my patients. Despite no adverse findings, and a record of well-managed mental illness and ongoing treatment, if I wanted to return to residency, I had to sign an agreement stipulating frequent monitoring by a “case-manager” and worksite “mentor.” I felt stigmatized and penalized for getting help. As I spoke out publicly against this process, I learned that my FFD experience is neither unique nor uncommon. Mental illness is deeply stigmatized within medicine. As a gay Black bipolar man, I hold multiple marginalized identities that inform and shape my experiences, yet the FFD committee did not have a single psychiatrist nor a single Black member. Instead, to make decisions on my case, they relied on the recommendations of the external psychiatrist, who met me for two days. In addition to the therapy and medications I had been taking for years, in order to return to work, I had to agree to a new type of therapy for the remainder of residency. I was incredulous that my employers felt it was appropriate to dictate my specific psychiatric care when I already had my own providers and my own care plan. My voice was not heard in this process, and despite my objections and the institutional mentors who spoke up for me, the FFD committee would not permit me to work without agreeing to their unmodified terms.

Institutions face the challenging task of simultaneously navigating physician illness, patient safety, and institutional liability. In our opinion, many institutions excessively scrutinize physicians with mental illness and initiate FFD evaluations for reasons that are disproportionately skewed toward minimizing institutional liability. Moreover, in the absence of demonstrated physician workplace impairment, institutions should have systems in place to work collaboratively with the physician to ensure that they have access to professional treatment and appropriate workplace accommodations. It is possible to be simultaneously disabled and completely competent; creative and supportive accommodation processes allow physicians with disabilities to thrive, and their patients to benefit from the care of a physician with personal experience navigating disability. If a physician’s mental illness, despite accommodations, begins to impact workplace safety, a FFD evaluation may be initiated; unfortunately, the FFD evaluation itself may become a source of further harm.

FFD evaluations often situate the physician as incapable of managing their own mental illness, suggesting that they must be closely monitored and restricted even when physicians come forward independently.⁷ These beliefs and concurrent policies can propagate harmful, inaccurate biases against physicians who live with mental illness. These biases are compounded by the structural racism endemic in healthcare and academic medicine.⁸ Dehumanization in medicine adds fuel to this fire, projecting the ideal physician persona as an invulnerable, infallible superhuman who can witness intense suffering and work inhumane hours without impact upon the their mental health and well-being. Altogether, these factors increase fear and discourage help-seeking among physicians with mental illness (Appendix Figure), ultimately harming physicians and patients in the process.⁹ Given that the FFD process involves evaluation, treatment, surveillance, and restrictions for individuals with stigmatized health conditions, these processes risk amplifying the impacts of trauma, racism, and oppression unless specifically designed to be antiracist, anti-oppressive, and trauma-informed. 

To encourage physician help-seeking, especially for stigmatized conditions, we must dismantle systems that traumatize physicians with mental illness (Appendix Figure) and build systems that invite and support courageous vulnerability and help-seeking.^5,6 Institutions can provide evaluation and oversight of physicians while also adopting trauma-informed care principles. A trauma-informed approach to FFD would ask: How can we create systems that are informed by a genuine understanding of suffering to promote healing and avoid re-traumatization? Trauma-informed care emphasizes safety, trustworthiness, transparency, cultural humility (an antiracist, anti-oppression framework), collaboration, peer support, and patient empowerment.¹⁰ FFD evaluations differ by institution and by state, with some being performed internally and others utilizing external state physician health programs. We believe our recommendations below apply independent of context (Table).

Institutional Changes

All institutions must publish a detailed description of the FFD process, including its purpose, the definition of impairment or potential impairment, and the steps of the FFD evaluation. The FFD evaluation should be as limited in scope as possible, without invasive inquiry about the physician’s life-long history. Physicians should be invited to include a peer-support person throughout the entire process. The FFD “return to work agreement” should incorporate meaningful input from the physician as the expert in their own experience and, if already in treatment, informed by their healthcare providers. Given the stigmatization of mental health conditions and inherent power differentials in FFD processes, it is paramount that committees be diverse (including but not limited to race/ethnicity, gender, sexual orientation, and mental illness) and comprised of physicians trained in trauma-informed processes who treat the conditions affecting the individual undergoing the FFD evaluation. Finally, trustworthiness requires accountability: We recommend that all FFD systems establish an external oversight body that is equipped to effect change in real time if a physician reports a potential process violation and that collects anonymous feedback from physicians to inform required continuous quality improvement.

State and Federal Changes

It is difficult to effect meaningful change without accurate measurement of physician suicide. Therefore, we recommend mandatory reporting of physician suicide and suspected suicide to publicly available, de-identified state registries. We call for each state medical licensing board to limit licensing questions to current impairment due to mental illness, substance use disorders, or other health condition, as recommended by the Federation of State Medical Boards.⁴ There is a critical need for federal legislation to fund improvements in workplace safety and enhanced access to mental health treatment on demand for physicians.

Especially in these extraordinary times, as physicians are being exposed to such high burdens of stress, suffering, loss, and moral injury, we must de-stigmatize mental illness, encourage help-seeking, and provide physicians struggling with mental illness with timely and compassionate support. By creating systems that are healing and supportive for physicians, we enhance healing for all.

Bipolar is my sun and my storm. As a physician, I am not ashamed of that. For my own health and that of my patients, I must work in a system where it is safe to come forward when I am struggling.

As I fought against what I felt was a toxic and injurious process, I was fortunate to not stand alone. More than 600 residents from 18 departments at my institution signed a petition in support of reforming the FFD process informed by my experience. My institution is in the early stages of responding to this display of strength and unity with a diverse taskforce dedicated to improving the Physician Well-being Committee and FFD process.

As I accompany my patients on their healing journeys, my own experience with recovery allows me to hold the hope of healing for them. My family, friends, mentors, and providers held these rays of hope for me when I was lost in my own darkness. I now know that being cured from disease is just one form of healing. My proximity to death grounds me as some of my patients approach the end of life. Notably, some of my primary care patients have read my story online and come to their appointments to tell me that they are proud to have me as their doctor, “bipolar and all.”

As a physician living with bipolar disorder, I am more intimately familiar with the psychiatric ward than I would like to admit. Despite a decade of medication and weekly therapy, I live with a disease which flares, not unlike many of the patients I care for.

–Justin L Bullock, MD, MPH

Mental health conditions are common among physicians. Approximately 28% of residents experience depression or depressive symptoms during their training,¹ and many will not seek mental health care due to fear of medical licensing implications.² These fears are well-founded. Executive directors of 13 of 35 state medical boards indicated that diagnosis of mental illness alone was sufficient for sanctioning physicians.³ Another study found that two-thirds of state licensing applications pose questions about providers’ mental health that violate the American with Disabilities Act.² What happens when a physician discloses and trusts the system to support their mental health–related needs? We address this question through the story of one trainee (JLB) recounting his experience with help-seeking and a fitness-for-duty (FFD) evaluation and conclude with recommendations to improve FFD processes.

Once again, I found myself sitting on a sheetless hospital bed with a baggy hospital gown draping my bony shoulders as I described my aborted suicide attempt to an attending psychiatrist. After a brief pause, the psychiatrist told me that they did not want to cause problems for my medical license and would drop my psychiatric hold. Even though they were the third psychiatrist to say this to me, their words caught me off guard given my recent attempt. I believe these psychiatrists factored my medical career into their clinical care because they understood that the simple act of being psychiatrically hospitalized placed my medical career in peril. After I completed a month-long outpatient treatment program, a psychiatrist and therapist cleared me to return to work.

I feel no shame about living with bipolar disorder and have always been transparent with my institution; the reason behind my absence was no secret. But before I could return to work, my case had to be reviewed by my institution’s Physician Well-being Committee. This committee was presented to me as a group that would help determine how to best support my return to work. However, before I had an opportunity to speak with the committee, I was informed that I would have to undergo a formal FFD evaluation. 

A FFD evaluation is indicated when there are credible reports of physician impairment or professional misconduct. Its purpose is to ensure that physicians can perform their essential job functions and that they are not a risk to patient safety. The Federation of State Medical Boards cautions that illness should not be conflated with impairment.⁴ Indeed, physicians with mental illness can function safely, thrive, and benefit patients and peers, especially when accommodations or modification reduce workplace barriers.^5,6

I can best describe FFD as a 2-month-long stigmatized interrogation. I was forced to provide hair, blood, and urine samples for drug tests, complete an extensive multi-day psychiatric interview—including questions about my childhood trauma—and given a personality test. I was asked to disclose all of my private mental health records and feared I would be penalized if I refused to answer any questions. Multiple people, including my program director, confirmed that there were no performance or professionalism concerns. My suicide attempt happened outside of work; in my eyes, I had a mental illness which had been appropriately treated, not a workplace issue. I voiced my concern that the committee discriminated against me based on my mental illness. The committee told me that their decision to conduct a FFD was warranted because I had a condition that could affect my cognition, despite the lack of evidence that it actually had. My institution’s Office for Prevention of Harassment and Discrimination concurred that this was legal practice.

All of this happened despite my transparency regarding my bipolar disorder. Before I began residency, I disclosed my illness to my institution’s disability office, and I requested and received workplace accommodations. I have appropriately called-out of work whenever I felt that my bipolar could interfere with my focus on patient care. I have been openly bipolar and at the same institution for 6 years. In that time, I have received multiple teaching awards and a graduation award for exemplifying the qualities of a true physician—all while managing bipolar flares, including four hospitalizations. To destigmatize mental illness, I have discussed suicidality and getting help multiple times in front of hundreds of medical students.

The FFD evaluation found no evidence of a substance use disorder, nonadherence to treatment, or danger to my patients. Despite no adverse findings, and a record of well-managed mental illness and ongoing treatment, if I wanted to return to residency, I had to sign an agreement stipulating frequent monitoring by a “case-manager” and worksite “mentor.” I felt stigmatized and penalized for getting help. As I spoke out publicly against this process, I learned that my FFD experience is neither unique nor uncommon. Mental illness is deeply stigmatized within medicine. As a gay Black bipolar man, I hold multiple marginalized identities that inform and shape my experiences, yet the FFD committee did not have a single psychiatrist nor a single Black member. Instead, to make decisions on my case, they relied on the recommendations of the external psychiatrist, who met me for two days. In addition to the therapy and medications I had been taking for years, in order to return to work, I had to agree to a new type of therapy for the remainder of residency. I was incredulous that my employers felt it was appropriate to dictate my specific psychiatric care when I already had my own providers and my own care plan. My voice was not heard in this process, and despite my objections and the institutional mentors who spoke up for me, the FFD committee would not permit me to work without agreeing to their unmodified terms.

Institutions face the challenging task of simultaneously navigating physician illness, patient safety, and institutional liability. In our opinion, many institutions excessively scrutinize physicians with mental illness and initiate FFD evaluations for reasons that are disproportionately skewed toward minimizing institutional liability. Moreover, in the absence of demonstrated physician workplace impairment, institutions should have systems in place to work collaboratively with the physician to ensure that they have access to professional treatment and appropriate workplace accommodations. It is possible to be simultaneously disabled and completely competent; creative and supportive accommodation processes allow physicians with disabilities to thrive, and their patients to benefit from the care of a physician with personal experience navigating disability. If a physician’s mental illness, despite accommodations, begins to impact workplace safety, a FFD evaluation may be initiated; unfortunately, the FFD evaluation itself may become a source of further harm.

FFD evaluations often situate the physician as incapable of managing their own mental illness, suggesting that they must be closely monitored and restricted even when physicians come forward independently.⁷ These beliefs and concurrent policies can propagate harmful, inaccurate biases against physicians who live with mental illness. These biases are compounded by the structural racism endemic in healthcare and academic medicine.⁸ Dehumanization in medicine adds fuel to this fire, projecting the ideal physician persona as an invulnerable, infallible superhuman who can witness intense suffering and work inhumane hours without impact upon the their mental health and well-being. Altogether, these factors increase fear and discourage help-seeking among physicians with mental illness (Appendix Figure), ultimately harming physicians and patients in the process.⁹ Given that the FFD process involves evaluation, treatment, surveillance, and restrictions for individuals with stigmatized health conditions, these processes risk amplifying the impacts of trauma, racism, and oppression unless specifically designed to be antiracist, anti-oppressive, and trauma-informed. 

To encourage physician help-seeking, especially for stigmatized conditions, we must dismantle systems that traumatize physicians with mental illness (Appendix Figure) and build systems that invite and support courageous vulnerability and help-seeking.^5,6 Institutions can provide evaluation and oversight of physicians while also adopting trauma-informed care principles. A trauma-informed approach to FFD would ask: How can we create systems that are informed by a genuine understanding of suffering to promote healing and avoid re-traumatization? Trauma-informed care emphasizes safety, trustworthiness, transparency, cultural humility (an antiracist, anti-oppression framework), collaboration, peer support, and patient empowerment.¹⁰ FFD evaluations differ by institution and by state, with some being performed internally and others utilizing external state physician health programs. We believe our recommendations below apply independent of context (Table).

Institutional Changes

All institutions must publish a detailed description of the FFD process, including its purpose, the definition of impairment or potential impairment, and the steps of the FFD evaluation. The FFD evaluation should be as limited in scope as possible, without invasive inquiry about the physician’s life-long history. Physicians should be invited to include a peer-support person throughout the entire process. The FFD “return to work agreement” should incorporate meaningful input from the physician as the expert in their own experience and, if already in treatment, informed by their healthcare providers. Given the stigmatization of mental health conditions and inherent power differentials in FFD processes, it is paramount that committees be diverse (including but not limited to race/ethnicity, gender, sexual orientation, and mental illness) and comprised of physicians trained in trauma-informed processes who treat the conditions affecting the individual undergoing the FFD evaluation. Finally, trustworthiness requires accountability: We recommend that all FFD systems establish an external oversight body that is equipped to effect change in real time if a physician reports a potential process violation and that collects anonymous feedback from physicians to inform required continuous quality improvement.

State and Federal Changes

It is difficult to effect meaningful change without accurate measurement of physician suicide. Therefore, we recommend mandatory reporting of physician suicide and suspected suicide to publicly available, de-identified state registries. We call for each state medical licensing board to limit licensing questions to current impairment due to mental illness, substance use disorders, or other health condition, as recommended by the Federation of State Medical Boards.⁴ There is a critical need for federal legislation to fund improvements in workplace safety and enhanced access to mental health treatment on demand for physicians.

Especially in these extraordinary times, as physicians are being exposed to such high burdens of stress, suffering, loss, and moral injury, we must de-stigmatize mental illness, encourage help-seeking, and provide physicians struggling with mental illness with timely and compassionate support. By creating systems that are healing and supportive for physicians, we enhance healing for all.

Bipolar is my sun and my storm. As a physician, I am not ashamed of that. For my own health and that of my patients, I must work in a system where it is safe to come forward when I am struggling.

As I fought against what I felt was a toxic and injurious process, I was fortunate to not stand alone. More than 600 residents from 18 departments at my institution signed a petition in support of reforming the FFD process informed by my experience. My institution is in the early stages of responding to this display of strength and unity with a diverse taskforce dedicated to improving the Physician Well-being Committee and FFD process.

As I accompany my patients on their healing journeys, my own experience with recovery allows me to hold the hope of healing for them. My family, friends, mentors, and providers held these rays of hope for me when I was lost in my own darkness. I now know that being cured from disease is just one form of healing. My proximity to death grounds me as some of my patients approach the end of life. Notably, some of my primary care patients have read my story online and come to their appointments to tell me that they are proud to have me as their doctor, “bipolar and all.”

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

After decades of off-label use, vinorelbine finally has a randomized clinical trial supporting its efficacy as a second-line treatment of mesothelioma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

However, the development of other treatment regimens, and notably immuno-oncology approaches, are pushing this classic chemotherapy option to later lines of therapy in patients with malignant pleural mesothelioma (MPM), a speaker said at the meeting.

Adding vinorelbine to active symptom control statistically improved progression-free survival (PFS), among patients with MPM who had prior platinum-based therapy, according to results of the randomized Vinorelbine in Mesothelioma (VIM) trial.

Median PFS reached 4.2 months in the vinorelbine arm, versus 2.8 months for active symptom control alone, study results show.

That finding , coupled with safety results, supports the off-label use of vinorelbine as a treatment option for patients with relapsed MPM, according to investigator Dean Anthony Fennell, FRCP, PhD, of the University of Leicester (England).

“Vinorelbine appears to be a safe and effective treatment and could be considered as a treatment option for patients with relapsed mesothelioma,” Prof. Fennell said in his presentation at ASCO (Abstract 8507).
 

Changing status

While that welcome pronouncement was a long time coming, there are now other promising treatment approaches that relegate vinorelbine to a “lower priority” in the treatment algorithm, said discussant Anna K. Nowak, MBBS, FRACP, PhD, of the University of Western Australia, Nedlands.

In October 2020, the U.S. Food and Drug Administration approved the combination of ipilimumab and nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma, on the basis of results from CHECKMATE-743, a randomized, open-label trial.

“Certainly, we know now that first-line ipilimumab and nivolumab is of very substantial benefit to these patients, and we still have clinical trials open in this space as well,” Prof. Nowak said in her discussion at ASCO.

There is “no doubt” that many patients with mesothelioma should at some point receive an IO agent, particularly now with recently reported randomized clinical trial evidence of an overall survival benefit, she added.

“This really pushes vinorelbine out to be a third- or fourth-line treatment,” she added, “and we know that there are usually diminishing returns from using chemotherapies further down the treatment algorithm.”
 

Trial details

The VIM trial described at ASCO by Prof. Fennell was a randomized, controlled phase 2 including 154 patients with MPM that had progressed after first-line chemotherapy.

“Vinorelbine has shown useful clinical activity in single-arm phase two studies, however, the specific efficacy of vinorelbine has not been evaluated in an appropriately controlled randomized trial,” Prof. Fennell said in this presentation.

Patients in the trial were randomized 2:1 to either vinorelbine plus active supportive care or active supportive care alone. Vinorelbine was given initially at 60 mg/m² weekly every 21 days, escalated to 80 mg/m² from cycle 2.

The median age of patients in VIM was approximately 71 years, and about 80% were male.

More partial responses were seen in the vinorelbine arm, at 3.1% of patients, compared with 1.8% for active supportive care, according to Prof. Fennell. Likewise, the rate of stable disease was higher in the vinorelbine arm, at 62.2%, versus 46.4% in the control arm.

The primary outcome of the study, PFS, was significantly improved in the vinorelbine arm, according to Dr. Fennell. The median PFS was 4.2 months in the vinorelbine arm and 2.8 months in the supportive care arm (P = .002), translating into a hazard ratio of 0.60 (95% confidence interval, 0.41-0.86), Prof. Fennell reported.

The most common grade 3-4 adverse event was neutropenia, occurring in 12.5% of the vinorelbine-treated patients and no patients managed with supportive care alone, according to the report. Other grade 3-4 adverse events occurred in fewer than 10% of patients and included dyspnea, lower respiratory infection, lymphopenia, and fatigue, among others.

Overall survival (OS) was not statistically different between vinorelbine and supportive care arms, with median OS of 9.3 months and 9.1 months, respectively.

However, a number of patients in the control arm went on to receive subsequent therapy, including 15 (or about 27%) who went into CONFIRM, a randomized phase 3 trial that, as recently reported, met its coprimary endpoints of improve OS and PFS with nivolumab vs. placebo in relapsed malignant mesothelioma.

Investigators also sought to test the hypothesis that BRCA1-negative patients might be chemoresistant, based in part on preclinical models demonstrating that BRCA1 predicted sensitivity to vinorelbine. However, there was no difference in PFS by BRCA1 expression in the VIM study, according to Prof. Fennell.

Taken together, findings of the VIM trial suggest vinorelbine is a “modestly active” agent with low cost and acceptable toxicity, according to Prof. Nowak.

“It is incumbent on us to have clear discussions with our patients on the risks and benefits of trying this as a subsequent-line therapy, in the context of this evidence that was generated as a second-line therapy,” she said in her discussant remarks on the study.

“I would say that it is a lower priority in our algorithm than cisplatin and pemetrexed, or of course, immuno-oncology agents,” she added.

Dr. Fennell reported disclosures related to AstraZeneca, Astex Therapeutics, Bayer, and multiple other pharmaceutical companies. Dr. Nowak reported disclosures with AstraZeneca, Atara Biotherapeutics, Boehringer Ingelheim, and multiple other pharmaceutical companies.

After decades of off-label use, vinorelbine finally has a randomized clinical trial supporting its efficacy as a second-line treatment of mesothelioma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

However, the development of other treatment regimens, and notably immuno-oncology approaches, are pushing this classic chemotherapy option to later lines of therapy in patients with malignant pleural mesothelioma (MPM), a speaker said at the meeting.

Adding vinorelbine to active symptom control statistically improved progression-free survival (PFS), among patients with MPM who had prior platinum-based therapy, according to results of the randomized Vinorelbine in Mesothelioma (VIM) trial.

Median PFS reached 4.2 months in the vinorelbine arm, versus 2.8 months for active symptom control alone, study results show.

That finding , coupled with safety results, supports the off-label use of vinorelbine as a treatment option for patients with relapsed MPM, according to investigator Dean Anthony Fennell, FRCP, PhD, of the University of Leicester (England).

“Vinorelbine appears to be a safe and effective treatment and could be considered as a treatment option for patients with relapsed mesothelioma,” Prof. Fennell said in his presentation at ASCO (Abstract 8507).
 

Changing status

While that welcome pronouncement was a long time coming, there are now other promising treatment approaches that relegate vinorelbine to a “lower priority” in the treatment algorithm, said discussant Anna K. Nowak, MBBS, FRACP, PhD, of the University of Western Australia, Nedlands.

In October 2020, the U.S. Food and Drug Administration approved the combination of ipilimumab and nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma, on the basis of results from CHECKMATE-743, a randomized, open-label trial.

“Certainly, we know now that first-line ipilimumab and nivolumab is of very substantial benefit to these patients, and we still have clinical trials open in this space as well,” Prof. Nowak said in her discussion at ASCO.

There is “no doubt” that many patients with mesothelioma should at some point receive an IO agent, particularly now with recently reported randomized clinical trial evidence of an overall survival benefit, she added.

“This really pushes vinorelbine out to be a third- or fourth-line treatment,” she added, “and we know that there are usually diminishing returns from using chemotherapies further down the treatment algorithm.”
 

Trial details

The VIM trial described at ASCO by Prof. Fennell was a randomized, controlled phase 2 including 154 patients with MPM that had progressed after first-line chemotherapy.

“Vinorelbine has shown useful clinical activity in single-arm phase two studies, however, the specific efficacy of vinorelbine has not been evaluated in an appropriately controlled randomized trial,” Prof. Fennell said in this presentation.

Patients in the trial were randomized 2:1 to either vinorelbine plus active supportive care or active supportive care alone. Vinorelbine was given initially at 60 mg/m² weekly every 21 days, escalated to 80 mg/m² from cycle 2.

The median age of patients in VIM was approximately 71 years, and about 80% were male.

More partial responses were seen in the vinorelbine arm, at 3.1% of patients, compared with 1.8% for active supportive care, according to Prof. Fennell. Likewise, the rate of stable disease was higher in the vinorelbine arm, at 62.2%, versus 46.4% in the control arm.

The primary outcome of the study, PFS, was significantly improved in the vinorelbine arm, according to Dr. Fennell. The median PFS was 4.2 months in the vinorelbine arm and 2.8 months in the supportive care arm (P = .002), translating into a hazard ratio of 0.60 (95% confidence interval, 0.41-0.86), Prof. Fennell reported.

The most common grade 3-4 adverse event was neutropenia, occurring in 12.5% of the vinorelbine-treated patients and no patients managed with supportive care alone, according to the report. Other grade 3-4 adverse events occurred in fewer than 10% of patients and included dyspnea, lower respiratory infection, lymphopenia, and fatigue, among others.

Overall survival (OS) was not statistically different between vinorelbine and supportive care arms, with median OS of 9.3 months and 9.1 months, respectively.

However, a number of patients in the control arm went on to receive subsequent therapy, including 15 (or about 27%) who went into CONFIRM, a randomized phase 3 trial that, as recently reported, met its coprimary endpoints of improve OS and PFS with nivolumab vs. placebo in relapsed malignant mesothelioma.

Investigators also sought to test the hypothesis that BRCA1-negative patients might be chemoresistant, based in part on preclinical models demonstrating that BRCA1 predicted sensitivity to vinorelbine. However, there was no difference in PFS by BRCA1 expression in the VIM study, according to Prof. Fennell.

Taken together, findings of the VIM trial suggest vinorelbine is a “modestly active” agent with low cost and acceptable toxicity, according to Prof. Nowak.

“It is incumbent on us to have clear discussions with our patients on the risks and benefits of trying this as a subsequent-line therapy, in the context of this evidence that was generated as a second-line therapy,” she said in her discussant remarks on the study.

“I would say that it is a lower priority in our algorithm than cisplatin and pemetrexed, or of course, immuno-oncology agents,” she added.

Dr. Fennell reported disclosures related to AstraZeneca, Astex Therapeutics, Bayer, and multiple other pharmaceutical companies. Dr. Nowak reported disclosures with AstraZeneca, Atara Biotherapeutics, Boehringer Ingelheim, and multiple other pharmaceutical companies.

After decades of off-label use, vinorelbine finally has a randomized clinical trial supporting its efficacy as a second-line treatment of mesothelioma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

However, the development of other treatment regimens, and notably immuno-oncology approaches, are pushing this classic chemotherapy option to later lines of therapy in patients with malignant pleural mesothelioma (MPM), a speaker said at the meeting.

Adding vinorelbine to active symptom control statistically improved progression-free survival (PFS), among patients with MPM who had prior platinum-based therapy, according to results of the randomized Vinorelbine in Mesothelioma (VIM) trial.

Median PFS reached 4.2 months in the vinorelbine arm, versus 2.8 months for active symptom control alone, study results show.

That finding , coupled with safety results, supports the off-label use of vinorelbine as a treatment option for patients with relapsed MPM, according to investigator Dean Anthony Fennell, FRCP, PhD, of the University of Leicester (England).

“Vinorelbine appears to be a safe and effective treatment and could be considered as a treatment option for patients with relapsed mesothelioma,” Prof. Fennell said in his presentation at ASCO (Abstract 8507).
 

Changing status

While that welcome pronouncement was a long time coming, there are now other promising treatment approaches that relegate vinorelbine to a “lower priority” in the treatment algorithm, said discussant Anna K. Nowak, MBBS, FRACP, PhD, of the University of Western Australia, Nedlands.

In October 2020, the U.S. Food and Drug Administration approved the combination of ipilimumab and nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma, on the basis of results from CHECKMATE-743, a randomized, open-label trial.

“Certainly, we know now that first-line ipilimumab and nivolumab is of very substantial benefit to these patients, and we still have clinical trials open in this space as well,” Prof. Nowak said in her discussion at ASCO.

There is “no doubt” that many patients with mesothelioma should at some point receive an IO agent, particularly now with recently reported randomized clinical trial evidence of an overall survival benefit, she added.

“This really pushes vinorelbine out to be a third- or fourth-line treatment,” she added, “and we know that there are usually diminishing returns from using chemotherapies further down the treatment algorithm.”
 

Trial details

The VIM trial described at ASCO by Prof. Fennell was a randomized, controlled phase 2 including 154 patients with MPM that had progressed after first-line chemotherapy.

“Vinorelbine has shown useful clinical activity in single-arm phase two studies, however, the specific efficacy of vinorelbine has not been evaluated in an appropriately controlled randomized trial,” Prof. Fennell said in this presentation.

Patients in the trial were randomized 2:1 to either vinorelbine plus active supportive care or active supportive care alone. Vinorelbine was given initially at 60 mg/m² weekly every 21 days, escalated to 80 mg/m² from cycle 2.

The median age of patients in VIM was approximately 71 years, and about 80% were male.

More partial responses were seen in the vinorelbine arm, at 3.1% of patients, compared with 1.8% for active supportive care, according to Prof. Fennell. Likewise, the rate of stable disease was higher in the vinorelbine arm, at 62.2%, versus 46.4% in the control arm.

The primary outcome of the study, PFS, was significantly improved in the vinorelbine arm, according to Dr. Fennell. The median PFS was 4.2 months in the vinorelbine arm and 2.8 months in the supportive care arm (P = .002), translating into a hazard ratio of 0.60 (95% confidence interval, 0.41-0.86), Prof. Fennell reported.

The most common grade 3-4 adverse event was neutropenia, occurring in 12.5% of the vinorelbine-treated patients and no patients managed with supportive care alone, according to the report. Other grade 3-4 adverse events occurred in fewer than 10% of patients and included dyspnea, lower respiratory infection, lymphopenia, and fatigue, among others.

Overall survival (OS) was not statistically different between vinorelbine and supportive care arms, with median OS of 9.3 months and 9.1 months, respectively.

However, a number of patients in the control arm went on to receive subsequent therapy, including 15 (or about 27%) who went into CONFIRM, a randomized phase 3 trial that, as recently reported, met its coprimary endpoints of improve OS and PFS with nivolumab vs. placebo in relapsed malignant mesothelioma.

Investigators also sought to test the hypothesis that BRCA1-negative patients might be chemoresistant, based in part on preclinical models demonstrating that BRCA1 predicted sensitivity to vinorelbine. However, there was no difference in PFS by BRCA1 expression in the VIM study, according to Prof. Fennell.

Taken together, findings of the VIM trial suggest vinorelbine is a “modestly active” agent with low cost and acceptable toxicity, according to Prof. Nowak.

“It is incumbent on us to have clear discussions with our patients on the risks and benefits of trying this as a subsequent-line therapy, in the context of this evidence that was generated as a second-line therapy,” she said in her discussant remarks on the study.

“I would say that it is a lower priority in our algorithm than cisplatin and pemetrexed, or of course, immuno-oncology agents,” she added.

Dr. Fennell reported disclosures related to AstraZeneca, Astex Therapeutics, Bayer, and multiple other pharmaceutical companies. Dr. Nowak reported disclosures with AstraZeneca, Atara Biotherapeutics, Boehringer Ingelheim, and multiple other pharmaceutical companies.

Primary care practices with zero burnout are more often solo practices owned by physicians and practices not involved in transformation initiatives, such as accountable care organizations (ACOs), according to an analysis published June 7 in Health Affairs.

The findings may have particular significance in an era when more physicians are being employed by hospitals and health systems, says lead author Samuel T. Edwards, MD, an assistant professor of medicine at Oregon Health & Science University, Portland.

“Market forces and various reform efforts have driven practices to consolidate, and we certainly see some signal here that burnout might be a potential negative consequence of that,” said Dr. Edwards, who is also a staff physician in internal medicine at the Veterans Affairs Portland Health Care System.
 

30% of practices reported zero burnout

Dr. Edwards told this news organization that he was surprised that 30% of the practices surveyed for this analysis reported zero burnout – meaning no member of the practice reported burnout – because reports of burnout are so pervasive in medicine.

For comparison, in 13% of practices surveyed, more than 40% of practice members reported burnout.

Burnout was assessed with a five-point measure that correlates with the emotional exhaustion scale of the Maslach Burnout Inventory.

It was also surprising, Dr. Edwards said, that practices with some of the heaviest workloads – solo practitioners juggling large numbers of patients, insurance plans, and regulatory requirements – were much more likely than larger practices to report zero burnout.

In this study, solo practices were 5.3 times as likely as practices with 6 to 10 clinicians to report zero burnout (95% confidence interval, 1.25-22.6).

The researchers found no link between burnout and patient volume or the proportion of patients with Medicaid insurance.

“People assume that working harder is associated with more burnout, and there are lots of studies that say that’s true. But in our study, it appears that people work really hard in some settings and are not burned out,” Dr. Edwards said.

He says in small offices, there may be a stronger sense of agency, a sense that everyone is on the same team, and there may be stronger relationships with patients.

The study included survey data from 715 small- to medium-size primary care practices in the United States that participated in the Agency for Healthcare Research and Quality’s EvidenceNOW quality improvement initiative between September 2015 and June 2017.

Zero-burnout practices shared several traits. They were more likely to have “a strong practice culture – one in which teamwork, communication, psychological safety, mindfulness of others, facilitative leadership, and understanding that people make and can learn from mistakes were among the key attributes,” Dr. Edwards and colleagues write.
 

Burnout higher with ACO participation

Organizations that participated in ACOs and other external primary care transformation projects were more likely to have high burnout rates. Specifically, 29% of these practices reported zero burnout, versus 53% that reported high rates of burnout.

Dr. Edwards said the reasons for that are unclear in this cross-sectional study, but there seemed to be an indication that getting involved in too many demonstration projects might be associated with burnout. He noted that participants in this study were already involved in the EvidenceNOW initiative.

Factors regarding electronic health records (EHRs) were not tied to burnout in this study. Dr. Edwards said they surveyed for both satisfaction with EHRs and EHR features and whether they were linked to zero burnout.

He speculates that this may indicate that by now, practices have adapted to using EHRs, though they continue to be a source of frustration for individual clinicians.

Debora Goetz Goldberg, PhD, MHA, MBA, associate professor at George Mason University, McLean, Virginia, told this news organization that she has found similar results in her research of primary care practices and burnout. She found that health system–owned practices had higher levels of burnout.

“We thought that probably was related to less autonomy and decision-making authority,” she said.

She pointed out that Dr. Edwards and colleagues found that physicians who had more “adaptive reserves” were more likely to have zero burnout. Her research found a similar association.

Such organizations, she explained, have a higher level of organizational development and a culture of innovation. They are more comfortable with change and adapt well.

“They are characterized by teamwork, strong communication, and a culture of learning,” she said.

By contrast, burnout may be higher in health system–owned practices because clinicians may feel they have less control over their work environment and feel a loss of autonomy, according to Dr. Goldberg.

“Moral distress,” which can happen when an individual’s professional values don’t line up with an organization’s values, may also play a part, she said. Physicians may be required to see more patients than they feel they can serve well in a day, for instance.

Reducing burnout may take building a more collaborative leadership style, she said.
 

No link between burnout and patient volume

The current research also highlighted leadership style as a potential driver of burnout.

Dr. Edwards and colleagues found that one of the strongest associations was between facilitative leadership and low burnout. Zero burnout is associated with participatory decision-making.

“Interestingly, we saw that that kind of leadership could exist in multiple settings,” he said. Health care professionals in smaller practices might know each other better and have a shared mission, but shared decision making can also exist in larger practices, he said.

Higher burnout was associated with traditional leadership models that are hierarchical and that operate with a command-and-control structure, according to the study.

The data may have implications for strategies regarding both the smallest and largest practices.

Initiatives that help small practices remain strong are valuable, especially for communities that depend on those practices, Dr. Edwards said.

The researchers give as an example the funding of primary care practice extension networks, which provide support similar to agricultural extension programs for farmers.

At the same time, “having agency at the practice level about how things work is really important in reducing burnout. So in a large system, finding ways to promote agency at the most local level possible can really help with burnout,” he said.

Dr. Edwards said his team controlled for the fact that mathematically, it’s more likely zero burnout would be reported in a solo practice than in a larger practice.

Every practice in this study, he said, had to have at least three persons who responded to the survey, and responses had to represent three roles – a clinician, a nonclinician staff member, and a clinical staff member. The response rate also had to be 50% within the practice, he explained.

All authors are supported by the Agency for Healthcare Research and Quality. Dr. Edwards was also supported by the Department of Veterans Affairs Health Services Research and Development. Dr. Goldberg has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Primary care practices with zero burnout are more often solo practices owned by physicians and practices not involved in transformation initiatives, such as accountable care organizations (ACOs), according to an analysis published June 7 in Health Affairs.

The findings may have particular significance in an era when more physicians are being employed by hospitals and health systems, says lead author Samuel T. Edwards, MD, an assistant professor of medicine at Oregon Health & Science University, Portland.

“Market forces and various reform efforts have driven practices to consolidate, and we certainly see some signal here that burnout might be a potential negative consequence of that,” said Dr. Edwards, who is also a staff physician in internal medicine at the Veterans Affairs Portland Health Care System.
 

30% of practices reported zero burnout

Dr. Edwards told this news organization that he was surprised that 30% of the practices surveyed for this analysis reported zero burnout – meaning no member of the practice reported burnout – because reports of burnout are so pervasive in medicine.

For comparison, in 13% of practices surveyed, more than 40% of practice members reported burnout.

Burnout was assessed with a five-point measure that correlates with the emotional exhaustion scale of the Maslach Burnout Inventory.

It was also surprising, Dr. Edwards said, that practices with some of the heaviest workloads – solo practitioners juggling large numbers of patients, insurance plans, and regulatory requirements – were much more likely than larger practices to report zero burnout.

In this study, solo practices were 5.3 times as likely as practices with 6 to 10 clinicians to report zero burnout (95% confidence interval, 1.25-22.6).

The researchers found no link between burnout and patient volume or the proportion of patients with Medicaid insurance.

“People assume that working harder is associated with more burnout, and there are lots of studies that say that’s true. But in our study, it appears that people work really hard in some settings and are not burned out,” Dr. Edwards said.

He says in small offices, there may be a stronger sense of agency, a sense that everyone is on the same team, and there may be stronger relationships with patients.

The study included survey data from 715 small- to medium-size primary care practices in the United States that participated in the Agency for Healthcare Research and Quality’s EvidenceNOW quality improvement initiative between September 2015 and June 2017.

Zero-burnout practices shared several traits. They were more likely to have “a strong practice culture – one in which teamwork, communication, psychological safety, mindfulness of others, facilitative leadership, and understanding that people make and can learn from mistakes were among the key attributes,” Dr. Edwards and colleagues write.
 

Burnout higher with ACO participation

Organizations that participated in ACOs and other external primary care transformation projects were more likely to have high burnout rates. Specifically, 29% of these practices reported zero burnout, versus 53% that reported high rates of burnout.

Dr. Edwards said the reasons for that are unclear in this cross-sectional study, but there seemed to be an indication that getting involved in too many demonstration projects might be associated with burnout. He noted that participants in this study were already involved in the EvidenceNOW initiative.

Factors regarding electronic health records (EHRs) were not tied to burnout in this study. Dr. Edwards said they surveyed for both satisfaction with EHRs and EHR features and whether they were linked to zero burnout.

He speculates that this may indicate that by now, practices have adapted to using EHRs, though they continue to be a source of frustration for individual clinicians.

Debora Goetz Goldberg, PhD, MHA, MBA, associate professor at George Mason University, McLean, Virginia, told this news organization that she has found similar results in her research of primary care practices and burnout. She found that health system–owned practices had higher levels of burnout.

“We thought that probably was related to less autonomy and decision-making authority,” she said.

She pointed out that Dr. Edwards and colleagues found that physicians who had more “adaptive reserves” were more likely to have zero burnout. Her research found a similar association.

Such organizations, she explained, have a higher level of organizational development and a culture of innovation. They are more comfortable with change and adapt well.

“They are characterized by teamwork, strong communication, and a culture of learning,” she said.

By contrast, burnout may be higher in health system–owned practices because clinicians may feel they have less control over their work environment and feel a loss of autonomy, according to Dr. Goldberg.

“Moral distress,” which can happen when an individual’s professional values don’t line up with an organization’s values, may also play a part, she said. Physicians may be required to see more patients than they feel they can serve well in a day, for instance.

Reducing burnout may take building a more collaborative leadership style, she said.
 

No link between burnout and patient volume

The current research also highlighted leadership style as a potential driver of burnout.

Dr. Edwards and colleagues found that one of the strongest associations was between facilitative leadership and low burnout. Zero burnout is associated with participatory decision-making.

“Interestingly, we saw that that kind of leadership could exist in multiple settings,” he said. Health care professionals in smaller practices might know each other better and have a shared mission, but shared decision making can also exist in larger practices, he said.

Higher burnout was associated with traditional leadership models that are hierarchical and that operate with a command-and-control structure, according to the study.

The data may have implications for strategies regarding both the smallest and largest practices.

Initiatives that help small practices remain strong are valuable, especially for communities that depend on those practices, Dr. Edwards said.

The researchers give as an example the funding of primary care practice extension networks, which provide support similar to agricultural extension programs for farmers.

At the same time, “having agency at the practice level about how things work is really important in reducing burnout. So in a large system, finding ways to promote agency at the most local level possible can really help with burnout,” he said.

Dr. Edwards said his team controlled for the fact that mathematically, it’s more likely zero burnout would be reported in a solo practice than in a larger practice.

Every practice in this study, he said, had to have at least three persons who responded to the survey, and responses had to represent three roles – a clinician, a nonclinician staff member, and a clinical staff member. The response rate also had to be 50% within the practice, he explained.

All authors are supported by the Agency for Healthcare Research and Quality. Dr. Edwards was also supported by the Department of Veterans Affairs Health Services Research and Development. Dr. Goldberg has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Primary care practices with zero burnout are more often solo practices owned by physicians and practices not involved in transformation initiatives, such as accountable care organizations (ACOs), according to an analysis published June 7 in Health Affairs.

The findings may have particular significance in an era when more physicians are being employed by hospitals and health systems, says lead author Samuel T. Edwards, MD, an assistant professor of medicine at Oregon Health & Science University, Portland.

“Market forces and various reform efforts have driven practices to consolidate, and we certainly see some signal here that burnout might be a potential negative consequence of that,” said Dr. Edwards, who is also a staff physician in internal medicine at the Veterans Affairs Portland Health Care System.
 

30% of practices reported zero burnout

Dr. Edwards told this news organization that he was surprised that 30% of the practices surveyed for this analysis reported zero burnout – meaning no member of the practice reported burnout – because reports of burnout are so pervasive in medicine.

For comparison, in 13% of practices surveyed, more than 40% of practice members reported burnout.

Burnout was assessed with a five-point measure that correlates with the emotional exhaustion scale of the Maslach Burnout Inventory.

It was also surprising, Dr. Edwards said, that practices with some of the heaviest workloads – solo practitioners juggling large numbers of patients, insurance plans, and regulatory requirements – were much more likely than larger practices to report zero burnout.

In this study, solo practices were 5.3 times as likely as practices with 6 to 10 clinicians to report zero burnout (95% confidence interval, 1.25-22.6).

The researchers found no link between burnout and patient volume or the proportion of patients with Medicaid insurance.

“People assume that working harder is associated with more burnout, and there are lots of studies that say that’s true. But in our study, it appears that people work really hard in some settings and are not burned out,” Dr. Edwards said.

He says in small offices, there may be a stronger sense of agency, a sense that everyone is on the same team, and there may be stronger relationships with patients.

The study included survey data from 715 small- to medium-size primary care practices in the United States that participated in the Agency for Healthcare Research and Quality’s EvidenceNOW quality improvement initiative between September 2015 and June 2017.

Zero-burnout practices shared several traits. They were more likely to have “a strong practice culture – one in which teamwork, communication, psychological safety, mindfulness of others, facilitative leadership, and understanding that people make and can learn from mistakes were among the key attributes,” Dr. Edwards and colleagues write.
 

Burnout higher with ACO participation

Organizations that participated in ACOs and other external primary care transformation projects were more likely to have high burnout rates. Specifically, 29% of these practices reported zero burnout, versus 53% that reported high rates of burnout.

Dr. Edwards said the reasons for that are unclear in this cross-sectional study, but there seemed to be an indication that getting involved in too many demonstration projects might be associated with burnout. He noted that participants in this study were already involved in the EvidenceNOW initiative.

Factors regarding electronic health records (EHRs) were not tied to burnout in this study. Dr. Edwards said they surveyed for both satisfaction with EHRs and EHR features and whether they were linked to zero burnout.

He speculates that this may indicate that by now, practices have adapted to using EHRs, though they continue to be a source of frustration for individual clinicians.

Debora Goetz Goldberg, PhD, MHA, MBA, associate professor at George Mason University, McLean, Virginia, told this news organization that she has found similar results in her research of primary care practices and burnout. She found that health system–owned practices had higher levels of burnout.

“We thought that probably was related to less autonomy and decision-making authority,” she said.

She pointed out that Dr. Edwards and colleagues found that physicians who had more “adaptive reserves” were more likely to have zero burnout. Her research found a similar association.

Such organizations, she explained, have a higher level of organizational development and a culture of innovation. They are more comfortable with change and adapt well.

“They are characterized by teamwork, strong communication, and a culture of learning,” she said.

By contrast, burnout may be higher in health system–owned practices because clinicians may feel they have less control over their work environment and feel a loss of autonomy, according to Dr. Goldberg.

“Moral distress,” which can happen when an individual’s professional values don’t line up with an organization’s values, may also play a part, she said. Physicians may be required to see more patients than they feel they can serve well in a day, for instance.

Reducing burnout may take building a more collaborative leadership style, she said.
 

No link between burnout and patient volume

The current research also highlighted leadership style as a potential driver of burnout.

Dr. Edwards and colleagues found that one of the strongest associations was between facilitative leadership and low burnout. Zero burnout is associated with participatory decision-making.

“Interestingly, we saw that that kind of leadership could exist in multiple settings,” he said. Health care professionals in smaller practices might know each other better and have a shared mission, but shared decision making can also exist in larger practices, he said.

Higher burnout was associated with traditional leadership models that are hierarchical and that operate with a command-and-control structure, according to the study.

The data may have implications for strategies regarding both the smallest and largest practices.

Initiatives that help small practices remain strong are valuable, especially for communities that depend on those practices, Dr. Edwards said.

The researchers give as an example the funding of primary care practice extension networks, which provide support similar to agricultural extension programs for farmers.

At the same time, “having agency at the practice level about how things work is really important in reducing burnout. So in a large system, finding ways to promote agency at the most local level possible can really help with burnout,” he said.

Dr. Edwards said his team controlled for the fact that mathematically, it’s more likely zero burnout would be reported in a solo practice than in a larger practice.

Every practice in this study, he said, had to have at least three persons who responded to the survey, and responses had to represent three roles – a clinician, a nonclinician staff member, and a clinical staff member. The response rate also had to be 50% within the practice, he explained.

All authors are supported by the Agency for Healthcare Research and Quality. Dr. Edwards was also supported by the Department of Veterans Affairs Health Services Research and Development. Dr. Goldberg has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Due to the condition’s persistence and the negative KOH prep, erythrasma was the most likely diagnosis.

Erythrasma is caused by a bacterial infection with Corynebacterium minutissimum. It occurs in intertriginous areas that tend to be moist and irritated by friction. The erythema is usually a dull red, rather than the bright red that one would see with yeast infections. In addition, there is typically central pallor.

Woods lamp examination can confirm the diagnosis by showing coral pink fluorescence. In this patient, however, there was no fluorescence because the patient had recently washed the area and, thus, removed the porphyrins produced by C minutissimum. Biopsy for pathology is not usually necessary.

Erythrasma is treated with topical clindamycin, fusidic acid, or mupirocin. Oral macrolides and tetracyclines are also effective.¹ Due to the chronicity of the erythrasma and the discomfort it caused, this patient opted for oral doxycycline 100 mg twice daily for 10 days. At follow-up 2 weeks later, the erythrasma had resolved.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Due to the condition’s persistence and the negative KOH prep, erythrasma was the most likely diagnosis.

Erythrasma is caused by a bacterial infection with Corynebacterium minutissimum. It occurs in intertriginous areas that tend to be moist and irritated by friction. The erythema is usually a dull red, rather than the bright red that one would see with yeast infections. In addition, there is typically central pallor.

Woods lamp examination can confirm the diagnosis by showing coral pink fluorescence. In this patient, however, there was no fluorescence because the patient had recently washed the area and, thus, removed the porphyrins produced by C minutissimum. Biopsy for pathology is not usually necessary.

Erythrasma is treated with topical clindamycin, fusidic acid, or mupirocin. Oral macrolides and tetracyclines are also effective.¹ Due to the chronicity of the erythrasma and the discomfort it caused, this patient opted for oral doxycycline 100 mg twice daily for 10 days. At follow-up 2 weeks later, the erythrasma had resolved.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Due to the condition’s persistence and the negative KOH prep, erythrasma was the most likely diagnosis.

Erythrasma is caused by a bacterial infection with Corynebacterium minutissimum. It occurs in intertriginous areas that tend to be moist and irritated by friction. The erythema is usually a dull red, rather than the bright red that one would see with yeast infections. In addition, there is typically central pallor.

Woods lamp examination can confirm the diagnosis by showing coral pink fluorescence. In this patient, however, there was no fluorescence because the patient had recently washed the area and, thus, removed the porphyrins produced by C minutissimum. Biopsy for pathology is not usually necessary.

Erythrasma is treated with topical clindamycin, fusidic acid, or mupirocin. Oral macrolides and tetracyclines are also effective.¹ Due to the chronicity of the erythrasma and the discomfort it caused, this patient opted for oral doxycycline 100 mg twice daily for 10 days. At follow-up 2 weeks later, the erythrasma had resolved.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.

The triad of sepsis studies

In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.

PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).

PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).

ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).

In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.

Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.

Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).

In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
 

The FRESH trial

The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).

FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.

Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).

Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.

Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.
 

Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.

The triad of sepsis studies

In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.

PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).

PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).

ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).

In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.

Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.

Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).

In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
 

The FRESH trial

The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).

FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.

Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).

Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.

Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.
 

Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.

The triad of sepsis studies

In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.

PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).

PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).

ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).

In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.

Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.

Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).

In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
 

The FRESH trial

The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).

FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.

Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).

Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.

Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.